Prostate cancer pathophysiology: Difference between revisions

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{{CMG}} {{AE}} {{sali}}
{{Prostate cancer}}
{{Prostate cancer}}
==Overview==
==Overview==
On [[microscopic]] [[histopathological]] analysis, increased [[gland]] density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of prostate cancer.
In [[prostate cancer]], the cells of these [[prostate glands]] mutate into [[cancer]] cells.The [[prostate gland]] require male [[hormones]], known as [[androgen]],to work properly. Androgens include [[testosterone]], which is made in the [[testes]], [[dehydroepiandrosterone]],made in the [[adrenal gland]]; and [[dihydrotestosterone]], which is converted from [[testosterone]] within the [[prostate]] itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased [[muscle]] [[mass]]. [[Prostate cancer]] is classified as an [[adenocarcinoma]], or [[glandular cancer]], that begins when normal [[semen]] screening [[prostate gland]] cells mutate into [[cancer]] cells. On [[microscopic]] [[histopathological]] analysis, increased [[gland]] density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of [[prostate]] cancer. [[Androgen]] is required to activate a sufficient number of androgen receptors so that [[transcription]] of death-signaling gene is expressed. Multiple genes like RNASEL, MSR1, AR, CYP17, SRD5A2, ZIP1, RUNX2 is involved in pathogenesis.


==Pathogenesis==
==Pathogenesis==


*Prostate cancers can be lethal because they heterogeneously contain both androgen-dependent and androgen-independent malignant cells<ref name="pmid8602401">{{cite journal |vauthors=Denmeade SR, Lin XS, Isaacs JT |title=Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer |journal=Prostate |volume=28 |issue=4 |pages=251–65 |date=April 1996 |pmid=8602401 |doi=10.1002/(SICI)1097-0045(199604)28:4<251::AID-PROS6>3.0.CO;2-G |url=}}</ref>  
*[[Prostate]] cancers can be lethal because they heterogeneously contain both [[androgen]]-dependent and [[androgen]]-independent [[malignant]] cells<ref name="pmid8602401">{{cite journal |vauthors=Denmeade SR, Lin XS, Isaacs JT |title=Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer |journal=Prostate |volume=28 |issue=4 |pages=251–65 |date=April 1996 |pmid=8602401 |doi=10.1002/(SICI)1097-0045(199604)28:4<251::AID-PROS6>3.0.CO;2-G |url=}}</ref>  
*For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs) so that transcription of death-signaling genes is expressed  
*For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of [[androgen]] [[receptors]] (ARs) so that [[transcription]] of death-signaling [[gene]] is expressed  
*Androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death  
*[[Androgens]] are capable of both stimulating proliferation as well as inhibiting the rate of the glandular [[epithelial cell]] death  
*Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelia and androgen-dependent prostate cancer cells
*Androgen withdrawal triggers the programmed [[cell death]] pathway in both normal prostate glandular [[epithelial]] and androgen-dependent prostate cancer cells
*Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents
*[[Androgen]]-independent prostate [[cancer]] cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the [[cellular]] machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents


==Inherited Prostate-Cancer–Susceptibility Genes==
==Inherited Prostate-Cancer–Susceptibility Genes==


