The role of neuroendocrine cells in prostate cancer: a comprehensive review of current literature and subsequent rationale to broaden and integrate current treatment modalities.

UNLABELLED: Neuroendocrine prostate carcinoma (NE-PCa) is a heterogeneous disease. Due to a high prevalence of NE (neuroendocrine) differentiation in patients who receive prolonged androgen deprivation treatment, the real incidence of NE-PCa remains unknown. Similarly, the biological steps from prostate carcinoma (PCa) toward NE differentiation are far less than definitive and, consequently, there is a lack of evidence to support any of the treatments as the "gold standard". MATERIALS AND METHODS: A systematic literature search was conducted using the PubMed, Scopus, and Embase databases to identify original articles and review articles regarding NE-PCa . Keywords were "prostate cancer" and "neuroendocrine". Articles published between 1995 and 2013, were reviewed and selected with the consensus of all of the authors. RESULTS: Fifty-one articles were selected by the authors for the purpose of this review. The principle findings were reported into some subsections: Epidemiology, Biological steps of NE differentiation (with some principle articles on animal and in vitro, since there is very little in the literature on human studies); for the treatment options, we had to expand the search on PubMed to a larger timeframe and selection since very little was specifically found in the first criteria: surgery, radiotherapy, ablative techniques, immunomodulation and epigenetic therapy were then reviewed. A multidisciplinary approach, advocated by many authors, although promising, has failed to demonstrate increased survival rates. Limitations of this review include the lack of a clear definition of NE-PCa and consequently, the lack of strong evidence provided by a large series with long-term follow-up. CONCLUSIONS: Supported from this extensive review, we propose it is worthwhile to investigate a new multimodal therapeutic approach to address advanced NE-PCa starting from a debulking (with radical intent) of the disease plus epigenetic therapy with stem cell differentiation stage factors (SCDSFs). In addition immunotherapy can be used to treat the cancer presenting phenotype in association with chemomodulation plus ablative therapies, in case of advanced or recurrent diseases. SCDSFs may be utilized to regulate cancer stem cells and possible new phenotypes could also be associated with ablative therapies. Hormonal deprivation, radiotherapy, chemotherapy, ex vivo vaccines and targeted therapies could also be used and reserved in case of failure.

The female prostate and prostate-specific antigen. Immunohistochemical localization, implications of this prostate marker in women and reasons for using the term "prostate" in the human female.

Prostate-specific antigen (PSA) is currently the most frequently used marker for the identification of normal and pathologically altered prostatic tissue in the male and female. Immunohistochemically PSA is expressed in the highly specialized apically-superficial layer of female and male secretory cells of the prostate gland, and as well as in uroepithelial cells at other sites of the urogenital tract of both sexes. Unique active moieties of cells of the female and the male prostate gland and in other parts of the urogenital tract are indicative of secretory and protective function of specialized prostatic and uroepithelial cells with strong immunological properties given by the presence of PSA. In clinical practice, PSA is a valuable marker for the diagnosis and monitoring of diseases of the male and the female prostate, especially carcinoma. In the female, similarly as in the male, the prostate (Skene's gland) is the principal source of PSA. The value of PSA in women increases in the pathological female prostate, e.g., carcinoma. Nevertheless, the total amount of PSA in the female is the sum of normal or pathological female prostate and non-prostatic female tissues production, e.g., of diseased female breast tissue. The expression of an antigen specific for the male prostate, i.e., PSA in female Skene's glands and ducts, and structural and functional parameters and diseases similar to that of the male prostate, have provided convincing evidence of the existence of a prostate in women and definitive preference of the term "prostate" over that of Skene's glands and ducts. The use of the term Skene's glands incorrectly implies that some other structure rather than prostate is involved, promoting the vestigial position of this female organ.

The normal female and the male breast epithelium does not express prostate-specific antigen. Preliminary immunohistochemical observations of autopsy breast tissues.

In the normal female and male breast epithelial structures any prostate-specific antigen (PSA) immunohistochemical positivity was observed. Variable PSA expression, which often borders the positivity, was observed in membranes of adipocytes of fat tissue and in the endothelium of small vessels in a female and a male breast. Based on these initial observations, tissue of the normal breast, male or female, can not be considered to be the principal source of PSA.

