Natural History Of Prostatic Carcinoma Research Articles

Epididymal Sparing Bilateral Orchidectomy with Epididymoplasty for Advanced Cancer Prostate: Our Experience in Rural Setup

Rise in incidence and variable natural history of prostatic carcinoma, presents a challenge to professionals involved in its management. Cases that come for evaluation and treatment in developing countries like ours are elderly and usually present in the late stages of the disease. Perhaps the best option remain at this stage is palliative in the form of channel TURP to improve the urine flow and suppress the cancer growth by androgen deprivation treatment (ADT). Further improvement of quality of life is achieved by supportive measures like good nutrition, vitamins and calcium supplementation to prevent demineralisation of bones and analgesic for pain relief. Bilateral Orchidectomy remains the most effective and permanent solution for ADT as it brings down serum testosterone level very rapidly to castration level of 20%. Epididymis functions only as the carrier of sperms and help in maturation during the passage. In no way it is involved in spermatogenesis or production of testosterone. Epididymal sparing bilateral orchidectomy with epididymoplasty achieves androgen deprivation to that of castration level. Left over epididymal bubbins in the scrotal sacs maintains the shape of scrotum and gives the patient a feel of scrotal sac not being empty.

Comparative expression of Hedgehog ligands at different stages of prostate carcinoma progression

Recent studies have revealed the potential involvement of Hedgehog (Hh) signalling in proliferation and invasive behaviour of prostate carcinoma (PCa). The aim of this study was to specify the role of Sonic Hh (Shh), Desert Hh (Dhh) and Indian Hh (Ihh) in the natural history of PCa. Hh ligands expression was compared in primary hormone-naive PCa (HNPC), hormone-treated PCa (HTPC) and hormone-refractory PCa (HRPC), using immunohistochemistry. Shh and Dhh were expressed by both epithelial and stromal cells of prostate tissues. Ihh was only expressed by stromal cells. For the three ligands, mRNA and immunostaining were not correlated. In HNPC, Shh epithelial expression was significantly associated with high Gleason scores (p = 0.03), metastatic lymph nodes (p = 0.004) and Dhh epithelial staining was associated with high pT stages (p = 0.003), seminal vesicle invasion (p = 0.03) and bladder neck invasion (p = 0.0008). Negative Shh staining in stromal cells was associated with high Gleason scores (p = 0.015), high pT stages (p = 0.01) and bladder neck invasion (p = 0.04). Concomitant absence of Shh and Dhh expression in stromal cells was an independent prognostic parameter for biological recurrence on multivariate analysis (p = 0.01). Epithelial expression of Shh and Dhh was increased in HTPC compared to HNPC (p = 0.02 and p = 0.04). Interestingly, in vitro, transcript analysis also showed increased expression of these 2 Hh ligands when androgen-sensitive LNCaP cells were maintained in androgen-free medium mimicking hormonal therapy. Epithelial expression of Dhh was increased (p < 0.0001) in HRPC compared to HNPC, while stromal expression of Shh and Dhh was decreased (p < 0.0001). In conclusion, the Hh signalling pathway is associated with pejorative pathological parameters in HNPC and is up-regulated in epithelial cells of HTPC and HRPC. Moreover, the lack of Hh molecules in stromal cells seems to be associated with invasive and hormone-refractory behaviours and suggests specific changes in stromal-epithelial crosstalks during PCa progression.

Ethnicity and its significance in the pathobiology of prostatic carcinoma in Southern Israel

Background Several studies have noted ethnic differences in the natural history of prostatic carcinoma. Southern Israel has been regarded as a melting pot and, perhaps more than the rest of the country, has encouraged the ingathering of immigrants from several countries, as well as a large Bedouin community. Objectives In an attempt to determine any differences that may exist in population groups in Israel, we have examined clinical and biologic markers in patients diagnosed with prostatic cancer in Southern Israel in 1996–2000. We wanted to demonstrate differences in the incidence and features of prostate carcinoma among the population groups in Southern Israel, and to evaluate their possible biologic significance. Methods Clinical parameter features, including the ethnicity origin of patients with prostatic adenocarcinoma, were reviewed in a cohort of 189 patients seen between 1996 and 2000. Tissue sections from specimens in a subset of 40 of these patients who had undergone prostatectomy were studied by immunohistochemistry for TP53, Bcl-2, and chromogranin A using the ABC peroxidase method. These markers were chosen because of their suggested impact on the biology of this tumor. Clinical correlations were examined. Results We confirm the presence of ethnic differences in the features of prostatic adenocarcinoma in our geographic area. Notably, patients of North African origin were treated surgically at a younger age than immigrants from East Europe. Higher total prostate-specific antigen levels and more robust tumor cell Bcl-2 expression were detected in the East European patients. The number of Bedouin subjects in our cohort of patients with prostatic cancer was much more limited than expected. No immigrants from Ethiopia were included in our study diagnosed with prostate carcinoma during this period. Conclusions The proportion of patients of European, especially East European, origin was relatively high among the cohort of 189. Their older age and the lower proportion of subjects that underwent surgery, together with the tendency toward higher total prostate-specific antigen levels and higher Bcl-2 expression, suggest that this ethnic group may not differ significantly from the African-American group in the United States. The low representation of Bedouin and absence of Ethiopian immigrants among our patients with prostate cancer may point to a genuinely low incidence or it may be related to inadequate medical supervision in these population groups.

