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Journal of Cellular Biochemistry 91:459–477 (2004) Pathological and Molecular Mechanisms of ProstateCarcinogenesis: Implications for Diagnosis, Detection,Prevention, and Treatment Angelo M. De Marzo,* Theodore L. DeWeese, Elizabeth A. Platz, Alan K. Meeker, Masashi Nakayama,Jonathan I. Epstein, William B. Isaacs, and William G. Nelson Departments of Oncology, Pathology, Radiation Oncology, Urology,The Johns Hopkins University School of Medicine, and the Department of Epidemiology,Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemalet al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA(>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakret al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scaleclinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate theprevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such asdiet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of themolecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise andprogress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostatecancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], researchregarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention.
Here, we review the subject of inflammation and prostate cancer as part of a ‘‘chronic epithelial injury’’ hypothesis ofprostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We alsopresent the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment. J. Cell.
Biochem. 91: 459–477, 2004. ß 2003 Wiley-Liss, Inc.
Key words: prostate cancer; prostateatrophy; prostatitis; benign prostatic hyperplasia; inflammation cancers, including those affecting the liver, esophagus, stomach, large intestine, and uri-nary bladder [Coussens and Werb, 2002]. In- flammation might influence the pathogenesis of sponsible for the development of many human cancers by (i) inflicting cell and genome damage,(ii) triggering restorative cell proliferation toreplace damaged cells, (iii) elaborating a portfo-lio of cytokines that promote cell replication,angiogenesis and tissue repair [Coussens and Grant sponsor: Public Health Services NIH/NCI; Grant numbers: R01CA084997, R01CA70196; Grant sponsor:NIH/NCI Specialized Program in Research Excellence Oxidative damage to DNA and other cellular (SPORE) in Prostate Cancer (Johns Hopkins); Grant components accompanying chronic or recurrent inflammation may connect prostate inflamma- *Correspondence to: Angelo M. De Marzo, Room 153, tion with prostate cancer. In response to in- Bunting-Blaustein Cancer Research Building, Sidney fections, inflammatory cells produce a variety of Kimmel Comprehensive Cancer Center at Johns Hopkins, toxic compounds designed to eradicate micro- 1650 Orleans Street, Baltimore, MD 21231-1000.
E-mail: [email protected] organisms. These include superoxide, hydrogen Received 16 September 2003; Accepted 17 September 2003 peroxide, singlet oxygen, as well as nitric oxide that can react further to form the highly reactive peroxynitrite. Some of these reactive based studies is difficult to ascertain [Giovan- oxygen and nitrogen species can directly inter- nucci, 2001], (iii) the clinical diagnosis of chronic act with DNA in the host bystander cells, or prostatitis itself can be challenging and is often react with other cellular components such as subjective [Roberts et al., 1998]. Although large- lipid, initiating a free radical chain reaction. If scale prospective epidemiological studies are the damage is severe, these compounds can lacking [Giovannucci, 2001], a recent review of kill host bystander cells as well as pathogens, the available epidemiological literature by Dennis et al. [2002] indicates that there may among host cell survivors [Xia and Zweier, be a small increase in the relative risk of the 1997; Eiserich et al., 1998]. As a consequence development of prostate cancer in men with a of an acquired defect in defenses against oxi- history of clinical prostatitis. Given the high dant and electrophilic carcinogens associated prevalence of prostate cancer, however, even a with GSTP1 CpG island hypermethylation (see small increase in relative risk can result in a below), prostate cells may acquire a heightened susceptibility to oxidative genome damage in In terms of the prevalence of clinical prostati- an inflammatory milieu, leading to neoplastic tis, a survey of clinical data in Olmstead county transformation and cancer progression. Other Minnesota reported that symptomatic prostati- support for the concept that prostate cancer can tis occurred in approximately 9% of men between result from excess oxidants and electrophiles 40 and 79 years of age, with half of these men comes from epidemiological studies suggesting suffering more than one episode, and it was that decreased prostate cancer risk is associated estimated that 1 in 11 men will be diagnosed with intake of various anti-oxidants and non- with some form of prostatitis by age 79 years steroidal anti-inflammatory drugs [Clark et al., [Roberts et al., 1998]. In terms of histological 1996, 1998; Heinonen et al., 1998; Norrish et al., prostatitis, inflammatory infiltrates of varying 1998; Gann et al., 1999; Nelson and Harris, intensity and character are readily apparent in 2000; Roberts et al., 2002]. In further support most radical prostatectomy [Gerstenbluth et al., of a critical role for oxidative genome damage 2002] and transurethral resection specimens during the pathogenesis of prostate cancer, [Nickel et al., 1999], and prostate needle biopsies variant polymorphic alleles at OGG1, the gene repairs the oxidized base 8-oxo-G in DNA, are system of prostatitis divides the cases into four associated with increased prostate cancer risk categories–3 that are associated with genitour- inary symptoms and 1 that is not [Krieger et al.,1999]. Category I, or acute bacterial prostatitis,is usually caused by Escherichia coli or other gram-negative bacteria or enterococcus. Acute bacterial prostatitis is infrequent and consists At least three major disease processes are ex- of an acutely swollen and tender prostate with tremely common in the prostate—prostatitis, acute inflammatory cells in expressed prostate benign prostatic hyperplasia (BPH), and ade- fluid. There is usually an associated urinary nocarcinoma. Why do three apparently distinct tract infection, and, at times systemic symp- types of lesions occur so commonly in the same toms of infection. Acute prostatitis is usually organ, and might these common processes be self-limited after treatment with antibiotics.
linked? Despite the fact that prostate inflam- Category II, or chronic bacterial prostatitis, is mation (histological prostatitis) and prostate quite rare, and consists of repeated bouts of cancer are often found in the same patient, lower urinary tract infection where the source associations between inflammation and pros- of infection can be localized to the prostate.
tate cancer have not been clearly shown. This This form is also usually treated with antibio- may be due in part to the following difficulties tics, often with multiple courses over time.
in performing association studies of prostate Category III is the most common form, account- cancer and prostatitis: (i) most prostate inflam- ing for approximately 90% of clinical pros- mation does not seem to cause symptoms [True tatitis syndromes, and is referred to as chronic et al., 1999], (ii) the incidence of asymptomatic prostatitis/chronic pelvic pain syndrome. The histologic prostatitis in non-selected population cardinal feature of this entity is pain, either in Pathological and Molecular Mechanisms of Prostate Carcinogenesis the perineum, external genitalia, or other sites BPH and prostate cancer has been reviewed in the pelvis. There is also frequently pain recently, where it was concluded that none of during or after ejaculation. The symptoms the epidemiologic studies published to date must be of at least 3 months in duration to be have provided clear evidence suggesting an considered chronic. This form is subdivided into etiologic role for BPH in the development of those cases where leukocytes are identifiable prostate cancer [Guess, 2001]. However, the on expressed prostatic fluids, post-prostate author also indicated that most of the studies massage urine, or semen (category IIIA— had at least some major bias and that it might inflammatory) and those that do not contain be perhaps more important to examine the biol- leukocytes in these fluids (category IIIB— ogy and pathology of any potential connection chronic prostatitis/chronic pelvic pain syn- drome). Category IV, or asymptomatic inflam- In terms of pathobiology, Bostwick et al.
matory prostatitis, represents the presence of prostate inflammation in histological tissue prostate cancer tend to occur in the same pa- sections from men with no history of urinary tient, share similar hormonal requirements for growth, and can occur in proximity. Pathologi- In addition to the putative increased risk of cally, it appears that transition zone cancers do prostate cancer with a history of symptomatic indeed appear to arise in the setting of nodules prostatitis, an increased prostate cancer risk of BPH [Bostwick et al., 1992; Leav et al., 2003, has been associated in some studies [e.g., Hayes and references therein], and occasionally from et al., 2000] with sexually transmitted infec- adenosis [Bostwick and Qian, 1995; Grignon tions [reviewed in Strickler and Goedert, 2001; and Sakr, 1996], which is also referred to as Dennis and Dawson, 2002], independent of the atypical adenomatous hyperplasia. While these specific pathogen, supporting the concept that transition zone tumors are often of somewhat inflammation itself might facilitate prostatic lower Gleason score, they are quite common in carcinogenesis, or, that the associative causa- tive organism(s) has not been identified. Of [Leav et al., 2003]. Often in radical prostatec- significance in this regard, two of the candidate tomies transition zone cancers are found inci- hereditary prostate cancer susceptibility genes dentally after the diagnosis of prostate cancer in identified thus far, RNASEL and MSR1, encode the peripheral zone, which is much more widely proteins that function in the host responses to a sampled at needle biopsy. Whether there are an variety of infectious agents [Zhou et al., 1997; equal number of transition zone cancers in men Platt and Gordon, 2001; Carpten et al., 2002; Xu without significant nodular hyperplasia is cur- rently not clear. Thus, although there is nostrong evidence linking the two, the relation Relation of Prostate Cancer, Benign Prostatic between BPH and prostate cancer remains an open issue. In addition, it is possible that BPH The fact that most prostate cancer and most and prostate cancer are both caused by similar inflammatory infiltrates are both present in the exposures, such that they commonly occur to- peripheral zone [McNeal, 1997] is consistent gether but are not directly linked in a precursor- with a link between inflammation and prostate cancer. What about the transition zone, the site What is the relation between transition zone of development of BPH? Is there a link between cancer and inflammation? While the relation cancer is unknown, it is known that BPH tissue Approximately 25% of prostate adenocarci- contains a variable amount of chronic and often nomas appear to arise in the transition zone.
acute inflammation in virtually 100% of speci- Thus, while the peripheral zone is the site of mens [Nickel et al., 1999]. It has been reported origin of prostate cancer in the majority of the cases, when compared to other organs that seem correlates with the amount of tissue injury ass- to be protected from cancer development (such ociated with inflammation [Hasui et al., 1994; as the seminal vesicles), prostate transition Irani et al., 1997; Schatteman et al., 2000; zone cancer is actually quite common. In terms Yaman et al., 2003], and some have submitted of epidemiological data, the relation between that the pathogenesis [Gleason et al., 1993], and/or clinical features [Nickel, 1994] of BPH contain at least some increase in chronic and/or may be related to prostate inflammation.
acute inflammation. Also, since the amount of Still unclear, however, is whether inflam- inflammation from field to field within a given mation comes prior to BPH nodule formation atrophy lesion can be highly variable we have or whether it is a response to the altered tissue recently suggested that to refer to a lesion as architecture resulting from the nodules. While PIA does not require easily recognizable inflam- no firm conclusions can be drawn presently, mation—thus, most forms of focal glandular the pathological literature is consistent with a atrophy can be considered PIA [Van Leenders model whereby inflammation, due to infection et al., 2003]. A working group to formalize or otherwise, is related to the development or terminology of the various atrophic lesions in progression of BPH, and in some circumstances the prostate is currently being formed, and a BPH is related to prostate cancer. Although, preliminary meeting with a group of patholo- more study of this issue is required, it is gists and other investigators was held at the plausible that inflammation may be related to In support of PIA as a prostate cancer pre- cursor, prostate inflammation, accompanied by focal epithelial atrophy, has been proposed to Pathologists have long recognized focal areas contribute to prostate cancer development in of epithelial atrophy in the prostate [Rich, 1934; rats [Reznik et al., 1981; Wilson et al., 1990].