*Rare autosomal dominant alleles account for a substantial proportion of cases of inherited, early-onset prostate cancer (defined as cancer occurring before 55 years of age)<ref name="pmid1565627">{{cite journal |vauthors=Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC |title=Mendelian inheritance of familial prostate cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue=8 |pages=3367–71 |date=April 1992 |pmid=1565627 |pmc=48868 |doi= |url=}}</ref>
*Rare [[autosomal dominant]] [[alleles]] account for a substantial proportion of cases of inherited, early-onset [[prostate]] cancer (defined as cancer occurring before 55 years of age)<ref name="pmid1565627">{{cite journal |vauthors=Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC |title=Mendelian inheritance of familial prostate cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue=8 |pages=3367–71 |date=April 1992 |pmid=1565627 |pmc=48868 |doi= |url=}}</ref>
*In families with men in whom prostate cancer is diagnosed at an older age, an X-linked allele may be responsible <ref name="pmid11309686">{{cite journal |vauthors=Cui J, Staples MP, Hopper JL, English DR, McCredie MR, Giles GG |title=Segregation analyses of 1,476 population-based Australian families affected by prostate cancer |journal=Am. J. Hum. Genet. |volume=68 |issue=5 |pages=1207–18 |date=May 2001 |pmid=11309686 |pmc=1226101 |doi=10.1086/320114 |url=}}</ref>
*In families with men in whom [[prostate]] cancer is diagnosed at an older age, an X-linked allele may be responsible.<ref name="pmid11309686">{{cite journal |vauthors=Cui J, Staples MP, Hopper JL, English DR, McCredie MR, Giles GG |title=Segregation analyses of 1,476 population-based Australian families affected by prostate cancer |journal=Am. J. Hum. Genet. |volume=68 |issue=5 |pages=1207–18 |date=May 2001 |pmid=11309686 |pmc=1226101 |doi=10.1086/320114 |url=}}</ref>
*The first molecular genetic study of familial prostate cancer in which polymorphic markers were used identified several regions of linkage; the chromosomal region 1q24–25, designated the locus of the hereditary prostate cancer (HPC1) gene, has been the most thoroughly investigated<ref name="pmid8910276">{{cite journal |vauthors=Smith JR, Freije D, Carpten JD, Grönberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB |title=Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search |journal=Science |volume=274 |issue=5291 |pages=1371–4 |date=November 1996 |pmid=8910276 |doi= |url=}}</ref>
*The first molecular [[genetic]] study of [[familial]] prostate cancer in which [[polymorphic]] markers were used identified several regions of linkage; the chromosomal region 1q24–25, designated the locus of the hereditary [[prostate]] cancer (HPC1) gene, has been the most thoroughly investigated<ref name="pmid8910276">{{cite journal |vauthors=Smith JR, Freije D, Carpten JD, Grönberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB |title=Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search |journal=Science |volume=274 |issue=5291 |pages=1371–4 |date=November 1996 |pmid=8910276 |doi= |url=}}</ref>
*Some analyses have confirmed a link between HPC1 and prostate cancer, but others have failed to detect an association<ref name="pmid11067781">{{cite journal |vauthors=Ostrander EA, Stanford JL |title=Genetics of prostate cancer: too many loci, too few genes |journal=Am. J. Hum. Genet. |volume=67 |issue=6 |pages=1367–75 |date=December 2000 |pmid=11067781 |pmc=1287913 |doi=10.1086/316916 |url=}}</ref>
*Some analyses have confirmed a link between HPC1 and [[prostate]] cancer, but others have failed to detect an association<ref name="pmid11067781">{{cite journal |vauthors=Ostrander EA, Stanford JL |title=Genetics of prostate cancer: too many loci, too few genes |journal=Am. J. Hum. Genet. |volume=67 |issue=6 |pages=1367–75 |date=December 2000 |pmid=11067781 |pmc=1287913 |doi=10.1086/316916 |url=}}</ref>


==RNASEL==
==RNASEL==
*The RNASEL gene encodes a widely expressed latent endoribonuclease that participates in an interferon-inducible RNA-decay pathway that is thought to degrade viral and cellular RNA.56-60
*The [[RNASEL]] [[gene]] encodes a widely expressed latent [[endoribonuclease]] that participates in an [[interferon]]-inducible [[RNA-decay pathway]] that is thought to degrade [[viral]] and [[cellular]] [[RNA]]<ref name="pmid3366783">{{cite journal |vauthors=Silverman RH, Jung DD, Nolan-Sorden NL, Dieffenbach CW, Kedar VP, SenGupta DN |title=Purification and analysis of murine 2-5A-dependent RNase |journal=J. Biol. Chem. |volume=263 |issue=15 |pages=7336–41 |date=May 1988 |pmid=3366783 |doi= |url=}}</ref>
*RNASEL has been linked to HPC1.61 In one family, four brothers with prostate cancer carried a disabling mutation of RNASEL, and in another family, four of six brothers with prostate cancer carried a base substitution affecting the RNASEL initiator methionine codon.61
*[[RNASEL]] has been linked to [[HPC1]]. In one family, four brothers with prostate cancer carried a disabling [[mutation]] of [[RNASEL]], and in another family, four of six brothers with prostate cancer carried a base substitution affecting the [[RNASEL]] initiator [[methionine]] [[codon]]<ref name="pmid11799394">{{cite journal |vauthors=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, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Grönberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J |title=Germline mutations in the ribonuclease L gene in families showing linkage with HPC1 |journal=Nat. Genet. |volume=30 |issue=2 |pages=181–4 |date=February 2002 |pmid=11799394 |doi=10.1038/ng823 |url=}}</ref>
*In preliminary population studies, the RNASEL allele with a termination codon at amino acid position 265 was found in 0.54 percent of unaffected white men, and the allele with the defective initiator methionine codon was not detected in any unaffected men.61
*The RNASEL allele with a termination codon at amino acid position 265 was also detected in 4.3 percent of Finnish men with familial prostate cancer and only 1.8 percent of control men.62
*Another study identified a mutant RNASEL allele, with a deletion at codon 157, in an Ashkenazi Jewish population; this allele was present in 6.9 percent of the men with prostate cancer and 2.9 percent of the elderly men without prostate cancer.63
*An increased risk of prostate cancer was also associated with yet another mutant RNASEL allele that encodes a less active enzyme.64
*A single study failed to detect any association between RNASEL alleles with inactivating mutations and prostate cancer.65