A tissue type transglutaminase in human seminal plasma.

PROBLEM: Initial studies from this laboratory of human seminal plasma (SePl) permitted the presumptive identification of the participation of transglutaminase (TGase) and prostaglandins as principal molecules contributing to the immunoregulatory activity of SePl. As a step toward confirmation and extension of these studies. SePl TGase has been partially purified, characterized, and localized. METHOD OF STUDY: An enzyme-enriched and partially purified preparation of SePl TGase obtained by molecular sieve and ion-exchange chromatography and the polyclonal antibody to this preparation were characterized by enzymatic analysis and evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE); immunoprecipitation and immunofluorescence (IF). RESULTS: A Ca(2+)-dependent, thrombin-independent, TGase enzyme from SePl was identified. A pH of 7.5 and a concentration of 2 mM calcium chloride were determined to be optimal for ascertaining the SePl TGase activity in a filter paper assay. Immunoprecipitation using polyclonal antibody prepared with a semipurified TGase preparation, concurrently comparing increasing serum dilution and enzyme activity, revealed a predominant protein band on SDS-PAGE of 83 kDa. IF studies using the polyclonal antibody on human prostate tissue showed reactivity with a variety of epithelial and stromal components. A significant (P < 0.05) correlation between the biochemical, i.e., enzyme activity of the SePl TGase active preparation, and immunologic activity, i.e., indirect IF staining titre of antibody to acinar epithelial cells and luminal contents, was observed. CONCLUSIONS: The results confirm and extend initial studies of the presumptive identification of a tissue type TGase associated with the immunoregulatory activity of human SePl and permit the characterization and immunohistologic localization of this macromolecule to the prostate. These observations provide a basis for further investigation of the immunoregulatory role of SePl and prostate TGase in the biology of reproduction and associated pathoses.

Sexual behaviour and increased anal cancer.

An increase in epidermoid anal cancer has been observed in the past 30 years (1959-89). This increase in anal cancer has been noted to be more pronounced in women than men. The absence of a significant interactive effect of the HIV and human papillomaviruses and the incidence of anal cancer has been noted in some studies. These observations provide the rationale for consideration of other aetiologic agents that may contribute to the increase of anal cancer in men and women. Within the context of their ability to serve as cancer initiating and promoting factors, spermatozoa and seminal plasma are suggested as aetiologic agents and/or cofactors which are common to men and women practising anal intercourse in whom an increase in anal cancer has been observed. It is further suggested that sexual behaviour, that is, anal intercourse, not sexual preference, is one of the primary factors in the development of anal cancer.

A retrospective and prospective overview of prostate-specific antigen.

Since the identification of prostate-specific antigen (PSA), continued technological advances have provided highly sensitive assays for its quantification. Given its lack of disease specificity, and its recent detection at low levels in an increasing number of non-prostatic tissues, PSA is far from being the perfect "tumour" marker (biological marker). However, the positive predictive value of PSA for assessing cancer risk makes PSA the most useful "tumour" marker for monitoring progression and response to treatment among patients with prostate cancer. Earlier detection through screening for elevated levels of PSA, while controversial, has been proposed as a way to decrease prostate cancer mortality. Haematogenous identification of PSA mRNA may provide stage-related prognostic information, and the use of ultrasensitive assays for PSA may permit earlier identification of residual or recurrent cancer, following treatment and the initiation of adjuvant therapy. Various PSA-related concepts, including the ratio of "free" PSA and complexes of PSA with the protease inhibitor, alpha1-antichymotrypsin, to total PSA, have been proposed and placed within diagnostic and management algorithms. Elevations of PSA in other irregularities of the prostate, notably in benign prostatic hyperplasia, and the increasing frequency and number of non-prostatic tissues, including those in women, expressing PSA, have implications for future immunoassays for PSA and strategies for immunotherapy using PSA-based monoclonal antibodies or vaccines, as well as for the molecular basis for its anomalous expression and physiological function(s).