Moore, 1936; Franks, 1954]. These focal areas Further support comes from the fact that PIA of epithelial atrophy, distinct from the diffuse shares several molecular alterations found in atrophy seen after androgen deprivation, usual- both PIN and carcinoma. For example, chromo- ly appear in the periphery of the prostate, where some 8 gain, detected by fluorescence in situ prostate cancers typically arise [Rich, 1934; hybridization (FISH) with a chromosome 8 cen- McNeal, 1988]. Many of these areas of epithelial tromere probe, was found in human PIA, PIN, atrophy are associated with acute or chronic and prostate cancer [Macoska et al., 2000; inflammation [Franks, 1954; McNeal, 1997; Shah et al., 2001]. Others have recently docu- Ruska et al., 1998; De Marzo et al., 1999], mented rare p53 mutations in one variant of contain proliferative epithelial cells [Liavag, PIA, referred to as post-atrophic hyperplasia 1968; Feneley et al., 1996; Ruska et al., 1998; De [Tsujimoto et al., 2002] and, our group has Marzo et al., 1999; Shah et al., 2001], and may recently shown that approximately 6% of PIA show morphological transitions in continuity lesions show evidence of somatic methylation with high grade prostatic intraepithelial neo- of the GSPT1 gene promoter [Nakayama et al., plasia (PIN) lesions [De Marzo et al., 1999; 2003a] (see description of GSTP1 promoter Putzi and De Marzo, 2000], putative prostate methylation below). While the cause of focal cancer precursors [McNeal and Bostwick, 1986; atrophy lesions is not known, they may arise either as a consequence of epithelial damage, lesions may show evidence of direct transitions e.g., from infection, ischemia [Billis, 1998], or to minute carcinoma lesions, with little or no toxin exposure (including dietary oxidants/ recognizable PIN component [Franks, 1954; electrophiles or endogenous chemicals such as Liavag, 1968; Montironi et al., 2002; Nakayama estrogens, etc.), followed by epithelial regenera- et al., 2003]. Focal atrophy of the prostate exists tion and associated secondary inflammation, or as a spectrum of morphologies and areas con- as a direct consequence of inflammatory oxidant taining it in the prostate can be quite extensive.
damage to the epithelium [De Marzo et al., Most of these morphological patterns fit into the 1999]. The process of aging itself has been categories of simple atrophy, or post-atrophic suggested to contribute to some morphological hyperplasia, as described by Ruska et al. [1998].
variants of prostate atrophy [McNeal, 1984].
Regardless of the etiology of PIA, the epithelial inflammation and the unexpectedly high pro- cells in these lesions exhibit many molecular liferation index, we have put forth the term signs of stress, expressing high levels of GSTP1, proliferative inflammatory atrophy (PIA) to en- compass these lesions [De Marzo et al., 1999]. In Marzo et al., 1999; Putzi and De Marzo, 2000; terms of the requirement for inflammatory cells Parsons et al., 2001b; Zha et al., 2001]. There in PIA, the majority of all focal atrophy lesions is also mounting evidence that many of the Pathological and Molecular Mechanisms of Prostate Carcinogenesis atrophic luminal cells in PIA represent a form of 2001; Chung et al., 2001; Gao and Isaacs, 2002; intermediate epithelial cell [Van Leenders et al., Meng and Dahiya, 2002]. In addition, genetic 2003]—cells with features intermediate be- alterations appear to accumulate with prostate tween basal and luminal secretory cells. Inter- cancer progression. Small prostate cancers are mediate epithelial cells have been postulated to present in nearly 30% of men between 30– be the targets of neoplastic transformation in 40 years of age in the U.S., though most men are the prostate [Verhagen et al., 1992; De Marzo diagnosed with prostate cancer at 50–70 years of et al., 1998a,b; van Leenders et al., 2000].
age [Sakr et al., 1994]. The progression of these It should be noted that not all authors have small prostate cancers to larger life-threatening found associations between prostate atrophy and cancers, and the accumulation of somatic ge- prostate cancer [McNeal, 1969; Billis, 1998; nome abnormalities, appears sensitive to envir- Anton et al., 1999; Billis and Magna, 2003], and onmental factors and lifestyle. Prostate cancer that in our own studies not all high grade PIN or incidence and mortality are very high in the U.S.
small carcinoma lesions are associated with cancer risks and death rates are characteristic studies of the connection between atrophy and of Asia [Miller, 1999; Hsing et al., 2000]. In cancer have focused on peripheral zone cancer support of an effect of environment and lifestyle nearly exclusively. Thus, additional studies are on prostate cancer development, Asian immi- required to more fully understand the relation grants to North America tend to acquire higher between focal atrophy and cancer in the prostate.
prostate cancer risks within one generation Our current concept is that PIA is a common [Haenszel and Kurihara, 1968; Shimizu et al., proliferative response to environmental stimuli 1991; Whittemore et al., 1995]. Whether the in aging men and that some high grade PIN and appearance of somatic genome alterations in carcinoma lesions arise as a consequence of prostate cancer cells is the result of chronic or genome damage in PIA, while others do not. A recurrent exposure to genome-damaging stres- corollary to this is that while only a subset of atrophy lesions may be pre-neoplastic, the fact damage, or a combination of both processes, that atrophic areas can be so widespread and multi-focal in the prostate is consistent with the hypothesis that many prostate cancers canindeed arise from PIA.
encompassing the promoter region of GSTP1,encoding the p-class glutathione S-transferase (GST), is an exceedingly common somatic ge- nome change found in prostate cancer [Lee et al., 1994; Millar et al., 1999; Lin et al., 2001; Nelson Similar to other types of epithelial cancer, et al., 2001b]. Immunohistochemistry has de- prostate cancers contain many somatic genomic monstrated that GSTP1 protein is normally alterations, including point mutations, dele- expressed in basal epithelial cells in the pros- tions, amplifications, chromosomal rearrange- tate, but is absent in most luminal columnar ments, and changes in DNA methylation [Isaacs secretory epithelial cells. In PIA lesions, strong et al., 1994; Bookstein, 2001; Chung et al., 2001; anti-GSTP1 staining is seen in many of the Gao and Isaacs, 2002; Meng and Dahiya, 2002; atrophic luminal epithelial cells, [De Marzo DeMarzo et al., 2003]. However, unlike some et al., 1999] consistent with the induction of carcinomas such as those of the colon/rectum expression in response to environmental stress.
[Kinzler and Vogelstein, 1997] and pancreas The luminal cells in PIA are not simply basal [Jaffee et al., 2002], where specific oncogenes cells, as shown by their lack of expression of p63 such as k-ras or tumor suppressor genes such [Parsons et al., 2001a]. In prostate cancer cells, as p53 are mutated at a very high frequency, gene mutations reported thus far in prostate island sequences represses GSTP1 transcrip- cancer appear quite heterogeneous, from case to tion [Lin et al., 2001]. Absence of GSTP1 case, or even from lesion to lesion in a single case [Isaacs et al., 1994; Mirchandani et al., 1995; methylation are also common in high-grade Qian et al., 1995; Ruijter et al., 1999; Bookstein, GSTP1 is not a classical tumor suppressor express high levels of the androgen receptor in gene [Lin et al., 2001]. Rather, GSTP1 more the prostate tend to develop PIN [Stanbrough likely plays a ‘‘caretaker’’ role, protecting et al., 2001]. Many somatic alterations of prostate epithelial cells against genome dam- been described in human prostate cancers, Vogelstein, 1997]. For example, mice with both particularly ‘‘androgen-independent’’ prostate GSTP1 alleles disrupted by gene targeting cancers appearing after treatment by andro- exhibit increased skin tumor formation after gen suppression and/or with anti-androgens topical exposure to the skin carcinogen 7,12- [Veldscholte et al., 1990; Newmark et al., 1992; dimethylbenz [a] anthracene (DMBA) [Hender- Suzuki et al., 1993, 1996; Gaddipati et al., son et al., 1998]. One prostate carcinogen that 1994; Schoenberg et al., 1994; Taplin et al., may be detoxified by GSTP1 is the dietary 1995, 1999; Visakorpi et al., 1995; Evans heterocyclic amine, 2-amino-1-methyl-6-pheny- et al., 1996; Tilley et al., 1996; Koivisto et al., limidazo [4,5-b]pyridine (PhIP), which forms 1997; Marcelli et al., 2000; Haapala et al., when meats are cooked at high temperatures or 2001]. ‘‘Androgen-independent’’ prostate can- ‘‘charbroiled’’ [Lijinsky and Shubik, 1964; Gross cers usually continue to express the androgen et al., 1993; Morgenthaler and Holzhauser, receptor, maintaining androgen-receptor de- 1995; Knize et al., 1997]. Dietary PhIP intake pendent signaling (i) in response to the reduced causes prostate cancer in rats [Shirai et al., levels of circulating androgens, such as with AR 1997; Stuart et al., 2000]. In humans, a study amplification accompanied by androgen recep- examining the association between PhIP and tor over-expression, (ii) in response to non- other heterocyclic amine intake and prostate androgens or anti-androgens as agonist ligands, cancer showed a modest, albeit inconsistent increased relative risk of prostate cancer with altered androgen receptor ligand specificity, or increasing consumption [Norrish et al., 1999], (iii) via ligand-independent activation of the although there are a large number of studies androgen receptor, such as may occur under the showing an association between an increased influence of other intracellular signal transduc- relative risk of overall prostate cancer and the tion pathways [Veldscholte et al., 1990; van der levels of consumption of red meat [reviewed in Kwast et al., 1991; Culig et al., 1993; Nazareth Kolonel, 2001]. In the most recent analysis from and Weigel, 1996; Koivisto et al., 1997; Tan the Health Professionals Follow-Up Study, et al., 1997; Hobisch et al., 1998; Craft et al., consumption of red meats was not associated 1999; Amler et al., 2000; Sadar and Gleave, with an increased risk of prostate cancer over- all, but was associated with increased risk of et al., 2001; Zegarra-Moro et al., 2002].
metastatic prostate cancer [Michaud et al., 2001]. GSTP1 can protect prostate cells againstPhIP damage: for LNCaP prostate cancer cells, NKX3.1, located at 8p21, encodes a prostate- specific homeobox gene essential for normal metabolically activated PhIP results in the prostate development [Bieberich et al., 1996; He et al., 1997; Sciavolino et al., 1997; Prescott adducts. Replacement of the GSTP1 gene by et al., 1998]. In mice, targeted disruption of stable transfection prevented PhIP–DNA dam- Nkx3.1 leads to prostatic epithelial hyperplasia age [Nelson et al., 2001a]. GSTP1 may also protect prostate cells against damage inflicted Abdulkadir et al., 2002]. In men, although loss directly by oxidants, such as those produced by of 8p21 DNA sequences has been reported in as protracted low dose ionizing radiation exposure many as 63% of PIN lesions and in more than (DeWeese et al., unpublished observations).