==MSR1==
==MSR1==
*The macrophage-scavenger receptor 1 (MSR1) gene, located at 8p22, has also emerged as a candidate prostate-cancer–susceptibility gene.66 It encodes subunits of a macrophage-scavenger receptor that is capable of binding a variety of ligands, including bacterial lipopolysaccharide and lipoteichoic acid, and oxidized high-density lipoprotein and low-density lipoprotein in the serum.67 Germ-line MSR1 mutations have been linked to prostate cancer in some families with hereditary prostate cancer, and one mutant MSR1 allele has been detected in approximately 3 percent of men with nonhereditary prostate cancer but only 0.4 percent of unaffected men (P=0.05).66,68 Expression of MSR1 appears to be restricted to macrophages in the prostate that are abundant at sites of inflammation.
*The [[macrophage-scavenger receptor 1]] (MSR1) gene, located at [[8p22]], has also emerged as a candidate [[prostate]]-[[cancer]]–susceptibility [[gene]]<ref name="pmid12244320">{{cite journal |vauthors=Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC, McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh PC, Isaacs WB, Meyers DA |title=Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk |journal=Nat. Genet. |volume=32 |issue=2 |pages=321–5 |date=October 2002 |pmid=12244320 |doi=10.1038/ng994 |url=}}</ref>
*It encodes subunits of a [[macrophage-scavenger receptor]] that is capable of binding a variety of ligands, including bacterial [[lipopolysaccharide]] and [[lipoteichoic acid]], and oxidized high-density [[lipoprotein]] and [[low-density lipoprotein]] in the serum<ref name="pmid11544267">{{cite journal |vauthors=Platt N, Gordon S |title=Is the class A macrophage scavenger receptor (SR-A) multifunctional? - The mouse's tale |journal=J. Clin. Invest. |volume=108 |issue=5 |pages=649–54 |date=September 2001 |pmid=11544267 |pmc=209390 |doi=10.1172/JCI13903 |url=}}</ref>
*[[Germ-line]] [[MSR1]] [[mutations]] have been linked to prostate cancer in some families with [[hereditary]] prostate cancer, and one [[mutant]] MSR1 [[allele]] has been detected in approximately 3 percent of men with non-hereditary prostate cancer but only 0.4 percent of unaffected men (P=0.05)<ref name="pmid8349824">{{cite journal |vauthors=Dejager S, Mietus-Snyder M, Friera A, Pitas RE |title=Dominant negative mutations of the scavenger receptor. Native receptor inactivation by expression of truncated variants |journal=J. Clin. Invest. |volume=92 |issue=2 |pages=894–902 |date=August 1993 |pmid=8349824 |pmc=294928 |doi=10.1172/JCI116664 |url=}}</ref>


