A Brief Review of Prostate Adenocarcinoma

Prostate cancer continues to be a major cause of cancer-related death in the male population of the western world, even with incidence rates on the rise worldwide. This increase in new prostate cancer diagnoses each year in the western world is presumably resulting from their lifestyle and environment (Tian, Guo, Zheng, & Ahmad, 2017). A clear clinical diagnosis of prostate adenocarcinoma rests in the hands of a pathologist following a needle biopsy. It often depends on the absence of the basal layer of the prostate specimen and the appearance of abnormal cell growth.

The vast majority of diagnosed prostate cancers are of the acinar adenocarcinoma type, which most often arises from non-primary periurethral prostatic ducts. In addition to the non-primary periurethral type, other types of adenocarcinomas consist of ductal carcinoma, accounting for 5% of the total prostate carcinoma caseload. It is rare to find histopathological findings indicating absolute ductal components of the tissue biopsy, with the majority of ductal adenocarcinomas found associating with acinar components of the tissue biopsy (Baig, Hamid, Mirza, & Syed, 2015). Acinar adenocarcinomas of the prostate have histological variants that have been newly classified by the World Health Organization in 2016. These include: atrophic pattern adenocarcinoma, pseudohyperplastic adenocarcinoma, microcystic adenocarcinoma, and foamy gland adenocarcinoma. These differ from the typical acinar adenocarcinoma in their glandular architecture and/or nuclear and cytoplasmic alterations. These variants of acinar adenocarcinomas may allow them to be deceptively benign, contributing to false-negative rates of 1-3% as they morphologically mimic benign prostate tissues (Humphrey, 2017).

The Genetic Programming

The genetic component of prostate adenocarcinoma has been elucidated over the past several decades, with hopes of finding novel biomarkers to accurately detect it, giving patients accurate risk stratification, and offering them a specifically targeted therapy. At this time, clinicians can assess patients’ risks using a combination of stage, grade, and PSA. However, some ambiguity exists with histological grading as patients with the same Gleason score can experience widely different outcomes. The role that somatic copy number alterations play in the tumor progression of prostate adenocarcinoma is important for oncogenic activation and the inactivation of tumor suppression mechanisms. These changes exist in 90% of all prostatic tumors, with a correlation observed between tumor progression and the proportion of the genome affected by these genomic lesions. Primary prostatic tumors often exhibit deletions in chromosomes 6q, 8p, 10q, 13q and include the genes NKX3-1, PTEN, BRCA2, and RB1. In cancer patients classified as castrate-resistant — that is, patients whose tumors proliferate despite lower-than-normal levels of testosterone — amplification of chromosomes X, 7, 8q, and 9q is observed. Included in these regions are the androgen receptor and MYC oncogene (Wallis & Nam, 2015). Tumor suppressor proteins apply the metaphorical “brake” to runaway cancer growths. In advanced prostate adenocarcinoma, a mutant p53 is associated with poor outcomes, leading to metastatic relapse and cancer-specific mortality in most cases. According to the Journal of Clinical Oncology’s recommendation, the incorporation of p53 status into clinical trials is now warranted (Mahon et al., 2018). The C-Myc oncogene, which encodes a transcription factor mediating cell cycle progression and cell proliferation, has been found to be amplified in 70% of clinically diagnosed prostate adenocarcinomas. Patients with this amplification should expect a significant risk of tumor recurrence after radiotherapy, as well as a risk of death from prostate cancer. It has also been shown that a loss of cyclin-dependent kinase inhibitor P27 Kip1, which inhibits cyclin E/CDK2 and cyclin D/CDK4 complexes, correlates with more aggressive prostatic cancer and higher Gleason scores (Hoogland, Kweldam, van Leenders, 2014).