90% of prostate cancers, no NKX3.1 mutationshave been detected, leading to controversy over whether NKX3.1 is the gene target of somatic alteration at 8p21 [Emmert-Buck et al., 1995; receptor (AR) both play critical roles in normal He et al., 1997; Voeller et al., 1997; Ornstein prostate development and function, and in most et al., 2001]. Nonetheless, loss of NKX3.1 ex- prostate diseases, including prostate cancer.
pression has been reported in as many as 20% of For example, transgenic mice engineered to PIN lesions, 6% of low stage prostate cancers, Pathological and Molecular Mechanisms of Prostate Carcinogenesis 22% of high stage prostate cancers, 34% of and Pten genes, haploinsufficiency for PTEN androgen-independent prostate cancers, and and/or NKX3.1 may be sufficient for a neo- plastic phenotype [Bhatia-Gaur et al., 1999; et al., 2000]. The relationship between somatic Podsypanina et al., 1999; Di Cristofano et al., NKX3.1 alterations and reduction in NKX3.1 expression during prostate cancer development PTEN, located at 10q, another site of frequent gene target for alteration during prostatic allelic loss in prostate cancer, encodes a phos- carcinogenesis. Targeted disruption of Cdkn1b phatase active against both proteins and lipid in mice results in prostatic hyperplasia, while substrates [Li et al., 1997; Myers et al., 1997, 1998; Steck et al., 1997; Teng et al., 1997]. PTEN alleles develop localized prostate cancers [Di has been proposed to function as a general Cristofano et al., 2001]. Reduced p27 expres- tumor suppressor by inhibiting the phospha- sion appears characteristic of human prostate tidylinositol 30-kinase/protein kinase B (PI3K/ cancer cells, particularly in prostate cancer Akt) signaling pathway, thought to be essential cases with a poor prognosis [Guo et al., 1997; for cell cycle progression and/or cell survival in Cheville et al., 1998; Cordon-Cardo et al., 1998; many cell types [Li et al., 1997; Furnari et al., Yang et al., 1998; De Marzo et al., 1998a].
1998; Ramaswamy et al., 1999; Sun et al., 1999].
Somatic loss of DNA sequences at 12p12-13, Like mice carrying disrupted Nkx3.1 alleles, near CDKN1B, have been reported for 23% of mice carrying disrupted Pten alleles manifest localized prostate cancers, 30% of prostate prostatic hyperplasia and dysplasia, and the progeny of breeding crosses between PtenÆ prostate cancer distant metastases [Kibel mice and Nkx3.1Æ mice develop PIN [Bhatia- et al., 2000]. The mechanism(s) by which soma- Gaur et al., 1999; Podsypanina et al., 1999; Di tic CDKN1B alterations leads to reduced p27 Cristofano et al., 2001; Kim et al., 2002], as well expression have not been elucidated. Provoca- as invasive carcinoma and lymph node metas- tively, p27 may be a target for repression by the tases [Abate-Shen et al., 2003]. PTEN, which is PI3K/Akt signaling pathway [Li and Sun, 1998; typically expressed by normal epithelial cells, Sun et al., 1999; Graff et al., 2000; Gottschalk is often expressed at a reduced level in hu- et al., 2001]. Thus, loss of PTEN function, man prostate cancer cells [McMenamin et al., accompanied by increased PI3K/Akt signaling, 1999]. Many somatic PTEN alterations have been reported for prostate cancers, including and in p27 protein half-life [Nakamura et al., homozygous deletions, loss of heterozygosity, 2000] Decreased p27 expression has also been mutations, and suspected CpG island hyper- documented in high grade PIN [De Marzo et al., methylation [Cairns et al., 1997; Li et al., 1997; 1998a; Fernandez et al., 1999] and in PIA Myers et al., 1997, 1998; Steck et al., 1997; Teng lesions [De Marzo et al., 1998a; Van Leenders et al., 1997; Gray et al., 1998; Suzuki et al., 1998; Wang et al., 1998; Vivanco and Sawyers, 2002].
Associations between somatic PTEN altera- tions and aberrant PTEN function in prostatecancer cells have been difficult to establish.
The karyotype of most human cancers is ab- Often, losses of 10q sequences near PTEN do not normal. Many types of cancer, including prostate appear to be accompanied by somatic mutations cancer, show chromosomal instability reflected of the remaining PTEN allele. Furthermore, by aberrations in both number and structure of chromosomes. The exceptions to this in solid more common in metastatic than in primary tumors are cancers with microsatellite instabil- prostate cancer lesions, a marked heterogeneity ity, which are genetically unstable at the single in PTEN defects in different metastatic sites nucleotide level but contain mostly diploid karyotypes. Chromosomal instability appears [Suzuki et al., 1998]. Perhaps, as is evident to be an important molecular mechanism driv- in mouse models featuring disrupted Nkx3.1 ing malignant transformation in many human epithelial tissues [Cahill et al., 1999], yet the prostate carcinogenesis. Interestingly, the telo- molecular mechanisms responsible for chromo- mere shortening found in high grade PIN was some destabilization during carcinogenesis are restricted to the luminal cells and was not largely unknown. One route to chromosomal present in the underlying basal cells. This instability is through defective telomeres [Coun- finding strongly suggests that basal cells are ter et al., 1992; Hackett and Greider, 2002; not the direct precursor cell to high grade PIN, Feldser et al., 2003]. Telomeres, which consist of but support the above mentioned concept that multiple repeats of a 6 base pair unit (TTAGGG), cells with an intermediate luminal cell pheno- complexed with several different binding pro- type are the likely direct target cell of transfor- teins, protect chromosome ends from fusing with mation in the prostate. Vukovic et al., recently other chromosome ends or other chromosomes reported Similar findings of reduced telomere containing double strand breaks [McClintock, length in high grade PIN and prostate cancer 1941]. However, in the absence of compensatory mechanisms, telomeric DNA is subject to loss due to cell division [Harley et al., 1990; Levyet al., 1992] and possibly oxidative damage [von Alterations in gene expression accompany- Zglinicki et al., 2000]. Critical telomere short- ing the development of prostate cancer have ening leads to chromosomal instability that, in been surveyed using transcriptome profiling technologies [Huang et al., 1999; Walker et al., incidence that is likely a result of chromosome 1999; Nelson et al., 2000; Xu et al., 2000; fusions, subsequent breakage, and rearrange- Dhanasekaran et al., 2001; Luo et al., 2001, ment [Blasco et al., 1997; Artandi et al., 2000].
2002; Magee et al., 2001; Stamey et al., 2001; Intriguingly, telomeres within human carcino- Waghray et al., 2001; Welsh et al., 2001]. Among mas are often found to be abnormally reduced in the many genes exhibiting over- or under- expression in localized prostate cancers, the products of at least two genes appear consis- human prostate cancer, the telomeres from tently increased. Hepsin, located at 19q11-13.2, prostate cancer tissue were consistently shorter encodes a transmembrane serine protease, nor- than those from cells in either the adjacent mally expressed at high levels in the liver and normal or BPH tissues [Sommerfeld et al., 1996].
other tissues [Tsuji et al., 1991]. The contribu- Others have also reported telomere shortening in tion of hepsin to the prostate cancer phenotype prostate cancer [Donaldson et al., 1999].
has not been discerned. Anti-sense oligonucleo- Most carcinomas arise from pre-invasive int- tides targeting Hepsin mRNA have been re- raepithelial precursor lesions, referred to as in- ported to retard the growth of hepatoma cells, traepithelial neoplasias (IEN) [O’Shaughnessy but HepsinÀ/À mice develop normally, exhibit et al., 2002]. These lesions show morphological normal liver regeneration, and have no striking features and molecular alterations characteris- phenotype [Torres-Rosado et al., 1993; Wu et al., tic of malignant neoplasia, including evidence of 1998; Yu et al., 2000]. a-Methylacyl-CoA race- genetic instability [Shih et al., 2001] but occur mase, a mitochondrial and peroxisomal enzyme within preexisting epithelia and are confined that acts on pristanoyl-CoA and C27-bile acyl- within the basement membrane. If genetic in- CoA substrates to catalyze the conversion of stability helps to drive cancer formation, and R- to S-stereoisomers in order to permit meta- telomeres shortening is a major mechanism bolism by b-oxidation [Schmitz et al., 1995], has leading to genetic instability, then telomere been reported to be over-expressed in almost all shortening should be present at the intraepithe- prostate cancers [Xu et al., 2000; Dhanasekaran lial phase of carcinoma. Recently we employed et al., 2001; Luo et al., 2001, 2002]. Germline an in situ telomere FISH technique TEL-FISH AMACR mutations have been reported to lead to and reported that telomere shortening is evid- adult-onset neuropathy [Ferdinandusse et al., ent in the majority of high-grade prostatic intraepithelial neoplasia (PIN) lesions [Meeker revealed that a-methylacyl-CoA racemase is et al., 2002], which are thought to be cancer occasionally present in normal prostate cells, precursor lesions of the prostate. Thus, telomere increased in prostatic intraepithelial neoplasia shortening is a prevalent biomarker in human cells, and further elevated in prostate cancer prostate, occurring early in the process of cells [Jiang et al., 2001, 2002; Beach et al., 2002; Pathological and Molecular Mechanisms of Prostate Carcinogenesis Luo et al., 2002; Rubin et al., 2002; Yang et al., contains basal cells [Hedrick and Epstein, 2002; Leav et al., 2003; Magi-Galluzzi et al., 1989]. More recently it has been shown that 2003; Zhou et al., 2003a]. Another gene product the product of the p63 gene is expressed in basal shown to be increased at the mRNA level in cell nuclei in the prostate, but not in prostate primary and hormone refractory metastatic luminal cells nor in the vast majority of prostate prostate cancer using gene expression arrays cancers [Signoretti et al., 2000; Parsons et al., is the polycomb group protein enhancer of zeste 2001a]. Since this marker may be more robust homolog 2 (EZH2), which has been postulated to in terms of surviving poor fixation or various be involved in the progression of prostate cancer types of tissue processing [Weinstein et al., 2002], many pathologists have begun to employp63 staining in clinical practice to furtherdetermine whether basal cells may be present in a suspicious lesion [Shah et al., 2002]. To increase the chances of finding basal cells, Zhou et al. [2003b] have recently suggested using acocktail of antibodies against basal cell cyto- It is estimated that approximately 1,000,000 by a large number of different investigators to prostate needle biopsies are performed per year be overexpressed in prostate cancer cells. Since in the U.S., and approximately 20% are positive negative staining for basal cell markers by itself for cancer. While there is no standard for the is not diagnostic of prostate cancer, positive number of cores taken, in many institutions staining for AMACR may increase the level of urologists are submitting 12 or more cores per confidence in establishing a definitive malig- patient, which is up from 6 several years ago.
nant diagnosis in a lesion deemed highly sus- Thus, between 6 and 12 million individual new picious by standard H&E staining [Jiang et al., needle biopsy cores are examined microscopi- 2001, 2002; Beach et al., 2002; Magi-Galluzzi cally by pathologists each year in the U.S. While et al., 2003; Zhou et al., 2003a]. Thus, many at times the diagnosis of prostate cancer on pathologists have begun to employ this marker.
needle biopsy can be quite straightforward, At our institution we routinely order the p63, many cases present diagnostic challenges. For 34BE12 (also referred to as keratin 903), and AMACR on atypical prostate needle biopsies prostate cancer that can be misdiagnosed as where the suspicion of cancer is high but prostate cancer [Epstein, 1995; Epstein and the findings on H&E section are insufficient Potter, 2001; DeMarzo et al., 2003]. These in- to render a clearly malignant diagnosis. In clude lesions such as atrophy adenosis (atypical the research setting, we have also employed adenomatous hyperplasia), PIN, nephrogenic double labeling against p63 (nuclear staining adenoma granulomatous prostatitis, and radia- positive in basal cells) and racemase (cytoplas- tion change in benign glands. It has been clear mic-only staining) in order to delineate both for many years that prostate basal cells, which markers on an individual tissue sections [Luo are uniformly present in normal appearing et al., 2002], although this double labeling can prostate acini and ducts, and in the vast be somewhat problematic on needle biopsies majority of benign mimics of prostate cancer, due to background cytoplasmic staining for p63.
are absent in prostate cancer [Brawer et al., As usual with any ancillary test, there are 1985]. Thus, ancillary tools such as immuno- pitfalls in the use of AMACR in diagnostic histochemistry against ‘‘basal cell specific cyto- pathology, since certain histological subtypes of keratins’’1 are often employed in difficult cases prostatic adenocarcinoma tend to be weak or to determine if a particular suspicious lesion negative for this marker [Zhou et al., 2003a],and, benign glands and high grade PIN may bepositive at times. Since there are so many 1Often staining for basal cells is performed with the diagnostic pitfalls in prostate needle biopsies, monoclonal antibody 34BE12, recognizing a range of high the importance of obtaining second opinions on molecular weight cytokeratins including keratin 5 and 14.