==AR, CYP17, AND SRD5A2==
==AR, CYP17, AND SRD5A2==


*Polymorphic variants of three genes involved in androgen action, the androgen-receptor (AR) gene, the cytochrome P-450c17 (CYP17) gene, and the steroid-5-α-reductase type II (SRD5A2) gene, have been implicated in modifying the risk of prostate cancer in genetic epidemiologic studies. In the case of AR, which encodes the androgen receptor, polymorphic polyglutamine (CAG) repeats have been described.69 Functional studies have suggested that shorter polyglutamine repeats may be associated with increased androgen-receptor transcriptional transactivation activity.70-73 Black Americans, who have a relatively high risk of prostate cancer, tend to have shorter androgen-receptor polyglutamine repeats, whereas Asians, who have a relatively low risk of prostate cancer, tend to have longer androgen-receptor polyglutamine repeats. Several genetic epidemiologic studies have shown a correlation between an increased risk of prostate cancer and the presence of short androgen-receptor polyglutamine repeats, but other studies have failed to detect such a correlation.74-80 Polymorphic polyglycine (GGC) repeats are also characteristic of AR and may also influence the risk of prostate cancer.76,79-81
*[[Polymorphic]] [[variants]] of three [[genes]] involved in [[androgen]] action, the androgen-receptor (AR) [[gene]], the [[cytochrome]] P-450c17 (CYP17) [[gene]], and the steroid-5-α-reductase type II (SRD5A2) gene, have been implicated in modifying the risk of [[prostate cancer]] in genetic epidemiologic studies. In the case of AR, which encodes the [[androgen receptor]], polymorphic polyglutamine (CAG) repeats have been described<ref name="pmid1740333">{{cite journal |vauthors=Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R |title=Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups |journal=Genomics |volume=12 |issue=2 |pages=241–53 |date=February 1992 |pmid=1740333 |doi= |url=}}</ref>
*CYP17 encodes cytochrome P-450c17α, an enzyme that catalyzes key reactions in sex-steroid biosynthesis. A variant CYP17 allele has been subjected to both population and genetic-linkage analyses to determine its association with prostate cancer, with inconsistent results.75,82-88 However, linkage data suggest that another variant CYP17 allele is associated with prostate cancer.89
*Functional studies have suggested that shorter [[polyglutamine]] [[repeats]] may be associated with increased [[androgen]]-receptor [[transcriptional]] [[transactivation]] activity<ref name="pmid8065934">{{cite journal |vauthors=Chamberlain NL, Driver ED, Miesfeld RL |title=The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function |journal=Nucleic Acids Res. |volume=22 |issue=15 |pages=3181–6 |date=August 1994 |pmid=8065934 |pmc=310294 |doi= |url=}}</ref>
*SRD5A2 encodes the predominant isozyme of 5-α-reductase in the prostate, an enzyme that converts testosterone to the more potent dihydrotestosterone. Two common polymorphic variant SRD5A2 alleles have been described.90,91 The alleles that encode enzymes with increased activity have been associated with an increased risk of prostate cancer and with a poor prognosis for men with prostate cancer.90,92 In addition to AR, CYP17, and SRD5A2, polymorphic variants of a number of other genes have been proposed as possible contributors to the risk of prostate cancer.93
*Black Americans, who have a relatively high risk of [[prostate]] [[cancer]], tend to have shorter androgen-receptor [[polyglutamine]] repeats, whereas Asians, who have a relatively low risk of [[prostate]] [[cancer]], tend to have longer [[androgen]]-receptor [[polyglutamine]] repeats. Several genetic epidemiologic studies have shown a correlation between an increased risk of [[prostate cancer]] and the presence of short [[androgen]]-receptor [[polyglutamine repeats]], but other studies have failed to detect such a correlation<ref name="pmid12202660">{{cite journal |vauthors=Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, Johnson ME, Montgomery JS, Cude K, Brockbank JC, Sartor O, Figg WD |title=Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status |journal=J. Clin. Oncol. |volume=20 |issue=17 |pages=3599–604 |date=September 2002 |pmid=12202660 |doi=10.1200/JCO.2002.11.085 |url=}}</ref>
 
*[[Polymorphic polyglycine]] (GGC) repeats are also characteristic of AR and may also influence the risk of [[prostate]] [[cancer]]<ref name="pmid7728763">{{cite journal |vauthors=Irvine RA, Yu MC, Ross RK, Coetzee GA |title=The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer |journal=Cancer Res. |volume=55 |issue=9 |pages=1937–40 |date=May 1995 |pmid=7728763 |doi= |url=}}</ref>
==GENETIC SUSCEPTIBILITY TO PROSTATE CANCER==
*[[CYP17]] encodes [[cytochrome]] [[P-450c17α]], an [[enzyme]] that catalyzes key reactions in sex-[[steroid]] [[biosynthesis]]. A variant [[CYP17]] [[allele]] has been subjected to both population and genetic-linkage analyses to determine its association with [[prostate]] [[cancer]], with inconsistent results<ref name="pmid11440959">{{cite journal |vauthors=Haiman CA, Stampfer MJ, Giovannucci E, Ma J, Decalo NE, Kantoff PW, Hunter DJ |title=The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer |journal=Cancer Epidemiol. Biomarkers Prev. |volume=10 |issue=7 |pages=743–8 |date=July 2001 |pmid=11440959 |doi= |url=}}</ref>
*[[SRD5A2]] encodes the predominant [[isozyme]] of [[5-α-reductase]] in the [[prostate]], an [[enzyme]] that converts [[testosterone]] to the more potent [[dihydrotestosterone]]. Two common [[polymorphic]] variant SRD5A2 alleles have been described<ref name="pmid11164181">{{cite journal |vauthors=Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA |title=V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression |journal=Urology |volume=57 |issue=1 |pages=199–204 |date=January 2001 |pmid=11164181 |doi= |url=}}</ref>
*The [[alleles]] that encode enzymes with increased activity have been associated with an increased risk of prostate cancer and with a poor prognosis for men with [[prostate cancer]]<ref name="pmid11164181">{{cite journal |vauthors=Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA |title=V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression |journal=Urology |volume=57 |issue=1 |pages=199–204 |date=January 2001 |pmid=11164181 |doi= |url=}}</ref>


