Molecular therapeutics in prostate cancer

The purpose of this review is to provide information on the molecular basis of prostate cancer biology and to identify some of the targets for therapy, and highlight some potential strategies for molecular treatment. Here we give a synopsis of what we have learned regarding molecular biology of cancer in general and the directions research might take in the future in order to impact prostate cancer specifically. This work is certainly not encyclopedic in nature and we apologize in advance to colleagues whose work we were no able to include. Hope lies in learning to utilize some of these molecular workings for better prevention, diagnosis, and treatment of the most common solid organ cancer in men. Prostate cancer is a formidable disease and at current rates of diagnosis will affect one-in-six men living in the United States (Greenlee et al., 2000) Many of these men are diagnosed at an early stage of the disease and can be effectively treated by surgery or radiation. However, a significant fraction of men are diagnosed with later stage disease or progress despite early curative therapeutic attempts. Unfortunately, many of these men succumb to prostate cancer, as management options are limited and not always successful. Through an understanding of the molecular processes that occur in the development and progression of prostate cancer, novel therapies will arise that will provide longer survival, better quality of life, and a chance for cure in men afflicted with this disease.     

Molecular epidemiology in cancer research

The use of molecular biomarkers in epidemiological investigations brings clear advantages of economy, speed and precision. Epidemiology--the study of the factors that control the patterns of incidence of disease--normally requires large numbers of subjects and/or long periods of time, because what is measured (the occurrence of disease) is a rare event. Biomarkers are measurable biological parameters that reflect, in some way, an individual's risk of disease-because they indicate exposure to a causative (or protective) agent, or because they represent an early stage in development of the disease, or because they allow an assessment of individual susceptibility. Biomarkers must be usable on one of the few materials available for biomonitoring of humans, i.e. blood, urine, exfoliated epithelial cells and, with some difficulty, biopsies. The approach of molecular epidemiology has a great potential is several areas of cancer research: investigating the aetiology of the disease; monitoring cancer risk in people exposed to occupational or environmental carcinogens; studying factors that protect from cancer; and assessing intrinsic factors that might predispose to cancer. The biomarkers most commonly employed in cancer epidemiology include: measurements of DNA damage--DNA breaks, altered bases, bulky adducts--in lymphocytes; the surrogate marker of chemical modifications to blood proteins, caused by agents that also damage DNA; the presence of metabolites of DNA-damaging agents (or the products of DNA damage themselves) in urine; chromosome alterations, including translocations, micronuclei and sister chromatid exchange, resulting from DNA damage; mutations in marker genes; DNA repair; and the differential expression of a variety of enzymes, involved in both activation and detoxification of carcinogens, that help to determine individual susceptibility. The molecular approach has been enthusiastically employed in several studies of occupational/environmental exposure to carcinogens. While the estimation of biological markers of exposure has certainly shown the expected effects in terms of DNA damage and adducts, the detection of the biological effects of exposure (e.g. at the level of chromosome alterations) has not been so clear-cut. This is true also when smokers are examined as a group compared with non-smokers. Several markers (especially of chromosome damage and mutation) show a strong correlation with age-indicating either an increasing susceptibility to damage with age, or an accumulation of long-lived changes. DNA repair--a crucial player in the removal of damage before it can cause mutation--may vary between individuals, and may be modulated by intrinsic or extrinsic factors, but limited data are available because of the lack of a reliable assay. Information on other enzymes determining individual susceptibility does exist, and some significant effects of phenotypic or genotypic polymorphisms have emerged, although the interactions between various enzymes make the situation very complex. The important question of whether oxidative DNA damage in normal cells is decreased by dietary antioxidants (vitamin C, carotenoids etc., from fruit and vegetables) has been tackled in antioxidant supplementation experiments. The use of poorly validated assays for base oxidation has not helped us to reach a definitive answer; it seems that, in any case, the level of oxidative damage has been greatly exaggerated. DNA-damaging agents lead to characteristic kinds of base changes (transitions, transversions, deletions). The investigation of the spectrum of mutations in cancer-related genes studied in tumour tissue should lead to a better understanding of the agents ultimately responsible for inducing the tumour. Similarly, studying mutations in a neutral marker gene (not involved in tumorigenesis) can tell us about the origins of the 'background' level of mutations. So far, interpretation of the growing databases is largely speculative. (ABSTRACT     

Molecular epidemiology of cancer

In this review the role of molecular markers for the assessment of individual exposure to carcinogenic agents was analyzed. Examples of the studies describing mutation patterns related to specific carcinogenic exposures are presented. The results of epidemiological studies of gene polymorphism and its role in the interaction between inheritance, environmental factors, and lifestyles are analyzed in detail. Adequate planning and performance of the epidemiological component of a study is a requirement for obtaining reproducible results reflecting molecular mechanisms of interest. Individual information on lifestyle factors (smoking, alcohol consumption, nutrition, physical activity, reproductive anamnesis) and environmental factors (occupational activity and carcinogen load at workplace), which influence not only the risk of developing cancer, but also the molecular features of a tumor, is crucial for adequate analysis and proper assessment of the results.     