These keratins are highly expressed in basal cells. Other prostate biopsy material has been emphasized antibodies against keratin 5 have also been employed.
sues, has been shown to reduce aflatoxin B1 damage when administered to a human clini-cal study cohort at high risk for aflatoxin ex- Abnormal genes and gene products appearing posure and liver cancer development in China in prostate cancer cells offer great promise as [Jacobson et al., 1997; Kensler et al., 1998; disease biomarkers. For example, GSTP1 CpG Wang et al., 1999]. Sulforaphane, an isothio- island hypermethylation, detected in prostate cyanate present in high amounts in cruciferous tissue, blood, urine, or prostate fluid, may be a vegetables, is also a potent inducer of carcino- molecular biomarker useful for prostate cancer gen-detoxification enzymes [Zhang et al., 1992, detection and staging. Although GSTP1 CpG 1994]. Diets rich in carcinogen-inducers like island hypermethylation has been found in sulforaphane have been associated with de- creased cancer risks [Cohen et al., 2000].
prostate cancers, approximately 70% of liver Such carcinogen-detoxification enzyme indu- cers need to be developed and tested in prostate cancers, this genome alteration has not been detected in DNA from any normal tissues [Lee The recognition that prostate inflammation et al., 1994; Esteller et al., 1998; Tchou et al., may contribute to the earliest steps in prostate 2000; Lin et al., 2001; Nakayama et al., 2003].
carcinogenesis also has profound implications GSTP1 CpG island hypermethylation has also for the prevention of prostate cancer. Animal been detected in 70% of PIN lesions [Brooks model studies suggest that non-steroidal anti- et al., 1998; Nakayama et al., 2003a]. For a inflammatory drugs might attenuate both pros- comprehensive review of GSTP1 methylation as tate cancer incidence and prostate cancer a biomarker in prostate cancer, see the accom- progression [Wechter et al., 2000]. In addition, panying article by Nakayama et al. [2003b].
several epidemiology studies have hinted at amodest protective effect of non-steroidal anti- inflammatory drug intake on either prostate cancer incidence, or on prostate cancer progres- Insights into the molecular pathogenesis of sion [Norrish et al., 1998; Nelson and Harris, prostate cancer may provide opportunities for 2000; Habel et al., 2002; Leitzmann et al., 2002; the discovery and development of new agents Roberts et al., 2002]. One target of these drugs, for prostate cancer prevention. Loss of GSTP1 cyclo-oxygenase-2 (COX-2), may be selectively ‘‘caretaker’’ activity during prostate carcinogen- expressed in PIA lesions in the prostate [Zha esis emphasizes the critical role of carcinogen et al., 2001]. A randomized clinical trial in- metabolism in protecting prostate cells ag- volving the administration of celecoxib, a selec- ainst neoplastic transformation, and suggests tive COX-2 inhibitor, or placebo to men with that therapeutic compensation for inadequate prostate cancer who undergo radical pros- GSTP1 ‘‘caretaker’’ function may help prevent tatectomy, has been initiated at the Sidney prostate cancer. The ‘‘oxidation tolerance’’ phe- notype associated with loss of GSTP1 ‘‘care- Johns Hopkins. The effects of COX-2 inhibition taker’’ function in LNCaP prostate cancer cells may provide a mechanistic rationale for but- other tissue markers will be ascertained. In the tressing defenses against oxidative genome future, as the process of inflammation in the damage via anti-oxidant supplementation to prostate, and the pathogenesis of PIA becomes better defined more specific targets will be In addition, augmentation of carcinogen-detox- identified, creating new opportunities for the ification capacity, using a variety of such discovery and development of selective inhibi- chemoprotective compounds, including isoth- tors of pathways mediating prostate cell and iocyanates, 1,2-dithiole-3-thiones, terpenoids, etc., is known to prevent a range of different cancers in different animal models by triggering the expression of many different carcinogen- detoxification enzymes [Kensler, 1997; Ramos-Gomez et al., 2001]. Oltipraz, an inducer of Finally, progressive elucidation of the mo- carcinogen-detoxification enzymes in liver tis- lecular mechanisms contributing to prostate Pathological and Molecular Mechanisms of Prostate Carcinogenesis cancer cell growth, survival, and metastasis Beach R, Gown AM, De Peralta-Venturina MN, Folpe AL, may lead to better treatments for established Yaziji H, Salles PG, Grignon DJ, Fanger GR, Amin MB.
prostate cancer. Of course, androgen signaling 2002. P504S immunohistochemical detection in 405prostatic specimens including 376 18-gauge needle pathways, essential for the growth and survival biopsies. Am J Surg Pathol 26:1588–1596.
of most prostate cancer cells, have already been Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai successfully targeted for prostate cancer treat- N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha ment. However, despite treatment with andro- GR, Abate-Shen C, Shen MM. 1999. Roles for Nkx3.1 in gen deprivation and/or anti-androgens, most prostate development and cancer. Genes Dev 13:966–977.
men with advanced prostate cancer ultimately Bieberich CJ, Fujita K, He WW, Jay G. 1996. Prostate- suffer cancer progression [van der Kwast et al., specific and androgen-dependent expression of a novel 1991; Amler et al., 2000; Feldman and Feldman, homeobox gene. J Biol Chem 271:31779–31782.
2001; Mousses et al., 2001]. Since these pro- Billis A. 1998. Prostatic atrophy: An autopsy study of a his- gressive androgen-independent cancers appear tologic mimic of adenocarcinoma. Mod Pathol 11:47–54.
Billis A, Magna LA. 2003. Inflammatory atrophy of the to still use the androgen receptor to promote prostate. Prevalence and significance. Arch Pathol Lab growth and survival, it is possible that the androgen receptor itself, and some of its post- Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, translational modifications, might be even DePinho RA, Greider CW. 1997. Telomere shortening better targeted with new treatment approaches and tumor formation by mouse cells lacking telomeraseRNA. Cell 91:25–34.
[Eder et al., 2002; Gioeli et al., 2002; Solit et al., Bookstein R. 2001. Tumor suppressor genes in prostate 2002]. Also, several newly recognized signal cancer. In: Chung LW, Isaacs WB, Simons JW, editors.
transduction pathways offer new treatment Prostate cancer: Biology, genetics, and the new therapu- possibilities. In particular, as described in this tics. Totowa, NJ: Humana press. pp 61–93.
review, loss of PTEN function during prostate Bostwick DG. 1996. Prospective origins of prostate carci- noma. Prostatic intraepithelial neoplasia and atypical cancer progression implicates PI3K/Akt cell adenomatous hyperplasia. Cancer 78:330–336.
growth and survival signaling pathway in the Bostwick DG, Qian J. 1995. Atypical adenomatous hyper- development of life-threatening prostate cancer plasia of the prostate. Relationship with carcinoma in 217 [Furnari et al., 1998; Ramaswamy et al., 1999; whole-mount radical prostatectomies. Am J Surg Pathol Sun et al., 1999]. Several new agents targeting Bostwick DG, Cooner WH, Denis L, Jones GW, Scardino various components of this pathway are under PT, Murphy GP. 1992. The association of benign development for prostate and other cancers prostatic hyperplasia and cancer of the prostate. Cancer [Neshat et al., 2001; Podsypanina et al., 2001; Solit et al., 2002; Vivanco and Sawyers, 2002].
Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP. 2000. Loss of NKX3.1expression in human prostate cancers correlates with Abate-Shen C, Banach-Petrosky WA, Sun X, Economides tumor progression [in process citation]. Cancer Res 60: KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM. 2003. Nkx3.1; Pten mutant mice develop invasive Brawer MK, Peehl DM, Stamey TA, Bostwick DG. 1985.
prostate adenocarcinoma and lymph node metastases.
Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res 45:3663–3667.
Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton Breslow N, Chan CW, Dhom G, Drury RA, Franks LM, CK, Humphrey PA, Milbrandt J. 2002. Conditional loss of Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, nkx3.1 in adult mice induces prostatic intraepithelial Tulinius H. 1977. Latent carcinoma of prostate of autopsy neoplasia. Mol Cell Biol 22:1495–1503.
in seven areas. Int J Cancer 20:680–688.
Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern Brooks JD, Weinstein M, Lin X, Sun Y, Pin SS, Bova GS, S, Lee D, Wang V, Leysens M, Higgins B, Martin J, Epstein JI, Isaacs WB, Nelson WG. 1998. CG island Gerald W, Dracopoli N, Cordon-Cardo C, Scher HI, methylation changes near the GSTP1 gene in prostatic Hampton GM. 2000. Dysregulated expression of andro- intraepithelial neoplasia. Cancer Epidemiol Biomarkers gen-responsive and nonresponsive genes in the andro- Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. 1999.
CWR22-R1. Cancer Res 60:6134–6141.
Genetic instability and darwinian selection in tumours.
Anton RC, Kattan MW, Chakraborty S, Wheeler TM. 1999.
Postatrophic hyperplasia of the prostate: Lack of associa- Cairns P, Okami K, Halachmi S, Halachmi N, Esteller tion with prostate cancer. Am J Surg Pathol 23:932–936.
M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D.
Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, 1997. Frequent inactivation of PTEN/MMAC1 in primary DePinho RA. 2000. Telomere dysfunction promotes non- prostate cancer. Cancer Res 57:4997–5000.
reciprocal translocations and epithelial cancers in mice.
Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, De Marzo AM, Nelson WG, Meeker AK, Coffey DS. 1998b.
Smith J, Stephan D, Wiley K, Brownstein M, Gildea Stem cell features of benign and malignant prostate D, Kelly B, Jenkins R, Hostetter G, Matikainen M, epithelial cells. J Urol 160:2381–2392.
Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De De Marzo AM, Marchi VL, Epstein JI, Nelson WG. 1999.
Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Proliferative inflammatory atrophy of the prostate: Im- Meyers D, Gronberg H, Meltzer P, Silverman R, Bailey- plications for prostatic carcinogenesis. Am J Pathol 155: Wilson J, Walsh P, Isaacs W, Trent J. 2002. Germline mutations in the ribonuclease L gene in families showing DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. 2003.
linkage with HPC1. Nat Genet 30:181–184.
Pathological and molecular aspects of prostate cancer.
Cheville JC, Lloyd RV, Sebo TJ, Cheng L, Erickson L, Bostwick DG, Lohse CM, Wollan P. 1998. Expression of Dennis LK, Dawson DV. 2002. Meta-analysis of measures p27kip1 in prostatic adenocarcinoma. Mod Pathol 11: of sexual activity and prostate cancer. Epidemiology Chung LWK, Isaacs WB, Simons JW. 2001. Prostate Dennis LK, Lynch CF, Torner JC. 2002. Epidemiologic cancer: Biology, genetics, and the new therapeutics.
association between prostatitis and prostate cancer.
Clark LC, Combs GF, Jr., Turnbull BW, Slate EH, Chalker Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, DK, Chow J, Davis LS, Glover RA, Graham GF, Gross Varambally S, Kurachi K, Pienta KJ, Rubin MA, EG, Krongrad A, Lesher JL, Jr., Park HK, Sanders BB, Chinnaiyan AM. 2001. Delineation of prognostic biomar- Jr., Smith CL, Taylor JR. 1996. Effects of selenium kers in prostate cancer. Nature 412:822–826.
supplementation for cancer prevention in patients with Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, carcinoma of the skin. A randomized controlled trial.
Pandolfi PP. 2001. Pten and p27KIP1 cooperate in Nutritional Prevention of Cancer Study Group [see prostate cancer tumor suppression in the mouse. Nat comments] [published erratum appears in JAMA 1997 May 21;277(19):1520]. JAMA 276:1957–1963.
Donaldson L, Fordyce C, Gilliland F, Smith A, Feddersen R, Clark LC, Dalkin B, Krongrad A, Combs GF, Jr., Turnbull Joste N, Moyzis R, Griffith J. 1999. Association between BW, Slate EH, Witherington R, Herlong JH, Janosko E, outcome and telomere DNA content in prostate cancer.
Carpenter D, Borosso C, Falk S, Rounder J. 1998.
Decreased incidence of prostate cancer with selenium Eder IE, Hoffmann J, Rogatsch H, Schafer G, Zopf D, supplementation: Results of a double-blind cancer pre- Bartsch G, Klocker H. 2002. Inhibition of LNCaP vention trial. Br J Urol 81:730–734.
prostate tumor growth in vivo by an antisense oligonu- Cohen JH, Kristal AR, Stanford JL. 2000. Fruit and cleotide directed against the human androgen receptor.
vegetable intakes and prostate cancer risk. J Natl Cancer Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Cordon-Cardo C, Koff A, Drobnjak M, Capodieci P, Osman Halliwell B, van der Vliet A. 1998. Formation of nitric I, Millard SS, Gaudin PB, Fazzari M, Zhang ZF, oxide-derived inflammatory oxidants by myeloperoxidase Massague J, Scher HI. 1998. Distinct altered patterns in neutrophils. Nature 391:393–397.
of p27KIP1 gene expression in benign prostatic hyper- Emmert-Buck MR, Vocke CD, Pozzatti RO, Duray PH, plasia and prostatic carcinoma [in process citation].
Jennings SB, Florence CD, Zhuang Z, Bostwick DG, Liotta LA, Linehan WM. 1995. Allelic loss on chromo- Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, some 8p12-21 in microdissected prostatic intraepithelial Greider CW, Harley CB, Bacchetti S. 1992. Telomere neoplasia. Cancer Res 55:2959–2962.
shortening associated with chromosome instability is Epstein JI. 1995. Prostate biopsy interpretation. New York, arrested in immortal cells which express telomerase Epstein JI, Potter SR. 2001. The pathological interpreta- Coussens LM, Werb Z. 2002. Inflammation and cancer.
tion and significance of prostate needle biopsy findings: Implications and current controversies. J Urol 166:402– Craft N, Shostak Y, Carey M, Sawyers CL. 1999. A mechanism for hormone-independent prostate cancer Epstein JI, Walsh PC, Sanfilippo F. 1996. Clinical and cost through modulation of androgen receptor signaling by impact of second-opinion pathology. Review of prostate the HER-2/neu tyrosine kinase. Nat Med 5:280–285.
biopsies prior to radical prostatectomy. Am J Surg Pathol Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H. 1993.
Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Mutant androgen receptor detected in an advanced-stage Herman JG. 1998. Inactivation of glutathione S-trans- prostatic carcinoma is activated by adrenal androgens ferase P1 gene by promoter hypermethylation in human and progesterone. Mol Endocrinol 7:1541–1550.
neoplasia. Cancer Res 58:4515–4518.
de Lange T. 1995. Telomere dynamics and genome in- Evans BA, Harper ME, Daniells CE, Watts CE, Matenhelia stability in human cancer. In: Blackburn EH, Greider S, Green J, Griffiths K. 1996. Low incidence of androgen CW, editors. Telomeres. Plainview, NY: Cold Spring receptor gene mutations in human prostatic tumors Harbor Laboratory Press. pp 265–293.
using single strand conformation polymorphism analy- De Marzo AM, Meeker AK, Epstein JI, Coffey DS. 1998a.
Prostate stem cell compartments: Expression of the cell Feldman BJ, Feldman D. 2001. The development of cycle inhibitor p27Kip1 in normal, hyperplastic, and androgen-independent prostate cancer. Nat Rev Cancer neoplastic cells. Am J Pathol 153:911–919.
Pathological and Molecular Mechanisms of Prostate Carcinogenesis Feldser DM, Hackett JA, Greider CW. 2003. Telomere Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, dysfunction and the initiation of genome instability. Nat Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, Vessella RL, Neubauer BL. 2000. Increased AKT activity Feneley MR, Young MP, Chinyama C, Kirby RS, Parkinson contributes to prostate cancer progression by dramati- MC. 1996. Ki-67 expression in early prostate cancer and cally accelerating prostate tumor growth and diminish- associated pathological lesions. J Clin Pathol 49:741–748.
ing p27Kip1 expression. J Biol Chem 275:24500–24505.
Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE, Allen JT, McLean BN, Brown AY, Vreken P, Waterham Watson GJ, Spurr NK, Snary D. 1998. Mutation and HR, Wanders RJ. 2000. Mutations in the gene encoding expression analysis of the putative prostate tumour- suppressor gene PTEN. Br J Cancer 78:1296–1300.
adult-onset sensory motor neuropathy. Nat Genet 24: Grignon DJ, Sakr WA. 1996. Atypical adenomatous hyper- plasia of the prostate: A critical review. Eur Urol 30: Fernandez PL, Arce Y, Farre X, Martinez A, Nadal A, Rey MJ, Peir N, Campo E, Cardesa A. 1999. Expression of Gross GA, Turesky RJ, Fay LB, Stillwell WG, Skipper PL, p27/kip1 is down-regulated in human prostate carcinoma Tannenbaum SR. 1993. Heterocyclic aromatic amine progression. J Pathol 187:563–566.
formation in grilled bacon, beef and fish and in grill Franks LM. 1954. Atrophy and hyperplasia in the prostate scrapings. Carcinogenesis 14:2313–2318.
proper. J Pathol Bacteriol 68:617–621.
Guess HA. 2001. Benign prostatic hyperplasia and prostate Furnari FB, Huang HJ, Cavenee WK. 1998. The phosphoi- nositol phosphatase activity of PTEN mediates a serum- Guo YP, Sklar GN, Borkowski A, Kyprianou N. 1997. Loss sensitive G1 growth arrest in glioma cells. Cancer Res of the cyclin-dependent kinase inhibitor P27(Kip1) protein in human prostate cancer correlates with tumor Gaddipati JP, McLeod DG, Heidenberg HB, Sesterhenn IA, grade. Clin Cancer Res 3:2269–2274.
Finger MJ, Moul JW, Srivastava S. 1994. Frequent Haapala K, Hyytinen ER, Roiha M, Laurila M, Rantala I, detection of codon 877 mutation in the androgen receptor Helin HJ, Koivisto PA. 2001. Androgen receptor altera- gene in advanced prostate cancers. Cancer Res 54:2861– tions in prostate cancer relapsed during a combined androgen blockade by orchiectomy and bicalutamide. Lab Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ. 1999. Lower prostate Habel LA, Zhao W, Stanford JL. 2002. Daily aspirin use and cancer risk in men with elevated plasma lycopene levels: prostate cancer risk in a large, multiracial cohort in the Results of a prospective analysis. Cancer Res 59:1225– US. Cancer Causes Control 13:427–434.
Hackett JA, Greider CW. 2002. Balancing instability: Dual Gao AC, Isaacs JT. 2002. Molecular basis of prostate roles for telomerase and telomere dysfunction in tumor- carcinogenesis. In: Coleman WB, Tsongalis GJ, editors.
The molecular basis of human cancer. Totowa, NJ: Haenszel W, Kurihara M. 1968. Studies of Japanese migrants. I. Mortality from cancer and other diseases Gardner WA, Bennett BD. 1992. The prostate overview: among Japanese in the United States. J Natl Cancer Inst Recent insights and speculations. In: Weinstein RS, Garnder WA, editors. Pathology and pathobiology of the Harley CB, Futcher AB, Greider CW. 1990. Telomeres urinary bladder and prostate. Baltimore: Williams and shorten during ageing of human fibroblasts. Nature Gerstenbluth RE, Seftel AD, MacLennan GT, Rao RN, Hasui Y, Marutsuka K, Asada Y, Ide H, Nishi S, Osada Y.
Corty EW, Ferguson K, Resnick MI. 2002. Distribution of 1994. Relationship between serum prostate specific chronic prostatitis in radical prostatectomy specimens antigen and histological prostatitis in patients with with up-regulation of bcl-2 in areas of inflammation.
benign prostatic hyperplasia. Prostate 25:91–96.
Hayes RB, Pottern LM, Strickler H, Rabkin C, Pope V, Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Swanson GM, Greenberg RS, Schoenberg JB, Liff J, Catling AD, White FM, Christian RE, Settlage RE, Schwartz AG, Hoover RN, Fraumeni JF, Jr. 2000. Sexual Shabanowitz J, Hunt DF, Weber MJ. 2002. Androgen behaviour, STDs and risks for prostate cancer. Br receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 277:29304– He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall Giovannucci E. 2001. Medical history and etiology of DJ, Gelmann EP, Abate-Shen C, Carter KC. 1997. A novel prostate cancer. Epidemiol Rev 23:159–162.
human prostate-specific, androgen-regulated homeobox Gleason PE, Jones JA, Regan JS, Salvas DB, Eble JN, gene (NKX3.1) that maps to 8p21, a region frequently Lamph WW, Vlahos CJ, Huang WL, Falcone JF, Hirsch deleted in prostate cancer. Genomics 43:69–77.
