Cancer Abstracts 2

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Mitochondria in cancer: not just innocent bystanders
            (Frezza and Gottlieb, 2009) Download
The first half of the 20th century produced substantial breakthroughs in bioenergetics and mitochondria research. During that time, Otto Warburg observed abnormally high glycolysis and lactate production in oxygenated cancer cells, leading him to suggest that defects in mitochondrial functions are at the heart of malignant cell transformation. Warburg's hypothesis profoundly influenced the present perception of cancer metabolism, positioning what is termed aerobic glycolysis in the mainstream of clinical oncology. While some of his ideas stood the test of time, they also frequently generated misconceptions regarding the biochemical mechanisms of cell transformation. This review examines experimental evidence which supports or refutes the Warburg effect and discusses the possible advantages conferred on cancer cells by 'metabolic transformation'.

Mitochondria in cancer cells: what is so special about them?
            (Gogvadze et al., 2008) Download
The past decade has revealed a new role for the mitochondria in cell metabolism--regulation of cell death pathways. Considering that most tumor cells are resistant to apoptosis, one might question whether such resistance is related to the particular properties of mitochondria in cancer cells that are distinct from those of mitochondria in non-malignant cells. This scenario was originally suggested by Otto Warburg, who put forward the hypothesis that a decrease in mitochondrial energy metabolism might lead to development of cancer. This review is devoted to the analysis of mitochondrial function in cancer cells, including the mechanisms underlying the upregulation of glycolysis, and how intervention with cellular bioenergetic pathways might make tumor cells more susceptible to anticancer treatment and induction of apoptosis.


The Warburg effect and mitochondrial stability in cancer cells
            (Gogvadze et al., 2010) Download
The last decade has witnessed a renaissance of Otto Warburg's fundamental hypothesis, which he put forward more than 80 years ago, that mitochondrial malfunction and subsequent stimulation of cellular glucose utilization lead to the development of cancer. Since most tumor cells demonstrate a remarkable resistance to drugs that kill non-malignant cells, the question has arisen whether such resistance might be a consequence of the abnormalities in tumor mitochondria predicted by Warburg. The present review discusses potential mechanisms underlying the upregulation of glycolysis and silencing of mitochondrial activity in cancer cells, and how pharmaceutical intervention in cellular energy metabolism might make tumor cells more susceptible to anti-cancer treatment.

The hallmarks of cancer
            (Hanahan and Weinberg, 2000) Download

Somatic mutation theory of carcinogenesis: why it should be dropped and replaced
            (Sonnenschein and Soto, 2000) Download
The somatic mutation theory of carcinogenesis has been the dominant force driving cancer research during the 20th century. In brief, it proposes that successive DNA mutations in a single cell cause cancer (monoclonality). This theory places carcinogenesis at the cellular and subcellular hierarchical levels of biological complexity. Its basic premises are that (1) cancer is a defect of the control of cell proliferation and (2) the default state of metazoan cells is quiescence. These two premises have recently been contradicted by evidence. Supporters of the theory have dealt with these lacks of fit by incorporating ad hoc explanations similar to the use of epicycles in pre-Copernican astronomy. We propose the adoption of an alternative theory, the tissue organization field theory of carcinogenesis and neoplasia. Its basic premises are that (1) proliferation is the default state of all cells and (2) carcinogenesis and neoplasia are defects of tissue architecture. Carcinogens would act initially by disrupting the normal interactions that take place among cells in the parenchyma and stroma of an organ (the equivalent of the "morphogenetic fields" of developing organisms). Stroma appears as the primary target of carcinogens. Carcinogenesis and neoplasia occur entirely through emergent (supracellular) phenomena. Neoplastic cells may be reprogrammed to behave like "normal" cells within normal tissues. We argue that it is necessary to abandon the somatic mutation theory. Researchers will then become free to adopt alternative reliable premises to build a theory that explains carcinogenesis as another outcome, aberrant as it may be, of biological organization.

References
Frezza, C. and E. Gottlieb (2009), ‘Mitochondria in cancer: not just innocent bystanders’, Semin Cancer Biol, 19 (1), 4-11. PubMed: 19101633
Gogvadze, V., S. Orrenius, and B. Zhivotovsky (2008), ‘Mitochondria in cancer cells: what is so special about them?’, Trends Cell Biol, 18 (4), 165-73. PubMed: 18296052
Gogvadze, V., B. Zhivotovsky, and S. Orrenius (2010), ‘The Warburg effect and mitochondrial stability in cancer cells’, Mol Aspects Med, 31 (1), 60-74. PubMed: 19995572
Hanahan, D. and R. A. Weinberg (2000), ‘The hallmarks of cancer’, Cell, 100 (1), 57-70. PubMed: 10647931
Sonnenschein, C. and A. M. Soto (2000), ‘Somatic mutation theory of carcinogenesis: why it should be dropped and replaced’, Mol Carcinog, 29 (4), 205-11. PubMed: 11170258