Reactive Oxygen Species More for Tumor Cell Initiation Less for Metastasis Formation

ROS and RNS are closely linked to degenerative diseases such as Alzheimer's disease, Parkinson, neuronal death including ischemic and hemorrhagic stroke, acute and chronic degenerative cardiac myocyte death, diabetes mellitus type 2 and cancer. As a by-product of oxidative phosphorylation (mitochondrial respiration), a steady stream of reactive species emerges from our cellular energy plant, the mitochondria. ROS and RNS potentially cause damage to all cellular components. Structure alterations, biomolecule fragmentation, and oxidation of side chains are trade-offs of the cellular energy production. ROS and RNS production results in the activation of cyto-solic stress pathways, DNA damage, and the upregulation of JNK, p38, and p53. Incomplete scavenging of ROS and RNS, e.g. by the enzymes superoxide dismutase and catalase particularly, affects the release of mitochondria cytochrome c with subsequent activation of caspase 9 and 3 and ultimately induces the intrinsic death pathway.

However, if normal protective cell growth mechanisms are defective due to (i) increased and uncontrolled ROS and RNS production, e.g. caused by increased glucose consumption, and (ii) the resulting glycolytic state does not lead to an elimination of affected cells (apoptosis), then ROS and RNS may cause mutagenesis of nuclear proto-oncogenes (initiation phase of carcinogenesis) and drive nuclear replication (promotion phase of carcinogenesis), resulting in the presence of a tumor promoter in a cancer cell.

It is widely accepted that increased levels of ROS contribute to carcinogenesis. However, this claim has been scarcely confirmed by experiments and may be only plausible for the initiation of a normal cell, which become a cancer cell during the process of dedifferentiation. In contrast, it has been clearly demonstrated that ROS are normal cellular signals and defense mechanisms that induce cell differentiation and apoptosis, the opposite process to cancer [3].

Otto Warburg recognized that cancer cells (not normal cells!) generate excessive lactate in the presence of oxygen (aerobic glycolysis) which is a return to the more glycolytic metabolism of embryonic tissue. In this context, Gillies and Gatenby [4] describe a more profound teleological understanding of the need for altered metabolism of invasive cancer cells. They used mathematical models and empirical observations to define the adaptive advantage of aerobic glycolysis during the somatic evolution of invasive cancer and explain its remarkable prevalence in human cancers. Increased consumption of glucose in metastatic lesions is not used for substantial energy production via Embden-Meyerhoff glycolysis, but rather for production of lactic acid, which gives the cancer cells a competitive advantage for invasion by causing an unfavorable environment for normal cells; furthermore, glucose is used for generation of reducing equivalents (NADPH) or anabolic precursors (ribose).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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