KS. 1993. Platelet derived growth factor (PDGF), andro- Hedrick L, Epstein JI. 1989. Use of keratin 903 as an gens and inflammation: Possible etiologic factors in the adjunct in the diagnosis of prostate carcinoma. Am J Surg development of prostatic hyperplasia. J Urol 149:1586– Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen Gottschalk AR, Basila D, Wong M, Dean NM, Brandts CH, JK, Hartman AM, Haapakoski J, Malila N, Rautalahti Stokoe D, Haas-Kogan DA. 2001. p27Kip1 is required for M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L, PTEN-induced G1 growth arrest. Cancer Res 61:2105– Virolainen M, Edwards BK. 1998. Prostate cancer and supplementation with alpha-tocopherol and beta- carotene: Incidence and mortality in a controlled trial prostate carcinogenesis. Proc Natl Acad Sci USA 99: [see comments]. J Natl Cancer Inst 90:440–446.
Henderson CJ, Smith AG, Ure J, Brown K, Bacon EJ, Wolf Kinzler KW, Vogelstein B. 1997. Cancer-susceptibility CR. 1998. Increased skin tumorigenesis in mice lacking genes. Gatekeepers and caretakers [news; comment] pi class glutathione S-transferases. Proc Natl Acad Sci [see comments]. Nature 386:761, 763.
Knize MG, Salmon CP, Mehta SS, Felton JS. 1997.
Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G, Analysis of cooked muscle meats for heterocyclic aro- Klocker H, Culig Z. 1998. Interleukin-6 regulates matic amine carcinogens. Mutat Res 376:129–134.
prostate-specific protein expression in prostate carci- Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen noma cells by activation of the androgen receptor. Cancer E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T, Kallioniemi OP. 1997. Androgen receptor gene Hsing AW, Tsao L, Devesa SS. 2000. International trends amplification: A possible molecular mechanism for and patterns of prostate cancer incidence and mortality.
androgen deprivation therapy failure in prostate cancer.
Huang GM, Ng WL, Farkas J, He L, Liang HA, Gordon D, Kolonel LN. 2001. Fat, meat, and prostate cancer. Epide- Yu J, Hood L. 1999. Prostate cancer expression profiling by cDNA sequencing analysis. Genomics 59:178–186.
Krieger JN, Nyberg L, Jr., Nickel JC. 1999. NIH consensus Irani J, Levillain P, Goujon JM, Bon D, Dore B, Aubert J.
definition and classification of prostatitis. JAMA 282: 1997. Inflammation in benign prostatic hyperplasia: Correlation with prostate specific antigen value. J Urol Leav I, McNeal JE, Ho SM, Jiang Z. 2003. Alpha- methylacyl-CoA racemase (P504S) expression in evolving Isaacs WB, Bova GS, Morton RA, Bussemakers MJ, Brooks carcinomas within benign prostatic hyperplasia and in JD, Ewing CM. 1994. Molecular biology of prostate cancers of the transition zone. Hum Pathol 34:228–233.
Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Jacobson LP, Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang Bova GS, Hsieh WS, Isaacs WB, Nelson WG. 1994.
QN, Yu LY, Qian GS, Kuang SY, Li YF, Fang X, Zarba A, Cytidine methylation of regulatory sequences near the Chen B, Enger C, Davidson NE, Gorman MB, Gordon pi-class glutathione S-transferase gene accompanies GB, Prochaska HJ, Egner PA, Groopman JD, Munoz A, human prostatic carcinogenesis. Proc Natl Acad Sci Helzlsouer KJ, Kensler TW. 1997. Oltipraz chemopre- vention trial in Qidong, People’s Republic of China: Study Leitzmann MF, Stampfer MJ, Ma J, Chan JM, Colditz GA, design and clinical outcomes. Cancer Epidemiol Biomar- Willett WC, Giovannucci E. 2002. Aspirin use in relation to risk of prostate cancer. Cancer Epidemiol Biomarkers Jaffee EM, Hruban RH, Canto M, Kern SE. 2002. Focus on pancreas cancer. Cancer Cell 2:25–28.
Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB.
Jemal A, Thomas A, Murray T, Thun M. 2002. Cancer 1992. Telomere end-replication problem and cell aging.
statistics, 2002. CA Cancer J Clin 52:23–47.
Jiang Z, Woda BA, Rock KL, Xu Y, Savas L, Khan A, Pihan Li DM, Sun H. 1998. PTEN/MMAC1/TEP1 suppresses the G, Cai F, Babcook JS, Rathanaswami P, Reed SG, Xu J, tumorigenicity and induces G1 cell cycle arrest in human Fanger GR. 2001. P504S: A new molecular marker for the glioblastoma cells. Proc Natl Acad Sci USA 95:15406– detection of prostate carcinoma. Am J Surg Pathol Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc Jiang Z, Wu CL, Woda BA, Dresser K, Xu J, Fanger GR, J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Yang XJ. 2002. P504S/alpha-methylacyl-CoA racemase: Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, A useful marker for diagnosis of small foci of prostatic Wigler MH, Parsons R. 1997. PTEN, a putative protein carcinoma on needle biopsy. Am J Surg Pathol 26:1169– tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947.
Kensler TW. 1997. Chemoprevention by inducers of Liavag I. 1968. Atrophy and regeneration in the pathogen- carcinogen detoxication enzymes. Environ Health Per- esis of prostatic carcinoma. Acta Path Microbiol Scandi- Kensler TW, He X, Otieno M, Egner PA, Jacobson LP, Chen Lijinsky W, Shubik P. 1964. Benzo(a)pyrene and other B, Wang JS, Zhu YR, Zhang BC, Wang JB, Wu Y, Zhang polynuclear hydrocarbons in charcoal-broiled meat.
QN, Qian GS, Kuang SY, Fang X, Li YF, Yu LY, Prochaska HJ, Davidson NE, Gordon GB, Gorman MB, Lin X, Tascilar M, Lee WH, Vles WJ, Lee BH, Veeraswamy Zarba A, Enger C, Munoz A, Helzlsouer KJ, et al. 1998.
R, Asgari K, Freije D, van Rees B, Gage WR, Bova GS, Oltipraz chemoprevention trial in Qidong, People’s Isaacs WB, Brooks JD, DeWeese TL, De Marzo AM, Republic of China: Modulation of serum aflatoxin Nelson WG. 2001. GSTP1 CpG island hypermethylation albumin adduct biomarkers. Cancer Epidemiol Biomar- is responsible for the absence of GSTP1 expression in human prostate cancer cells. Am J Pathol 159:1815– Kibel AS, Faith DA, Bova GS, Isaacs WB. 2000. Loss of heterozygosity at 12P12-13 in primary and metastatic Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM, prostate adenocarcinoma. J Urol 164:192–196.
Bittner ML, Trent JM, Isaacs WB. 2001. Human prostate Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, cancer and benign prostatic hyperplasia: Molecular Parsons R, Shen MM, Abate-Shen C. 2002. Cooperativity dissection by gene expression profiling. Cancer Res 61: of Nkx3.1 and Pten loss of function in a mouse model of Pathological and Molecular Mechanisms of Prostate Carcinogenesis Luo J, Zha S, Gage WR, Dunn TA, Hicks JL, Bennett CJ, intratumor distribution of p53 mutations in human Ewing CM, Platz EA, Ferdinandusse S, Wanders RJ, prostate cancer. Am J Pathol 147:92–101.
Trent JM, Isaacs WB, De Marzo AM. 2002. Alpha- Montironi R, Mazzucchelli R, Scarpelli M. 2002. Pre- methylacyl-CoA racemase: A new molecular marker for cancerous lesions and conditions of the prostate: From prostate cancer. Cancer Res 62:2220–2226.
morphological and biological characterization to chemo- Macoska JA, Trybus TM, Wojno KJ. 2000. 8p22 loss prevention. Ann NY Acad Sci 963:169–184.
concurrent with 8c gain is associated with poor outcome Moore RA. 1936. The evolution and involution of the in prostate cancer. Urology 55:776–782.
prostate gland. Am J Pathol 12:599–624.
Magee JA, Araki T, Patil S, Ehrig T, True L, Humphrey PA, Morgenthaler PM, Holzhauser D. 1995. Analysis of muta- Catalona WJ, Watson MA, Milbrandt J. 2001. Expression tions induced by 2-amino-1-methyl-6-phenylimidazo[4,5- profiling reveals hepsin overexpression in prostate b]pyridine (PhIP) in human lymphoblastoid cells. Carci- Magi-Galluzzi C, Luo J, Isaacs WB, Hicks JL, De Marzo Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, AM, Epstein JI. 2003. Alpha-methylacyl-CoA racemase: Bittner M, Pretlow T, Elkahloun AG, Trepel JB, A variably sensitive immunohistochemical marker for Kallioniemi OP. 2001. Failure of hormone therapy in the diagnosis of small prostate cancer foci on needle prostate cancer involves systematic restoration of andro- biopsy. Am J Surg Pathol 27:1128–1133.
gen responsive genes and activation of rapamycin Marcelli M, Ittmann M, Mariani S, Sutherland R, Nigam R, sensitive signaling. Oncogene 20:6718–6723.
Murthy L, Zhao Y, DiConcini D, Puxeddu E, Esen A, Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Eastham J, Weigel NL, Lamb DJ. 2000. Androgen Parsons R, Tonks NK. 1997. P-TEN, the tumor suppres- receptor mutations in prostate cancer. Cancer Res 60: sor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 94:9052–9057.
McClintock B. 1941. The stability of broken ends of Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, chromosomes in Zea mays. Genetics 26:234–282.
Hemmings BA, Wigler MH, Downes CP, Tonks NK. 1998.
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, The lipid phosphatase activity of PTEN is critical for its Sellers WR. 1999. Loss of PTEN expression in paraffin- tumor supressor function. Proc Natl Acad Sci USA 95: embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59:4291– Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR. 2000. Forkhead transcription fac- McNeal JE. 1969. Origin and development of carcinoma in tors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol 20:8969–8982.
McNeal JE. 1984. Ageing and the prostate. In: Brockle- Nakayama M, Bennett CJ, Hicks JL, Epstein JI, Platz EA, hurst JC, editor. Urology in the elderly. Edinburgh, UK: Nelson WG, De Marzo AM. 2003a. Hypermethylation of the human GSTP1 CpG island is present in a subset of McNeal JE. 1988. Normal histology of the prostate. Am proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: A McNeal JE. 1997. Prostate. In: Sternberg SS, editor.
detailed study using laser-capture microdissection. Am Histology for pathologists. Philadelphia, PA: Lippincott- Nakayama M, Gonzalgo ML, Yegnasubramanian S, Lin X, McNeal JE, Bostwick DG. 1986. Intraductal dysplasia: A Demarzo AM, Nelson WG. 2003b. GSTP1 CpG island premalignant lesion of the prostate. Hum Pathol 17: hypermethylation as a molecular biomarker for prostate Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ, Nazareth LV, Weigel NL. 1996. Activation of the human De Marzo AM. 2002. Telomere shortening is an early androgen receptor through a protein kinase A signaling somatic DNA alteration in human prostate tumorigen- pathway. J Biol Chem 271:19900–19907.