*As we have seen, the genetics of the prostate have proved difficult to study. Prostate cancer, once generally diagnosed at an advanced stage in older men, is now more often detected at an early stage in younger men as a consequence of more widespread screening for the disease. This trend toward earlier diagnosis of prostate cancer has most likely changed the definition of a “case” of cancer, since many men who would have qualified as controls in previous genetic and epidemiologic studies are now known to have prostate cancer as a result of PSA screening. Despite these limitations, genetic studies have provided remarkable clues to the causes of prostate cancer. For example, in addition to the expected role of androgens in facilitating the development of prostate cancer, the possibility that viral or bacterial infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate-cancer genes — an insight that will profoundly affect future studies of the etiology of prostate cancer and may ultimately lead to new approaches to the prevention of prostate cancer (Table 1).61,66,67,94
* [[Prostate cancer]] is classified as an [[adenocarcinoma]], or [[glandular]] cancer. The region of prostate gland where the [[adenocarcinoma]] is most common is the peripheral zone.<ref>{{cite web|title=Prostate Cancer|url=http://www.cancer.gov/cancertopics/types/prostate|website=National Cancer Institute|accessdate=12 October 2014}}</ref>  
* Prostate cancer is classified as an [[adenocarcinoma]], or [[glandular]] cancer. The region of prostate gland where the [[adenocarcinoma]] is most common is the peripheral zone.<ref>{{cite web|title=Prostate Cancer|url=http://www.cancer.gov/cancertopics/types/prostate|website=National Cancer Institute|accessdate=12 October 2014}}</ref>  


* Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as [[carcinoma in situ]] or [[prostatic intraepithelial neoplasia]] (PIN).<ref name='metastasis-route'>{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  
* Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as [[carcinoma in situ]] or [[prostatic intraepithelial neoplasia]] (PIN).<ref name="metastasis-route">{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  


* Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time these cancer cells begin to multiply and spread to the surrounding prostate tissue (the [[stroma]]) forming a [[tumor]].<ref name='metastasis-route'>{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  
* Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time these cancer cells begin to multiply and spread to the surrounding prostate tissue (the [[stroma]]) forming a [[tumor]].<ref name="metastasis-route">{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  


* Eventually, the [[tumor]] may grow large enough to invade nearby [[organs]] such as the [[seminal vesicles]] or the [[rectum]], or the tumor cells may develop the ability to travel in the [[blood stream]] and [[lymphatic system]].<ref name='metastasis-route'>{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  
* Eventually, the [[tumor]] may grow large enough to invade nearby [[organs]] such as the [[seminal vesicles]] or the [[rectum]], or the tumor cells may develop the ability to travel in the [[blood stream]] and [[lymphatic system]].<ref name="metastasis-route">{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>  