Prostate Adenocarcinoma Skips Town

The dissemination of prostate tumors from their respective primary sites is most commonly observed to colonize bone tissue, occurring in approximately 65% to 75% of men with advanced prostate cancer. This is mediated by heterotypic cyclical interactions between the mobilized tumor cells and the bone matrix. The process involves the release of osteoclast-targeted growth factors from tumor cells, which activate them to resorb bone matrix. In response, growth factors sequestered in bone matrix are mobilized and stimulate tumor cell growth and survival, chemotaxic attraction to bone tissue, and adhesion to bone marrow epithelium.

Primary prostate tumor cells express higher levels of PAR1, which alters the expression of integrin alphaV Beta3. This is responsible for prostate cancer cells binding to the endothelium of the vasculature, allowing for extravasation. PAR1 also induces the release of a myriad of matrix metalloproteinase (MMPs), which degrade surrounding stromal tissue, allowing for primary site detachment and metastasis. With respect to prostatic-related bone lesions observed in radiography, these lesions appear more osteoblastic in appearance with associated bone resorption regions, indicating sclerotic growth around tumor cell deposits with osteolytic bone loss. Interestingly, endothelin-1 growth factor production in the prostate epithelium seems to stimulate osteoblastic proliferation quite vigorously, which explains the development of osteoblastic bone lesions found in patients with prostatic adenocarcinoma metastasis. Overall, these metastatic lesions occur most often in the lumbar spine, ribs, and pelvis. Clinically, these patients experience skeletal complications including pathologic fractures, spinal cord compression, and debilitating bone pain with 12-53 months of life remaining post bone metastasis. It has been demonstrated that the use of bisphosphonates, specifically Zoledronic acid, can markedly interfere with metastasis by inhibiting integrin, AlphaV Beta3 adhesions to endothelium, as well as reducing the expression of several MMPs (Abrahamsson, 2004).

Prostate Adenocarcinoma Is Out For Blood

The role angiogenesis plays in the pathogenesis of prostatic cancers is vital. However, there has yet to be a potent, long-term anti-angiogenesis therapy, which piques the interest of cancer researchers and clinicians. VEGF’s importance as a substrate in the development of angiogenesis has been elucidated for many years in the scientific literature, specifically the alternative splicing of VEGF pre-mRNA producing either antiangiogenic or proangiogenic isoforms. Specifically, prostatic tumors up-regulate the proangiogenic isoform mediated by the serine/arginine-rich splicing factor 1 (SRSF1) which in turn is regulated by serine/arginine protein kinase 1 (SRPK1). Until recently, SRPK1 has been shown to be elevated in pancreatic, colon, and breast cancers with higher stages of disease also noted. Moreover, more recent studies have indicated that elevated SRPK1 expression is found in prostate cancer types, more specifically, relating to a higher primary tumor stage, extracapsular perineural invasion and extracapsular extension. Given this new body of evidence, it would suggest that SRPK1 could be used as a potent target for anti-angiogenesis of prostatic tumors in the future (Bullock et al., 2015).

An alternative perspective into the derivation of angiogenesis in solid tumors can be examined through a neural lens. The flipping of the “angiogenesis switch” from histologically hyperplastic growths to grossly identifiable tumors has been shown to be in response to noradrenaline derived from the autonomic nervous system in mouse models. By releasing noradrenaline into the microenvironment of prostatic tissue it can bind to its respective endothelial-beta-adrenergic receptors initiating a cellular signal cascade in which the cell suppresses oxidative phosphorylation. In response, prostatic cells induce angiogenesis. Additionally, it has been demonstrated that knockout of the endothelial Adrb2 gene, which is responsible for encoding the B2-adrenergic receptor, leads to inhibiting tumor-associated angiogenesis through a process of metabolic oxidative phosphorylated enhancement. If a double gene knockout involving Adrb2 and the Cox10 gene, a gene responsible for encoding cytochrome IV oxidase assembly factor, is induced, prostatic cell proliferation resumes by preventing angiogenesis. It is important to note that angiogenesis inhibition fails to be a long-term viable option for many cancers including cancers of the prostate, speculatively due to resistance. However, co-targeting angiogenesis with concomitant therapies affecting both the neuronal and endothelial metabolic components may be most effective in reducing tumor progression (Zahalka et al., 2017).