Nelson JE, Harris RE. 2000. Inverse association of Meng MV, Dahiya R. 2002. Molecular genetics of prostate prostate cancer and non-steroidal anti-inflammatory cancer. In: Carroll PR, Grossfeld GD, editors. Prostate drugs (NSAIDs): Results of a case–control study. Oncol cancer. Hamilton, Ontario, BC: Decker, Inc.
Michaud DS, Augustsson K, Rimm EB, Stampfer MJ, Nelson PS, Han D, Rochon Y, Corthals GL, Lin B, Monson Willet WC, Giovannucci E. 2001. A prospective study on A, Nguyen V, Franza BR, Plymate SR, Aebersold R, intake of animal products and risk of prostate cancer.
Hood L. 2000. Comprehensive analyses of prostate gene expression: Convergence of expressed sequence tag Millar DS, Ow KK, Paul CL, Russell PJ, Molloy PL, Clark databases, transcript profiling and proteomics. Electro- SJ. 1999. Detailed methylation analysis of the glu- tathione S-transferase pi (GSTP1) gene in prostate Nelson CP, Kidd LC, Sauvageot J, Isaacs WB, De Marzo cancer [in process citation]. Oncogene 18:1313–1324.
AM, Groopman JD, Nelson WG, Kensler TW. 2001a.
Miller GJ. 1999. Prostate cancer among the Chinese: Protection against 2-hydroxyamino-1-methyl-6-phenyli- Pathological and epidemiological and nutritional con- midazo[4,5-b]pyridine cytotoxicity and DNA adduct for- siderations. In: Resnick MI, Thompson IM, editors. Ad- mation in human prostate by glutathione S-transferase vanced therapy of prostate disease. Hamilton, Ontario, Nelson WG, De Marzo AM, DeWeese TL. 2001b. The Mirchandani D, Zheng J, Miller GJ, Ghosh AK, Shibata molecular pathogenesis of prostate cancer: Implications DK, Cote RJ, Roy-Burman P. 1995. Heterogeneity in for prostate cancer prevention. Urology 57:39–45.
Nelson WG, De Marzo AM, Isaacs WB. 2003. Prostate Prescott JL, Blok L, Tindall DJ. 1998. Isolation and androgen regulation of the human homeobox cDNA, Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL.
Putzi MJ, De Marzo AM. 2000. Morphologic transitions 2001. Enhanced sensitivity of PTEN-deficient tumors to between proliferative inflammatory atrophy and high- inhibition of FRAP/mTOR. Proc Natl Acad Sci USA grade prostatic intraepithelial neoplasia. Urology 56: Newmark JR, Hardy DO, Tonb DC, Carter BS, Epstein JI, Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF, Isaacs WB, Brown TR, Barrack ER. 1992. Androgen Lieber MM, Jenkins RB. 1995. Chromosomal anomalies receptor gene mutations in human prostate cancer. Proc in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization. Cancer Nickel JC. 1994. Prostatic inflammation in benign prosta- tic hyperplasia—The third component? Can J Urol 1: Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR. 1999. Regulation of G1 Nickel JC, Downey J, Young I, Boag S. 1999. Asymptomatic progression by the PTEN tumor suppressor protein is inflammation and/or infection in benign prostatic hyper- linked to inhibition of the phosphatidylinositol 3-kinase/ Akt pathway. Proc Natl Acad Sci USA 96:2110–2115.
Norrish AE, Jackson RT, McRae CU. 1998. Non-steroidal Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto anti-inflammatory drugs and prostate cancer progres- M, Talalay P, Kensler TW. 2001. From the cover: Sensi- tivity to carcinogenesis is increased and chemoprotective Norrish AE, Ferguson LR, Knize MG, Felton JS, Sharpe SJ, efficacy of enzyme inducers is lost in nrf2 transcription Jackson RT. 1999. Heterocyclic amine content of cooked factor-deficient mice. Proc Natl Acad Sci USA 98:3410– meat and risk of prostate cancer. J Natl Cancer Inst 91: Reznik G, Hamlin MH II, Ward JM, Stinson SF. 1981.
O’Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg Prostatic hyperplasia and neoplasia in aging F344 rats.
AJ, Hong WK, Fabian CJ, Sigman CC, Bertagnolli MM, Stratton SP, Lam S, Nelson WG, Meyskens FL, Alberts Rich AR. 1934. On the frequency of occurrenec of occult DS, Follen M, Rustgi AK, Papadimitrakopoulou V, carcinoma of the prostate. J Urol 33:215–223.
Scardino PT, Gazdar AF, Wattenberg LW, Sporn MB, Roberts RO, Lieber MM, Rhodes T, Girman CJ, Bostwick Sakr WA, Lippman SM, Von Hoff DD. 2002. Treatment DG, Jacobsen SJ. 1998. Prevalence of a physician- and prevention of intraepithelial neoplasia: An impor- assigned diagnosis of prostatitis: The Olmsted county tant target for accelerated new agent development. Clin study of urinary symptoms and health status among Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert- Roberts RO, Jacobson DJ, Girman CJ, Rhodes T, Lieber Buck MR, Vocke CD, Linehan WM, Ferretti JA. 2001.
MM, Jacobsen SJ. 2002. A population-based study of Expression studies and mutational analysis of the daily nonsteroidal anti-inflammatory drug use and androgen regulated homeobox gene NKX3.1 in benign prostate cancer. Mayo Clin Proc 77:219–225.
and malignant prostate epithelium. J Urol 165:1329– Rubin MA, Zhou M, Dhanasekaran SM, Varambally S, Barrette TR, Sanda MG, Pienta KJ, Ghosh D, Chinnai- Parsons JK, Gage WR, Nelson WG, De Marzo AM. 2001a.
yan AM. 2002. Alpha-methylacyl coenzyme A racemase P63 protein expression is rare in prostate adenocarci- as a tissue biomarker for prostate cancer. JAMA 287: noma: Implications for cancer diagnosis and carcinogen- Ruijter ET, Miller GJ, van de Kaa CA, van Bokhoven A, Parsons JK, Nelson CP, Gage WR, Nelson WG, Kensler Bussemakers MJ, Debruyne FM, Ruiter DJ, Schalken TW, De Marzo AM. 2001b. GSTA1 expression in normal, JA. 1999. Molecular analysis of multifocal prostate preneoplastic, and neoplastic human prostate tissue.
cancer lesions. J Pathol 188:271–277.
Ruska KM, Sauvageot J, Epstein JI. 1998. Histology and Platt N, Gordon S. 2001. Is the class A macrophage scav- cellular kinetics of prostatic atrophy. Am J Surg Pathol enger receptor (SR-A) multifunctional?—The mouse’s Sadar MD, Gleave ME. 2000. Ligand-independent activa- Platz EA. 1998. Prostatitis and prostate cancer. New tion of the androgen receptor by the differentiation agent Developments in Prostate Cancer Treatment 3:71–73.
butyrate in human prostate cancer cells. Cancer Res Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD.
Parsons R. 1999. Mutation of Pten/Mmac1 in mice causes 1993. The frequency of carcinoma and intraepithelial neoplasia in multiple organ systems. Proc Natl Acad Sci neoplasia of the prostate in young male patients [see Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, BJ, Pontes JJ, Haas GP. 1994. High grade prostatic Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, intraepithelial neoplasia (HGPIN) and prostatic adeno- Hedrick-Ellenson L, Parsons R. 2001. An inhibitor of carcinoma between the ages of 20–69: An autopsy study mTOR reduces neoplasia and normalizes p70/S6 kinase activity in PtenÆ mice. Proc Natl Acad Sci USA 98: Schatteman PH, Hoekx L, Wyndaele JJ, Jeuris W, Van Marck E. 2000. Inflammation in prostate biopsies of men Pathological and Molecular Mechanisms of Prostate Carcinogenesis without prostatic malignancy or clinical prostatitis: Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian Correlation with total serum PSA and PSA density. Eur SV. 1997. Identification of a candidate tumour suppres- sor gene, MMAC1, at chromosome 10q23.3 that is Schmitz W, Albers C, Fingerhut R, Conzelmann E.
mutated in multiple advanced cancers. Nat Genet 1995. Purification and characterization of an alpha- methylacyl-CoA racemase from human liver. Eur J Strickler HD, Goedert JJ. 2001. Sexual behavior and evid- ence for an infectious cause of prostate cancer. Epidemiol Schoenberg MP, Hakimi JM, Wang S, Bova GS, Epstein JI, Fischbeck KH, Isaacs WB, Walsh PC, Barrack ER. 1994.
Stuart GR, Holcroft J, de Boer JG, Glickman BW.
Microsatellite mutation (CAG24 ! 18) in the androgen 2000. Prostate mutations in rats induced by the sus- receptor gene in human prostate cancer. Biochem Bio- pected human carcinogen 2-amino-1-methyl-6-phenyli- midazo[4,5-b]pyridine. Cancer Res 60:266–268.
Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, MM, Abate-Shen C. 1997. Tissue-specific expression of Gavrilova N, Mueller B, Liu X, Wu H. 1999. PTEN murine Nkx3.1 in the male urogenital system. Dev Dyn modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Shah R, Mucci NR, Amin A, Macoska JA, Rubin MA. 2001.
Akt/protein kinase B signaling pathway. Proc Natl Acad Postatrophic hyperplasia of the prostate gland: Neoplas- tic precursor or innocent bystander? Am J Pathol 158: Suzuki H, Sato N, Watabe Y, Masai M, Seino S, Shimazaki J. 1993. Androgen receptor gene mutations in human Shah RB, Zhou M, LeBlanc M, Snyder M, Rubin MA. 2002.
prostate cancer. J Steroid Biochem Mol Biol 46:759– Comparison of the basal cell-specific markers, 34betaE12 and p63, in the diagnosis of prostate cancer. Am J Surg Suzuki H, Akakura K, Komiya A, Aida S, Akimoto S, Shimazaki J. 1996. Codon 877 mutation in the androgen Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, receptor gene in advanced prostate cancer: Relation to Vogelstein B. 2001. Evidence that genetic instability antiandrogen withdrawal syndrome. Prostate 29:153– occurs at an early stage of colorectal tumorigenesis.
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Sidransky D, Isaacs WB, Bova GS. 1998. Interfocal Mack TM. 1991. Cancers of the prostate and breast heterogeneity of PTEN/MMAC1 gene alterations in among Japanese and white immigrants in Los Angeles multiple metastatic prostate cancer tissues. Cancer Res Shirai T, Sano M, Tamano S, Takahashi S, Hirose M, Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M, Futakuchi M, Hasegawa R, Imaida K, Matsumoto K, Gumerlock PH, deVere White RW, Pretlow TG, Harris Wakabayashi K, Sugimura T, Ito N. 1997. The prostate: SE, Wilson EM, Mohler JL, French FS. 1997. Dehydroe- A target for carcinogenicity of 2-amino-1-methyl-6-phe- piandrosterone activates mutant androgen receptors nylimidazo[4,5-b]pyridine (PhIP) derived from cooked expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocri- Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, Yang A, Montironi R, McKeon F, Loda M.
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner 2000. P63 is a prostate basal cell marker and is required AE, Ogata GK, Keer HN, Balk SP. 1995. Mutation of the for prostate development [in process citation]. Am androgen-receptor gene in metastatic androgen-indepen- dent prostate cancer. N Engl J Med 332:1393–1398.
Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB, Rajeshkumar B, Balk SP. 1999. Selection for androgen Scher HI, Rosen N. 2002. 17-Allylamino-17-demethox- receptor mutations in prostate cancers treated with ygeldanamycin induces the degradation of androgen androgen antagonist. Cancer Res 59:2511–2515.
receptor and HER-2/neu and inhibits the growth of Tchou JC, Lin X, Freije D, Isaacs WB, Brooks JD, Rashid A, prostate cancer xenografts. Clin Cancer Res 8:986–993.
De Marzo AM, Kanai Y, Hirohashi S, Nelson WG. 2000.
Sommerfeld HJ, Meeker AK, Piatyszek MA, Bova GS, Shay GSTP1 CpG island DNA hypermethylation in hepatocel- JW, Coffey DS. 1996. Telomerase activity: A prevalent lular carcinomas. Int J Oncol 16:663–676.
marker of malignant human prostate tissue. Cancer Res Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El- Stamey TA, Warrington JA, Caldwell MC, Chen Z, Fan Z, Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills Mahadevappa M, McNeal JE, Nolley R, Zhang Z. 2001.
GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Molecular genetic profiling of Gleason grade 4/5 prostate Yung WK, Fujii G, Berson A, Steck PA, et al. 1997.
cancers compared to benign prostatic hyperplasia. J Urol MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225.
Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP.
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller 2001. Prostatic intraepithelial neoplasia in mice expres- GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, sing an androgen receptor transgene in prostate epithe- Lippman SM, Carlin SM, Ryan A, Szczepanek CM, lium. Proc Natl Acad Sci USA 98:10823–10828.
Crowley JJ, Coltman CA, Jr. 2003. The influence of Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Finasteride on the development of prostate cancer. N Ligon AH, Langford LA, Baumgard ML, Hattier T, Tilley WD, Buchanan G, Hickey TE, Bentel JM. 1996.
shortening in human fibroblasts. Free Radic Biol Med Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen Vukovic B, Park PC, Al-Maghrabi J, Beheshti B, Sweet J, independence. Clin Cancer Res 2:277–285.
Evans A, Trachtenberg J, Squire J. 2003. Evidence of Torres-Rosado A, O’Shea KS, Tsuji A, Chou SH, Kurachi K.
multifocality of telomere erosion in high-grade prostatic 1993. Hepsin, a putative cell-surface serine protease, is intraepithelial neoplasia (HPIN) and concurrent carci- required for mammalian cell growth. Proc Natl Acad Sci Waghray A, Schober M, Feroze F, Yao F, Virgin J, Chen True LD, Berger RE, Rothman I, Ross SO, Krieger JN.
YQ. 2001. Identification of differentially expressed genes 1999. Prostate histopathology and the chronic prostatitis/ by serial analysis of gene expression in human prostate chronic pelvic pain syndrome: A prospective biopsy Walker MG, Volkmuth W, Sprinzak E, Hodgson D, Klingler Tsuji A, Torres-Rosado A, Arai T, Le Beau MM, Lemons RS, T. 1999. Prediction of gene function by genome-scale Chou SH, Kurachi K. 1991. Hepsin, a cell membrane- expression analysis: Prostate cancer-associated genes.
associated protease. Characterization, tissue distribu- tion, and gene localization. J Biol Chem 266:16948– Wang SI, Parsons R, Ittmann M. 1998. Homozygous deletion of the PTEN tumor suppressor gene in a subset Tsujimoto Y, Takayama H, Nonomura N, Okuyama A, of prostate adenocarcinomas. Clin Cancer Res 4:811– Aozasa K. 2002. Postatrophic hyperplasia of the prostate in Japan: Histologic and immunohistochemical features Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB, and p53 gene mutation analysis. Prostate 52:279–287.
Qian GS, Kuang SY, Zarba A, Egner PA, Jacobson van der Kwast TH, Schalken J, Ruizeveld de Winter JA, LP, Munoz A, Helzlsouer KJ, Groopman JD, Kensler van Vroonhoven CC, Mulder E, Boersma W, Trapman J.
TW. 1999. Protective alterations in phase 1 and 2 1991. Androgen receptors in endocrine-therapy-resistant metabolism of aflatoxin B1 by oltipraz in residents of human prostate cancer. Int J Cancer 48:189–193.
Qidong, People’s Republic of China. J Natl Cancer Inst van Leenders G, Dijkman H, Hulsbergen-van de Kaa C, Ruiter D, Schalken J. 2000. Demonstration of intermedi- Wechter WJ, Leipold DD, Murray ED, Jr., Quiggle D, ate cells during human prostate epithelial differentiation McCracken JD, Barrios RS, Greenberg NM. 2000. E-7869 in situ and in vitro using triple-staining confocal (R-flurbiprofen) inhibits progression of prostate cancer in scanning microscopy. Lab Invest 80:1251–1258.
the TRAMP mouse. Cancer Res 60:2203–2208.
Van Leenders GJ, Gage WR, Hicks JL, Van Balken B, Weinstein MH, Signoretti S, Loda M. 2002. Diagnostic Aalders TW, Schalken JA, De Marzo AM. 2003. Inter- utility of immunohistochemical staining for p63, a sensi- mediate cells in human prostate epithelium are enriched tive marker of prostatic basal cells. Mod Pathol 15:1302– in proliferative inflammatory atrophy. Am J Pathol 162: Welsh JB, Sapinoso LM, Su AI, Kern SG, Wang-Rodriguez Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, J, Moskaluk CA, Frierson HF, Jr., Hampton GM. 2001.
Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt Analysis of gene expression identifies candidate markers RG, Otte AP, Rubin MA, Chinnaiyan AM. 2002. The and pharmacological targets in prostate cancer. Cancer polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629.
Whittemore AS, Kolonel LN, Wu AH, John EM, Gallagher Veldscholte J, Voorhorst-Ogink MM, Bolt-de Vries J, van RP, Howe GR, Burch JD, Hankin J, Dreon DM, West Rooij HC, Trapman J, Mulder E. 1990. Unusual specifi- DW, et al. 1995. Prostate cancer in relation to diet, city of the androgen receptor in the human prostate physical activity, and body size in blacks, whites, and tumor cell line LNCaP: High affinity for progestagenic Asians in the United States and Canada. J Natl Cancer and estrogenic steroids. Biochim Biophys Acta 1052:187– Wilson MJ, Ditmanson JV, Sinha AA, Estensen RD. 1990.
Verhagen AP, Ramaekers FC, Aalders TW, Schaafsma HE, Plasminogen activator activities in the ventral and Debruyne FM, Schalken JA. 1992. Colocalization of basal dorsolateral prostatic lobes of aging Fischer 344 rats.
and luminal cell-type cytokeratins in human prostate Wu Q, Yu D, Post J, Halks-Miller M, Sadler JE, Morser J.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen 1998. Generation and characterization of mice deficient R, Palmberg C, Palotie A, Tammela T, Isola J, Kallio- in hepsin, a hepatic transmembrane serine protease.
niemi OP. 1995. In vivo amplification of the androgen receptor gene and progression of human prostate cancer.
Xia Y, Zweier JL. 1997. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macro- Vivanco I, Sawyers CL. 2002. The phosphatidylinositol phages. Proc Natl Acad Sci USA 94:6954–6958.
3-kinase AKT pathway in human cancer. Nat Rev Cancer Xu J, Stolk JA, Zhang X, Silva SJ, Houghton RL, Matsumura M, Vedvick TS, Leslie KB, Badaro R, Reed Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC, SG. 2000. Identification of differentially expressed genes Gelmann EP. 1997. Coding region of NKX3.1, a prostate- in human prostate cancer using subtraction and micro- specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Res 57:4455–4459.
Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu von Zglinicki T, Pilger R, Sitte N. 2000. Accumulation of JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing single-strand breaks is the major cause of telomere CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Pathological and Molecular Mechanisms of Prostate Carcinogenesis Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC, hepatocyte regeneration ability. Thromb Haemost 84: McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. 2002.
PC, Isaacs WB, Meyers DA. 2002a. Germline mutations Disruption of androgen receptor function inhibits pro- and sequence variants of the macrophage scavenger liferation of androgen-refractory prostate cancer cells.
receptor 1 gene are associated with prostate cancer risk.
Zha S, Gage WR, Sauvageot J, Saria EA, Putzi MJ, Ewing Xu J, Zheng SL, Turner A, Isaacs SD, Wiley KE, Hawkins CM, Faith DA, Nelson WG, De Marzo AM, Isaacs WB.
GA, Chang BL, Bleecker ER, Walsh PC, Meyers DA, 2001. Cyclooxygenase-2 is up-regulated in proliferative Isaacs WB. 2002b. Associations between hOGG1 se- inflammatory atrophy of the prostate, but not in prostate quence variants and prostate cancer susceptibility.
carcinoma. Cancer Res 61:8617–8623.
Zhang Y, Talalay P, Cho CG, Posner GH. 1992. A major Yaman O, Gogus C, Tulunay O, Tokatli Z, Ozden E. 2003.
inducer of anticarcinogenic protective enzymes from Increased prostate-specific antigen in subclinical prosta- broccoli: Isolation and elucidation of structure. Proc Natl titis: The role of aggressiveness and extension of in- Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P.
Yang RM, Naitoh J, Murphy M, Wang HJ, Phillipson J, 1994. Anticarcinogenic activities of sulforaphane and deKernion JB, Loda M, Reiter RE. 1998. Low p27 structurally related synthetic norbornyl isothiocyanates.
expression predicts poor disease-free survival in patients Proc Natl Acad Sci USA 91:3147–3150.
with prostate cancer. J Urol 159:941–945.
Zhou A, Paranjape J, Brown TL, Nie H, Naik S, Dong B, Yang XJ, Wu CL, Woda BA, Dresser K, Tretiakova M, Chang A, Trapp B, Fairchild R, Colmenares C, Silverman Fanger GR, Jiang Z. 2002. Expression of alpha-methyla- RH. 1997. Interferon action and apoptosis are defective in cyl-CoA racemase (P504S) in atypical adenomatous mice devoid of 20,50-oligoadenylate-dependent RNase L.
hyperplasia of the prostate. Am J Surg Pathol 26:921– Zhou M, Jiang Z, Epstein JI. 2003a. Expression and Yatani R, Chigusa I, Akazaki K, Stemmermann GN, Welsh diagnostic utility of alpha-methylacyl-CoA-racemase RA, Correa P. 1982. Geographic pathology of latent (P504S) in foamy gland and pseudohyperplastic prostate prostatic carcinoma. Int J Cancer 29:611–616.
cancer. Am J Surg Pathol 27:772–778.
Yu IS, Chen HJ, Lee YS, Huang PH, Lin SR, Tsai TW, Zhou M, Shah R, Shen R, Rubin MA. 2003b. Basal cell Lin SW. 2000. Mice deficient in hepsin, a serine pro- cocktail (34betaE12 þ p63) improves the detection of tease, exhibit normal embryogenesis and unchanged prostate basal cells. Am J Surg Pathol 27:365–371.

Source: http://demarzolab.pathology.jhmi.edu/docs/reprints/DeMarzo_J_Cell_Biochem_Review_2004.pdf