* Prostate cancer is considered a [[malignant]] tumor because it is a [[mass]] of [[cells]] which can invade other parts of the body. This invasion of other organs is called [[metastasis]]. Prostate cancer most commonly metastasizes to the [[bone]]s, [[lymph node]]s, [[rectum]], and [[bladder]].<ref name='metastasis-route'>{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>
* Prostate cancer is considered a [[malignant]] tumor because it is a [[mass]] of [[cells]] which can invade other parts of the body. This invasion of other organs is called [[metastasis]]. Prostate cancer most commonly metastasizes to the [[bone]]s, [[lymph node]]s, [[rectum]], and [[bladder]].<ref name="metastasis-route">{{cite web | url = http://www.med-ed.virginia.edu/courses/path/gu/prostate3.cfm | title = Male Genitals - Prostate Neoplasms | accessdate = 2011-04-28 | work = Pathology study images | publisher = University of Virginia School of Medicine | archiveurl = http://www.webcitation.org/5yHQ19Rrp | archivedate = 2011-04-28 | quote = There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.}}</ref>
[[Image:Normal cancer cell division from NIH-2.png|thumb|left|When normal cells are damaged beyond repair, they are eliminated by [[apoptosis]]. Cancer cells avoid apoptosis and continue to multiply in an unregulated manner.]]
<br clear="center" />
<br clear="left"/>
*[[Prostate gland]] is a [[zinc]]-accumulating, [[citrate]]-producing organ<ref>{{cite journal|doi=10.9790/0853-1506020411}}</ref>
*Prostate gland is a zinc-accumulating, citrate-producing organ<ref>{{cite journal|doi=10.9790/0853-1506020411}}</ref>
*The [[protein ZIP1]] is required for the active transport of [[zinc]] into [[prostate]] cells  
*The protein ZIP1 is required for the active transport of zinc into prostate cells  
*[[Zinc]] have important role to change the [[metabolism]] of the cell in order to produce [[citrate]], an important component of [[semen]].
*Zinc have important role to change the metabolism of the cell in order to produce citrate, an important component of semen  
*The process of [[zinc]] accumulation and [[citrate]] production is energy inefficient and prostate cells sacrifice enormous of [[energy]] [[(ATP)]] in order to complete this task.  
*The process of zinc accumulation and citrate production is energy inefficient and prostate cells sacrifice enormous of energy (ATP) in order to complete this task.  
*[[Prostate cancer]] cells are generally devoid of zinc. This allows prostate cancer cells to save energy not making citrate, and utilize the new abundance of energy to grow and spread.
*Prostate cancer cells are generally devoid of zinc. This allows prostate cancer cells to save energy not making citrate, and utilize the new abundance of energy to grow and spread
*The absence of [[zinc]] is thought to occur via a silencing of the [[gene]] that producing the [[transporter protein ZIP1]].
*The absence of zinc is thought to occur via a silencing of the gene that producing the transporter protein ZIP1
*[[ZIP1]] is now called a [[tumor suppressor gene]] product for the [[gene]] [[SLC39A1]].The cause of [[epigenetic silencing]] is unknown.
*ZIP1 is now called a tumor suppressor gene product for the gene SLC39A1.The cause of epigenetic silencing is unknown
*[[Zinc]] inhibits [[BF-kB]] pathways, is anti-proliferative,and induces [[apoptosis]] in abnormal cells.
*Zinc inhibits BF-kB pathways, Is anti- proliferative,and induces apoptosis in abnormal cells
*Unfortunately, oral ingestion of [[zinc]] is not effective because high concentrations of [[zinc]] into prostate cells is not possible without the active transporter [[ZIP1]].
*Unfortunately, oral ingestion of zinc is not effective because high concentrations of zinc into prostate cells is not possible without the active transporter ZIP1
*[[RUNX2]] is a transcription factor that prevents the cancer cells from undergoing [[apoptosis]] thereby contributing to the development of [[prostate cancer]].
*RUNX2 is a transcription factor that prevents the cancer cells from undergoing apoptosis thereby contributing to the development of prostate cancer
*The [[androgen]] receptor helps prostate cancer cells to survive and is a target for many anticancer research studies; so far, inhibiting androgen receptor.
*The androgen receptor helps prostate cancer cells to survive and is a target for many anticancer research studies; so far, inhibiting androgen receptor  
*[[Prostate specific membrane antigen]](PSMA) stimulates the development of prostate cancer by increasing [[folate]] levels for cancer cells to use to survive and grow.
*Prostate specific membrane antigen(PSMA) stimulates the development of prostate cancer by increasing folate levels for cancer cells to use to survive and grow
*PSMA increases available [[folate]] for use by [[hydrolyzing]] [[glutamate]] [[folate]].
*PSMA increases available folates for use by hydrolyzing glutamate folate


==Gross Pathology==
==Gross Pathology==
Prostate cancer is uncommonly apparent on gross.<ref name=radio> Prostatic carcinoma.Dr Ian Bickle and Dr Saqba Farooq et al.  Radiopaedia.org 2015.http://radiopaedia.org/articles/prostatic-carcinoma-1</ref>
[[Prostate]] [[cancer]] is uncommonly apparent on gross.<ref name="radio">Prostatic carcinoma.Dr Ian Bickle and Dr Saqba Farooq et al.  Radiopaedia.org 2015.http://radiopaedia.org/articles/prostatic-carcinoma-1</ref>


==Microscopic Pathology==
==Microscopic Pathology==
'''Major criteria''':<ref name=pmid17213347>{{cite journal |author=Humphrey PA |title=Diagnosis of adenocarcinoma in prostate needle biopsy tissue |journal=J. Clin. Pathol. |volume=60 |issue=1 |pages=35–42 |year=2007 |month=January |pmid=17213347 |pmc=1860598 |doi=10.1136/jcp.2005.036442 |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860598/?tool=pubmed}}</ref><ref>{{Cite web | title =Prostate cancer.Libre pathology 2015| url =http://librepathology.org/wiki/index.php/Prostate_cancer#Microscopic }}</ref>
'''Major criteria''':<ref name="pmid17213347">{{cite journal |author=Humphrey PA |title=Diagnosis of adenocarcinoma in prostate needle biopsy tissue |journal=J. Clin. Pathol. |volume=60 |issue=1 |pages=35–42 |year=2007 |month=January |pmid=17213347 |pmc=1860598 |doi=10.1136/jcp.2005.036442 |url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860598/?tool=pubmed}}</ref><ref>{{Cite web | title =Prostate cancer.Libre pathology 2015| url =http://librepathology.org/wiki/index.php/Prostate_cancer#Microscopic }}</ref>


* Architecture
* Architecture
Line 79: Line 77:
* Basal cells lacking
* Basal cells lacking