Prostate Adenocarcinoma Cells That Don’t Fear the Reaper

Targeting prostatic cancer cells for programmed cell death has been a promising approach for many years. This is accomplished by specifically utilizing the cell’s innate apoptotic and autophagy mechanisms. The cell’s use of the Bcl-2 regulators is initiated by the release of cytochrome C from the mitochondria into the cytosol, which in turn, activates the caspase cascade resulting in apoptotic cell death. Cell autophagy uses the PI3K/Akt/mTOR pathway to inhibit prostatic tumor growth. The use of Plumbagin (PLB), a naphthoquinone constituent, shows promise in initiating both autophagy and apoptotic machinery, targeting a multitude of intracellular mechanisms in human prostatic cancers. Previously confirmed to initiate apoptotic and autophagy mechanisms in prostate cancer-induced NUDE mice studies, PLB influences the redox status of the cell, inhibits NF-kB activation, upregulates p53, and inhibits the PI3K/Akt/mTOR pathways. According to a 2015 study, PLB proved effective in triggering human prostatic cell apoptosis and autophagy processes in PC-3 and DU145 prostate cells. It achieves this by targeting the levels of reactive oxygen species in the cytosol, activating the apoptotic pathways mediated by mitochondrial cytochrome C release, inhibiting PI3K/Akt/mTOR pathways, and inhibiting p38 MAPK pathways. Interestingly, PLB also down-regulates PBEF/visfatin, which increases the basal level and PLB-mediated apoptosis/autophagy pathways in both cell lines tested. It is important to note that autophagy has been demonstrated to be cytotoxic for prostatic cell types in early tumor progression and switches to cytoprotective in later stages of tumorigenesis (Zhou et al., 2015).

There is a great debate in current literature about whether PSA (prostate-specific antigen) screening is an effective biomarker for detecting prostate cancer, or even if it acts as an accurate tool for grading cancer, in part due to prostate cancer’s heterogeneity and different rates of progression in various patient groups. PSA is a serine protease secreted by prostate epithelium to liquefy human semen, allowing sperm to swim freely in the uterus once ejaculated. PSA levels rise as cells progress from benign prostatic hyperplasia to prostate cancer and continue to rise as cancer develops into advanced stages. However, PSA levels can drop in patients treated with 5-alpha reductase inhibitors or men who experience acute prostatitis, which adds complexity when interpreting results. Next-generation biomarkers should not only accurately diagnose prostate cancer but also determine cancer progression. Once patients can make sound decisions by removing doubt in the results, they will be better equipped to determine the proper course of treatment that promotes improved quality of life. As it stands today, there is a significant risk of over-diagnosing and over-treating prostate cancer patients due to the limitations of PSA screening. The race to find novel biomarkers has begun with promising contenders being prostate cancer-related exosomes that could be used for risk stratification, as well as to decrease the number of patients returning for repeat biopsies. Another possible biomarker is the circulating prostate cancer cell (CPTC), which is very rarely found in the systemic circulation of non-cancer harboring patients. In prostate cancer patients, CPTCs can be accurately measured and used for risk stratification, estimating patient survival rates, and facilitating the proper use of anti-cancer drug selection therapy (Chistiakov, Myasoedova, Grechko, Melnichenko, & Orekhov, 2018).

Sources

1. Abrahamsson, P. (2004). Pathophysiology of Bone Metastases in Prostate Cancer. European Urology Supplements,3-9.
2. Baig, F. A., Hamid, A., Mirza, T., & Syed, S. (2015). Ductal and Acinar Adenocarcinoma of Prostate: Morphological and Immunohistochemical Characterization. Oman Medical Journal,30, 162-166.
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