Overview of Biological Functions of Cancer Cells

Understanding of biological functions of cancer cells is of universal importance and prerequisite for establishing effective strategy for prevention, diagnosis, treatment and prognosis of cancer. Since our grasp of cancer as a result of aberrant action of several gene products that regulate normal cellular function, much effort has been made to characterize cellular functions peculiar to cancer cells and its molecular basis. Apoptosis is a cellular mechanism that maintains a balance of various cellular functions through the active elimination of unnecessary cells from the living organism. Its appropriate execution is important for proper animal development, namely early embryogenesis, later morphogenesis and body-shape-making. In adult, apoptosis is still important for balancing homeostasis and, as highlighted in this review, for preventing growth of aberrantly proliferating or malignantly transformed cells. All of normal cells, with an important exception in germ cells, will die according to their pre-programmed longevity, in other words, aging and senescence, in which proper arrangement of chromosomes will be distorted. Even before the longevity, cells exposed to serious damages that include the exposure to ultraviolet, radioactivity, medicines etc. undergo cell death by apoptosis or necrosis, another style of cell death involving passive or unpredicted processes. In general, cancer cells arise from a summation of mutations occurred on some genes that are critically important for normal cell proliferation and/or cell death. It means that cancer cells acquire not only the ability to proliferate aggressively but also the ability to escape from being killed by themselves (anti-apoptosis) or by other reasons (anti-longevity or anti-necrotic cell death). With an emphasis on anti-apoptotic mechanism of cancer cell function, our studies on human cancer cells have demonstrated the following:

Analysis of Bladder Carcinoma Cells Focusing on its Resistance to Apoptosis

There are several experimental conditions that promote apoptosis in cultured cancer cells. They include application of Fas ligand, a death inducer, or anti-Fas antibody, hypoxia, hydrogen peroxide, irradiation, and chemical inhibitors for metabolic enzymes or signaling pathways etc.. Serum starvation serves as one of such pro-apoptotic cellular conditions examined to date. At the initial stage of carcinogenesis, cancer cells are not necessarily surrounded by capillary system. Under such microenvironment, however, cancer cells can proliferate effectively; thereby they are capable of inducing angiogenesis that will help cancer cells to populate more and to undergo invasion and metastasis. We have employed human bladder carcinoma cell line 5637 as a model cell system to analyze molecular mechanism of serum starvation-resistant growth of cancer cells. Survival and growth of this cell line in serum-free conditions have been reported to involve the actions of ligands for epidermal growth factor receptor/kinase (EGFR/kinase), suggesting that protein tyrosine phosphorylation plays a central part of survival signaling. In support of this, immunoblotting with anti-phosphotyrosine antibody has demonstrated that a number of proteins become tyrosine-phosphorylated in response to serum starvation. Interestingly, time course of increase in tyrosine phosphorylation is quite slow; about eight hours are required for its plateau phase, indicating that up-regulation of EGFR/kinase ligands, if any, may need some hours to be promoted. Immunoprecipitation studies have demonstrated that 170-kDa EGFR/kinase is tyrosine-phosphorylated in serum-starved 5637 cells; however, it is different from a more prominently tyrosine-phosphorylated protein of 145 kDa. Mass spectrometric analysis has demonstrated that it is β-subunit of hepatocyte growth factor receptor/kinase (HGFR/kinase or c-Met). Although HGFR/kinase and its cognate high affinity ligand HGF/scatter factor (SF) have been originally identified in liver cells (hepatocytes), they are ubiquitously expressed in many kinds of cells and tissues, and implicated in a number of cellular functions (growth, differentiation, apoptosis etc.). Therefore, it is possible to think that, in addition to EGFR/kinase and its ligands, HGFR/kinase and HGF/SF are involved in the survival mechanism of 5637 cells under serum-free conditions. (to be continued)

Research Background and problems on Egg Project

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