* Cytological abnormalities:
* [[Cytological]] abnormalities:
:* [[Nuclear]] enlargement (subtle)
:* [[Nuclear]] enlargement (subtle)
:* [[Nucleoli]] (prominent)
:* [[Nucleoli]] (prominent)
Line 87: Line 85:
*Wispy blue mucin
*Wispy blue mucin
*Pink [[amorphous]] secretions
*Pink [[amorphous]] secretions
*Intraluminal crystalloid
*[[Intraluminal]] crystalloid
*Amphophilic [[cytoplasm]]
*Amphophilic [[cytoplasm]]
*Adjacent High-grade [[prostatic intraepithelial neoplasia]] (HGPIN)
*Adjacent High-grade [[prostatic intraepithelial neoplasia]] (HGPIN)

Latest revision as of 23:39, 24 May 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

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Overview

In prostate cancer, the cells of these prostate glands mutate into cancer cells.The prostate gland require male hormones, known as androgen,to work properly. Androgens include testosterone, which is made in the testes, dehydroepiandrosterone,made in the adrenal gland; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass. Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen screening prostate gland cells mutate into cancer cells. On microscopic histopathological analysis, increased gland density, small circular glands, basal cells lacking, and cytological abnormalities are characteristic findings of prostate cancer. Androgen is required to activate a sufficient number of androgen receptors so that transcription of death-signaling gene is expressed. Multiple genes like RNASEL, MSR1, AR, CYP17, SRD5A2, ZIP1, RUNX2 is involved in pathogenesis.

Pathogenesis

  • Prostate cancers can be lethal because they heterogeneously contain both androgen-dependent and androgen-independent malignant cells[1]
  • For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs) so that transcription of death-signaling gene is expressed
  • Androgens are capable of both stimulating proliferation as well as inhibiting the rate of the glandular epithelial cell death
  • Androgen withdrawal triggers the programmed cell death pathway in both normal prostate glandular epithelial and androgen-dependent prostate cancer cells
  • Androgen-independent prostate cancer cells do not initiate the programmed cell death pathway upon androgen ablation; however, they do retain the cellular machinery necessary to activate the programmed cell death cascade when sufficiently damaged by exogenous agents

Inherited Prostate-Cancer–Susceptibility Genes

  • Rare autosomal dominant alleles account for a substantial proportion of cases of inherited, early-onset prostate cancer (defined as cancer occurring before 55 years of age)[2]
  • In families with men in whom prostate cancer is diagnosed at an older age, an X-linked allele may be responsible.[3]
  • The first molecular genetic study of familial prostate cancer in which polymorphic markers were used identified several regions of linkage; the chromosomal region 1q24–25, designated the locus of the hereditary prostate cancer (HPC1) gene, has been the most thoroughly investigated[4]
  • Some analyses have confirmed a link between HPC1 and prostate cancer, but others have failed to detect an association[5]

RNASEL

MSR1

AR, CYP17, AND SRD5A2

  • Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time these cancer cells begin to multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor.[18]


Gross Pathology

Prostate cancer is uncommonly apparent on gross.[20]

Microscopic Pathology

Major criteria:[21][22]

  • Architecture
  • Increased gland density
  • Small circular glands
  • In rare subtypes - large branching glands
  • Basal cells lacking

Minor criteria:

Prostate adenocarcinoma: Microscopic View

{{#ev:youtube|1SZPLS1dxTo}}

Gleason score

Prostate: Adenocarcinoma (Gleason grade 1)

{{#ev:youtube|F7V0Zl7a2FY}}

Prostate: Adenocarcinoma (Gleason grade 2)

{{#ev:youtube|YSOLiSklIXw}}

Prostate: Adenocarcinoma (Gleason grade 3)

{{#ev:youtube|TG8vR_pE7yA}}

Prostate: Adenocarcinoma (Gleason grade 4)

{{#ev:youtube|R2Cl4HScdGc}}

Prostate: Adenocarcinoma (Gleason grade 5)

