Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes -- in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing -- affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

The fundamental role of epigenetic events in cancer

Induction of apoptotic program in cell-free extracts : requirement for datp and cytochrome c

In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a caspase inhibitor, zVAD-fmk. In vitro, exogenous cytochrome c bypassed the inhibitory effect of Bcl-2. Cytochrome c release was unaccompanied by changes in mitochondrial membrane potential. Thus, Bcl-2 acts to inhibit cytochrome c translocation, thereby blocking caspase activation and the apoptotic process.

https://science.sciencemag.org/content/sci/275/5303/1132.full.pdf

The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis

Apoptosis is a major form of cell death, characterized initially by a series of stereotypic morphological changes. In the nematode Caenorhabditis elegans, the gene ced-3 encodes a protein required for developmental cell death. Since the recognition that CED-3 has sequence identity with the mammalian cysteine protease interleukin-1 beta-converting enzyme (ICE), a family of at least 10 related cysteine proteases has been identified. These proteins are characterized by almost absolute specificity for aspartic acid in the P1 position. All the caspases (ICE-like proteases) contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site motif. Capases are synthesized as inactive proenzymes comprising an N-terminal peptide (prodomain) together with one large and one small subunit. The crystal structures of both caspase-1 and caspase-3 show that the active enzyme is a heterotetramer, containing two small and two large subunits. Activation of caspases during apoptosis results in the cleavage of critical cellular substrates, including poly(ADP-ribose) polymerase and lamins, so precipitating the dramatic morphological changes of apoptosis. Apoptosis induced by CD95 (Fas/APO-1) and tumour necrosis factor activates caspase-8 (MACH/FLICE/Mch5), which contains an N-terminus with FADD (Fas-associating protein with death domain)-like death effector domains, so providing a direct link between cell death receptors and the caspases. The importance of caspase prodomains in the regulation of apoptosis is further highlighted by the recognition of adapter molecules, such as RAIDD [receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain]/CRADD (caspase and RIP adapter with death domain), which binds to the prodomain of caspase-2 and recruits it to the signalling complex. Cells undergoing apoptosis following triggering of death receptors execute the death programme by activating a hierarchy of caspases, with caspase-8 and possibly caspase-10 being at or near the apex of this apoptotic cascade.

/pdf/caspases-the-executioners-of-apoptosis-2w1nis6q3n.pdf

Caspases: the executioners of apoptosis

https://www.urologic.theclinics.com/article/S0094-0143(05)70346-3/pdf

New approaches to adjuvant therapy for patients with adverse histopathologic findings following radical prostatectomy

This Viewpoint discusses ways to improve the physical examination using principles of measurement science and technology development.

Reengineering the Physical Examination for the New Millennium

Prediagnostic serum selenium levels and the risk of prostate cancer development

Publisher Summary Prostate cancer is one of the most common malignancies in Western men, and risk factors include age, race, inherited genes, and environmental factors, such as diet. Although the precise molecular mechanisms underlying carcinogenesis and progression are currently unknown, histological studies indicate a multistage developmental progression. The existence of premalignant lesions has been demonstrated in the prostate based on shared histological and molecular features with adenocarcinoma, as well as prevalence and severity. Prostate cancer arises from the accumulation of genetic and epigenetic alterations. Cytogenetic analyses have demonstrated the prevalence of chromsomal aberrations associated with prostate tumorigenesis and many genes that map to deleted or amplified regions have been investigated for their roles in disease progression. In recent years, genome-wide profiling of prostate tumors has led to the identification of a number of biomarkers and pathways that are altered in prostate cancer, some of which may be potential molecular targets for therapy. Despite the advancing knowledge of genes altered in prostate adenocarcinoma, the precise molecular pathways, their combinatorial relation, and the ordering of events utilized in the development of preneoplastic lesions and adenocarcinoma are still being refined. To elucidate mechanisms and to begin to test new therapies and preventative strategies for human prostate cancer, a number of groups have been developing novel animal models of prostate cancer. These models will help to define many aspects of the molecular and cellular pathogenesis of prostate cancer, such as the role of inflammation, angiogenesis, and stromal-epithelial interactions. This chapter highlights the recent advances in the understanding of the molecular pathology of prostatic adenocarcinoma and the latest developments in mouse prostate cancer models.

Molecular Pathogenesis of Prostate Cancer: Somatic, Epigenetic, and Genetic Alterations

Purpose
Sex steroid hormone concentrations and insulin-like growth factor (IGF) proteins have been independently associated with risk of cancer, chronic diseases, and mortality. However, studies that evaluated the inter-relation between the sex hormones and IGF pathways have provided mixed results. We examined the association between endogenous sex hormones and sex hormone-binding globulin (SHBG) with IGF-1 and IGF-binding protein 3 (IGFBP-3) in a population-based sample of US men.

/pdf/association-between-endogenous-sex-steroid-hormones-and-4ng4l2ouy4.pdf

William G. Nelson

Papers

New approaches to adjuvant therapy for patients with adverse histopathologic findings following radical prostatectomy

Reengineering the Physical Examination for the New Millennium

Prediagnostic serum selenium levels and the risk of prostate cancer development

Molecular Pathogenesis of Prostate Cancer: Somatic, Epigenetic, and Genetic Alterations

Association between endogenous sex steroid hormones and insulin-like growth factor proteins in US men