Up-regulation of Skp2 after Prostate Cancer Cell Adhesion to Basement Membranes Results in BRCA2 Degradation and Cell Proliferation

Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by beta1 integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its down-regulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma.

CELL-CELL ADHESION MOLECULES AND SIGNALING INTERMEDIATES AND THEIR ROLE IN THE INVASIVE POTENTIAL OF PROSTATE CANCER CELLS

The highly variable natural history of prostate carcinoma may be reflected in heterogeneity of invasive potential between tumors. We have examined two prostate cancer cell lines of low invasive potential (CAHPV10 and PZHPV7) and three cell lines of high invasive potential (DU-145, PC-3, LNCapFGC), to determine whether specific adhesion molecule profiles correlated with their invasive behavior. Using an in vitro invasion assay, we demonstrated that DU-145, LNCapFGC and PC-3 cells were highly invasive compared with CA-HPV-10 and PZ-HPV-7 cells. LNCapFGC cells expressed high levels of E-cadherin, alpha-, beta- and gamma-catenin, desmoglein, desmoplakin and GSK3beta using immunoblotting. This was, in general, comparable to immunohistochemical staining. PC-3 cells had no E-cadherin or alpha-catenin, but expressed a high level of the HGF/SF receptor c-Met. In contrast, DU-145 cells were found to express E-cadherin and low levels for all other protein molecules, except c-Met. The DU-145 cell line also lacked alpha-catenin expression. In CA-HPV-10 and PZ-HPV-7 cells, there was no detection of APC, PECAM-1, P-cadherin or Wnt-1. DU-145, LNCapFGC and PC-3 cells formed cell-cell aggregates, which were reduced by inclusion of anti-E-cadherin antibody and the motogen HGF/SF. These results show that prostate cancer cells exhibit a diverse expression of cell-cell adhesion molecules and their signaling intermediates. The expression of these adhesion molecules bears an important relationship with the invasive phenotype of these cells.

The natural history of prostate carcinoma based on a Danish population treated with no intent to cure

Prostate carcinoma is one of the most commonly diagnosed cancers among Western males. In Denmark, the traditional therapeutic approach to prostate carcinoma regardless of tumor stage has been limited to palliative procedures. This conservative approach combined with a complete cancer and personal registration in Denmark provides an opportunity to describe the still debatable natural history of prostate carcinoma. The data, originating from hospital records and death certificates, included a complete prostate carcinoma population residing in Aarhus County diagnosed between January 1, 1979 and December 31, 1983. The patients were retrospectively followed from diagnosis until death (median length of follow-up, 15.0 years). The total number of 719 new cases of prostate cancer were diagnosed without any screening programs. Forty-five percent of patients were diagnosed incidentally, and 31% of all patients had organ-confined disease (T1a-T2, Nx, M0). The disease specific survival rates at 1, 5, and 10 years were 80%, 38%, and 17%, respectively, and 62% of the patients died primarily of prostate carcinoma. A multivariate analysis demonstrated a statistically significant relationship between disease specific death and T classification, tumor differentiation, and erythrocyte sedimentation rate at diagnosis. Prostate carcinoma patients have a poor survival and the majority of the patients diagnosed suffer and die from their disease rather than with it. Nevertheless, approximately one-third of patients neither suffer nor die from their disease. Therefore, the development of prognostic markers to improve the identification of patients who will benefit from early aggressive treatment is important. [See editorial on pages 827-33, this issue.]

The natural history of prostate carcinoma based on a Danish population treated with no intent to cure

The natural history of prostate carcinoma based on a Danish population treated with no intent to cure

Prostatic Carcinoma: 5-Year Followup of Patients With Surgically Staged Disease Undergoing Extended Field Radiation

We analyzed all patients who had undergone pre-radiation staging pelvic lympadenectomy from 1969 to 1979. Of 70 patients with a minimum followup of 5 years 33 had positive and 37 had negative nodes. Three of the 33 patients with positive lymph nodes were alive without disease at the time of our study, compared to 20 of 37 with negative lymph nodes.Our review suggests that extended field radiation has minimal or no impact on the natural history of prostatic carcinoma in patients with positive nodes. Patients with stages T1 and T2 lesions, and negative nodes do well with external beam therapy.

Origin and development of carcinoma in the prostate.

Detailed histologic study of 45 cancerous prostate glands in 134 autopsies provided new information on the natural history of prostatic carcinoma. Origin of carcinoma was limited to one of two histologically distinct regions, but with no apparent predilection for the “posterior lobe” or sub capsular area. Carcinoma selectively originated from active gland epithelium rather than a trophic glands, and distinctive premalignant changes accompanied its origin. Evidence from volume distribution data suggests that there are not two types of prostatic carcinoma with different biologic potential, but a single species having slow growth rate with a logarithmic growth curve. The development of carcinoma in the gland follows predictable patterns, including early involvement of the capsule and perineural spaces. The later course of tumor growth is characterized by loss of differentiation and the ability to penetrate the capsule and periurethral stroma. This suggests a gradual increase in biologic malignant potential which is closely linked to tumor size. Probably the capacity for distant metastasis is almost limited to large carcinomas, and penetration of the gland capsule may be the most important predisposing factor.