Prostate cancer pathophysiology

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

Overview[edit | edit source]

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[edit | edit source]

• 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[edit | edit source]

• 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[edit | edit source]

• 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^[6]
• 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^[7]

MSR1[edit | edit source]

• The macrophage-scavenger receptor 1 (MSR1) gene, located at 8p22, has also emerged as a candidate prostate-cancer–susceptibility gene^[8]
• 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^[9]
• 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)^[10]

AR, CYP17, AND SRD5A2[edit | edit source]

• 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^[11]
• Functional studies have suggested that shorter polyglutamine repeats may be associated with increased androgen-receptor transcriptional transactivation activity^[12]
• 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^[13]
• Polymorphic polyglycine (GGC) repeats are also characteristic of AR and may also influence the risk of prostate cancer^[14]
• 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^[15]
• 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^[16]
• 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^[16]

• 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.^[17]

• 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).^[18]

• 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]

• 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.^[18]

• 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 bones, lymph nodes, rectum, and bladder.^[18]

• Prostate gland is a zinc-accumulating, citrate-producing organ^[19]
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Gross Pathology[edit | edit source]

Prostate cancer is uncommonly apparent on gross.^[20]

Microscopic Pathology[edit | edit source]

Major criteria:^[21][22]

• Architecture

• Increased gland density
• Small circular glands

• In rare subtypes - large branching glands

• "Infiltrative growth" pattern - malignant glands between benign ones

• Basal cells lacking

• Cytological abnormalities:

• Nuclear enlargement (subtle)
• Nucleoli (prominent)

Minor criteria:

• Nuclear hyperchromasia
• Wispy blue mucin
• Pink amorphous secretions
• Intraluminal crystalloid
• Amphophilic cytoplasm
• Adjacent High-grade prostatic intraepithelial neoplasia (HGPIN)
• Mitoses - quite rare

Prostate adenocarcinoma: Microscopic View[edit | edit source]

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Gleason score[edit | edit source]

• See Gleason score

Prostate: Adenocarcinoma (Gleason grade 1)[edit | edit source]

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Prostate: Adenocarcinoma (Gleason grade 2)[edit | edit source]

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Prostate: Adenocarcinoma (Gleason grade 3)[edit | edit source]

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Prostate: Adenocarcinoma (Gleason grade 4)[edit | edit source]

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Prostate: Adenocarcinoma (Gleason grade 5)[edit | edit source]

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References[edit | edit source]

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