Demarzolab.pathology.jhmi.edu

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