{{#ev:youtube|F7V0Zl7a2FY}}

References

  1. ↑ Denmeade SR, Lin XS, Isaacs JT (April 1996). "Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer". Prostate. 28 (4): 251–65. doi:10.1002/(SICI)1097-0045(199604)28:4<251::AID-PROS6>3.0.CO;2-G. PMID 8602401.
  2. ↑ Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC (April 1992). "Mendelian inheritance of familial prostate cancer". Proc. Natl. Acad. Sci. U.S.A. 89 (8): 3367–71. PMC 48868. PMID 1565627.
  3. ↑ Cui J, Staples MP, Hopper JL, English DR, McCredie MR, Giles GG (May 2001). "Segregation analyses of 1,476 population-based Australian families affected by prostate cancer". Am. J. Hum. Genet. 68 (5): 1207–18. doi:10.1086/320114. PMC 1226101. PMID 11309686.
  4. ↑ Smith JR, Freije D, Carpten JD, Grönberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB (November 1996). "Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search". Science. 274 (5291): 1371–4. PMID 8910276.
  5. ↑ Ostrander EA, Stanford JL (December 2000). "Genetics of prostate cancer: too many loci, too few genes". Am. J. Hum. Genet. 67 (6): 1367–75. doi:10.1086/316916. PMC 1287913. PMID 11067781.
  6. ↑ Silverman RH, Jung DD, Nolan-Sorden NL, Dieffenbach CW, Kedar VP, SenGupta DN (May 1988). "Purification and analysis of murine 2-5A-dependent RNase". J. Biol. Chem. 263 (15): 7336–41. PMID 3366783.
  7. ↑ 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, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Grönberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J (February 2002). "Germline mutations in the ribonuclease L gene in families showing linkage with HPC1". Nat. Genet. 30 (2): 181–4. doi:10.1038/ng823. PMID 11799394.
  8. ↑ Xu J, Zheng SL, Komiya A, Mychaleckyj JC, Isaacs SD, Hu JJ, Sterling D, Lange EM, Hawkins GA, Turner A, Ewing CM, Faith DA, Johnson JR, Suzuki H, Bujnovszky P, Wiley KE, DeMarzo AM, Bova GS, Chang B, Hall MC, McCullough DL, Partin AW, Kassabian VS, Carpten JD, Bailey-Wilson JE, Trent JM, Ohar J, Bleecker ER, Walsh PC, Isaacs WB, Meyers DA (October 2002). "Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk". Nat. Genet. 32 (2): 321–5. doi:10.1038/ng994. PMID 12244320.
  9. ↑ Platt N, Gordon S (September 2001). "Is the class A macrophage scavenger receptor (SR-A) multifunctional? - The mouse's tale". J. Clin. Invest. 108 (5): 649–54. doi:10.1172/JCI13903. PMC 209390. PMID 11544267.
  10. ↑ Dejager S, Mietus-Snyder M, Friera A, Pitas RE (August 1993). "Dominant negative mutations of the scavenger receptor. Native receptor inactivation by expression of truncated variants". J. Clin. Invest. 92 (2): 894–902. doi:10.1172/JCI116664. PMC 294928. PMID 8349824.
  11. ↑ Edwards A, Hammond HA, Jin L, Caskey CT, Chakraborty R (February 1992). "Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups". Genomics. 12 (2): 241–53. PMID 1740333.
  12. ↑ Chamberlain NL, Driver ED, Miesfeld RL (August 1994). "The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function". Nucleic Acids Res. 22 (15): 3181–6. PMC 310294. PMID 8065934.
  13. ↑ Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, Johnson ME, Montgomery JS, Cude K, Brockbank JC, Sartor O, Figg WD (September 2002). "Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status". J. Clin. Oncol. 20 (17): 3599–604. doi:10.1200/JCO.2002.11.085. PMID 12202660.
  14. ↑ Irvine RA, Yu MC, Ross RK, Coetzee GA (May 1995). "The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer". Cancer Res. 55 (9): 1937–40. PMID 7728763.
  15. ↑ Haiman CA, Stampfer MJ, Giovannucci E, Ma J, Decalo NE, Kantoff PW, Hunter DJ (July 2001). "The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer". Cancer Epidemiol. Biomarkers Prev. 10 (7): 743–8. PMID 11440959.
  16. ↑ 16.0 16.1 Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA (January 2001). "V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression". Urology. 57 (1): 199–204. PMID 11164181.
  17. ↑ "Prostate Cancer". National Cancer Institute. Retrieved 12 October 2014.
  18. ↑ 18.0 18.1 18.2 18.3 "Male Genitals - Prostate Neoplasms". Pathology study images. University of Virginia School of Medicine. Archived from the original on 2011-04-28. Retrieved 2011-04-28. There are many connections between the prostatic venous plexus and the vertebral veins. The veins forming the prostatic plexus do not contain valves and it is thought that straining to urinate causes prostatic venous blood to flow in a reverse direction and enter the vertebral veins carrying malignant cells to the vertebral column.
  19. ↑ . doi:10.9790/0853-1506020411. Missing or empty |title= (help)
  20. ↑ Prostatic carcinoma.Dr Ian Bickle and Dr Saqba Farooq et al. Radiopaedia.org 2015.http://radiopaedia.org/articles/prostatic-carcinoma-1
  21. ↑ Humphrey PA (2007). "Diagnosis of adenocarcinoma in prostate needle biopsy tissue". J. Clin. Pathol. 60 (1): 35–42. doi:10.1136/jcp.2005.036442. PMC 1860598. PMID 17213347. Unknown parameter |month= ignored (help)
  22. ↑ "Prostate cancer.Libre pathology 2015".

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