Molecular assays for detecting Aphanomyces invadans in ulcerative mycotic fish lesions

The pathogenic oomycete Aphanomyces invadans is the primary etiological agent in ulcerative mycosis, an ulcerative skin disease caused by a fungus-like agent of wild and cultured fish. We developed sensitive PCR and fluorescent peptide nucleic acid in situ hybridization (FISH) assays to detect A. invadans. Laboratory-challenged killifish (Fundulus heteroclitus) were first tested to optimize and validate the assays. Skin ulcers of Atlantic menhaden (Brevoortia tyrannus) from populations found in the Pamlico and Neuse River estuaries in North Carolina were then surveyed. Results from both assays indicated that all of the lesioned menhaden (n = 50) collected in September 2004 were positive for A. invadans. Neither the FISH assay nor the PCR assay cross-reacted with other closely related oomycetes. These results provided strong evidence that A. invadans is the primary oomycete pathogen in ulcerative mycosis and demonstrated the utility of the assays. The FISH assay is the first molecular assay to provide unambiguous visual confirmation that hyphae in the ulcerated lesions were exclusively A. invadans.     

Molecular modelling and simulations in cancer research

The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.     

Molecular pathology of ovarian cancer

Ovarian cancer is the leading cause of death among women with gynecologic malignancies. Epithelial tumors typically constitute 80-90% of ovarian malignancies and are classified primarily as serous, mucinous, endometrioid or clear cell. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations. We describe such genetic alterations with specific reference to histologic subtypes.     

Molecular genetics of ovarian cancer

This is a review of the approaches that can be used to analyze genetic changes in ovarian cancer. Traditional gene localization methods are discussed, followed by a section on gene identification techniques. Once a putative disease-associated gene has been cloned, mutations have to be identified and analyzed. There are numerous mutation detection methods, and the most common ones are outlined. In the penultimate section, the role of immunohistochemistry as a surrogate method for mutation analysis is considered. Finally, the possible use of functional assays is discussed. At present, it would appear that DNA chip technology for the detection of mutations, and microarray analysis of gene expression, are two important techniques likely to have a significant impact on the genetic analysis of ovarian cancer.     

Molecular profiling of human cancer

Traditionally, tumours have been categorized on the basis of histology. However, the staining pattern of cancer cells viewed under the microscope is insufficient to reflect the complicated underlying molecular events that drive the neoplastic process. By surveying thousands of genes at once, using DNA arrays, it is now possible to read the molecular signature of an individual patient's tumour. When the signature is analysed with clustering algorithms, new classes of cancer emerge that transcend distinctions based on histological appearance alone. Using DNA arrays, protein arrays and appropriate experimental models, the ultimate goal is to move beyond correlation and classification to achieve new insights into disease mechanisms and treatment targets.     

Skin cancer: lights on genome lesions

Sunlight generates skin damage mainly by inducing DNA lesions in epidermal cells. The recent development of transgenic mice expressing specific photolyases has identified cyclobutane pyrimidine dimers as the major player in ultraviolet-induced damage, including skin cancer.     

Molecular biology of colorectal cancer in clinical practice

Molecular Biology - The review summarizes current data on the molecular genetic mechanisms underlying the pathogenesis of colorectal cancer (CRC) and addresses the connections between these...     

Molecular mechanisms in prostate cancer. A review

Genetic studies have provided remarkable clues to the causes of prostate cancer (PCa). For example, in addition to the expected role of androgens in facilitating the development of PCa, the possibility that infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate cancer genes; that insight will profoundly affect future studies and may ultimately lead to new approaches to the prevention of prostate cancer. The identification of key molecular alterations in prostate cancer cells implicates carcinogen defenses, including GSTP1, growth factor signaling pathways (such as NKX3.1, PTEN and p27) and androgens as critical determinants of the phenotype of PCa cells and defines specific targets for detection, diagnosis and treatment of PCa.     

Molecular mechanisms of lymphangiogenesis in development and cancer

The lymphatic system, also named the second vascular system, plays a critical role in tissue homeostasis and immunosurveillance. The past two decades of intensive research have led to the identification and detailed understanding of many molecular players and mechanisms regulating the formation of the lymphatic vasculature during embryonic development. Furthermore, clinical and experimental data clearly demonstrate that the formation of new lymphatic vessels by sprouting lymphangiogenesis from pre-existing lymphatic vessels, or by the de novo formation of lymphatic capillaries also occurs in various pathological conditions, such as cancer and organ transplant rejection, while lymphangiogenesis is non-functional in primary edema. In cancer, lymphatic vessels are one major gateway for invasive tumor cells to leave the primary tumor site and to establish distant organ metastasis. Therefore, the specific targeting of the lymphatic vasculature at the tumor site could be a promising approach to prevent metastasis formation.     

Molecular links between endometriosis and cancer

Endometriosis is the leading cause of morbidity among premenopausal women affecting about 1 in 10 females. The features shared by endometriosis and cancer include the ability to evade apoptosis, the stem cell-like ability and angiogenic potential. As such characteristics are encoded by the cell's genetic constitution, acquired mutations are responsible for the malignant transformation of endometriosis. Indeed, a number of tumour-suppressor genes and proto-oncogenes, such as protein 53 (P53) and B-cell lymphoma 2 (BCL-2) respectively, are mutated and as a result differentially expressed between endometriotic and malignant tissue associated with endometriosis. Moreover, cytokines and macrophages, both of which are inflammatory mediators have been implicated in the transformation process. The angiogenic properties possessed by cancer arising from endometriosis signifies a bad prognosis, while the stem cell-like activity possessed by both endometriosis and cancer has been attributed to the effect of oestrogen. A number of differences between endometriosis and cancer are found at the molecular level. Considering the link between these two pathologies, the three components which fuel the malignant transformation of endometriosis can be embodied in the endometriosis-induced carcinoma (EIC) triangle which shows the intricate relationship between endocrinologic, immunologic and genetic components.