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. The western world appreciates this increase in new prostate cancer diagnoses each year presumably resulting from their lifestyle and environment (Tian, Guo, Zheng, & Ahmad, 2017). A clear clinical diagnosis of prostate adenocarcinoma is the hands of a pathologist following a needle-biopsy and depends on the absence of the basal layer of the prostate specimen as well as the appearance of abnormal cell growth. The vast majority of diagnosed prostate cancers are of the acinar adenocarcinoma type, which arises most often from other 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 which include: atrophic pattern adenocarcinoma, pseudohyperplastic adenocarcinoma, microcystic adenocarcinoma, and foamy gland adenocarcinoma which differ from typical acinar adenocarcinoma in their glandular architecture and/or their 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, as well as offering them a specifically targeted therapy. At this time, clinicians are able to risk assess patients by using the combination of stage, grade, and PSA. However, there is some ambiguity with histological grading as patients with the same Gleason score can experience widely different outcomes. The role somatic copy number alteration play in tumor progression of prostate adenocarcinoma is important for oncogenic activation as well as inactivation of tumor suppression mechanisms. These changes exist in 90% of all prostatic tumors with a correlation observed between the progression of tumors 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, patients harboring tumors which 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 “break” on runaway cancer growths. In advanced prostate adenocarcinoma, 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, incorporation of p53 status into clinical trails is now warranted (Mahon et al., 2018). The C-Myc oncogene, which encodes a transcription factor mediating cell cycle progression and proliferation of the cell, has been found to be amplified in 70% of prostate adenocarcinomas clinically diagnosed. Patients with this amplification should expect to be in significant risk of tumor recurrence after radiotherapy as well as experience prostate cancer related death. 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).
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Prostate Adenocarcinoma Skips Town
The dissemination of prostate tumors from their respective primary sites are most commonly observed to colonize bone tissue occurring in approximately 65% to 75% of men with advanced prostate cancer mediated by heterotypic cyclical interactions between the mobilized tumor cells and the bone matrix. This 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 expression of integrin alphaV Beta3 which is responsible for prostate cancer cells binding to 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 proliferate quite vigorously which explains the development of osteoblatic 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 observe skeletal complications including pathologic fractures, spinal cord compression, and debilitating bone pain with 12-53 months of life remaining since bone metastasis. It has been demonstrated that the use of bisphosphonates can markedly interfere with metastasis specifically referring to the use of Zoledronic acid, which has been shown to inhibit integrin, AlphaV Beta3 adhesions to endothelium, as well as reduce 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 long-term potent 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 alterative 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 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 mice 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 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 reduction of 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 by specifically utilizing the cell’s innate apoptotic and autophagy mechanisms. The cells 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 also 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, inhibition of NF-kB activation, upregulation of p53, and inhibition of the PI3K/Akt/mTOR pathways. According to a 2015 study, PLB proved to be effective in triggering human prostatic cell apoptosis and autophagy processes in PC-3 and DU145 prostate cells by targeting the levels of reactive oxygen species in the cytosol, activating the apoptotic pathways mediated by mitochondrial cytochrome C release, inhibition of PI3K/Akt/mTOR pathways, as well as inhibiting p38 MAPK pathways. Interestingly, PLB also down-regulates PBEF/visfatin, which increased the basal level and PLB-mediated apoptosis/autophagy pathways in both cell lines tested. It is important to note that autophagy has been demonstrated be 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 great debate in the current literature 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 differential progressions in various groups of patients. PSA is a serine protease secreted by prostate epithelium in order 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 continues to rise as cancer develops into more advanced stages. However, PSA levels can drop in patients treated with 5-alpha reductase inhibitors or men who experience acute prostatitis, which adds a level of complexity to interpreting its result. Next generation biomarkers should not only accurately diagnose prostate cancer but also determine the progression of that cancer. Once patients are able to make a sound decision by removing doubt in the results, they will be better equipped to determine the proper course of treatment that leaves the patient with improved quality of life. As of today, there is great risk in over diagnosing and over treating prostate cancer patients due to the limitations of PSA screening. The race to find novel biomarkers is underway with promising contenders being prostate cancer related exosomes which could be utilized for risk stratification as well as to decrease the number of patients returning for repeat biopsies. One other possible biomarker is the circulating prostate cancer cell (CPTC), which is very rarely found in systemic circulation of non-cancer harboring patients. In prostate cancer patients, CPTCs can be accurately measured and used for risk stratifications, estimating patient survival rates, and allow for proper use of anti-cancer drug selection therapy (Chistiakov, Myasoedova, Grechko, Melnichenko, & Orekhov, 2018).
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