Cancer morphogenesis: role of mitochondrial failure.

Adenosine triphosphate (ATP) required for normal cell metabolism is mainly supplied by mitochondrial oxidative phosphorylation (OXPHOS), which is limited by available oxygen and modulated by cell signaling pathways. Primary or secondary OXPHOS failure shifts cell metabolism towards ATP generation by glycolysis (Warburg effect). The objective of this paper is to clarify the role of mitochondrial dysfunction in cancer morphogenesis and to elucidate how faulty morphogen gradient signaling and inflammatory mediators that regulate OXPHOS can cause cancer-induced morphogenesis. Developmental morphogenesis and cancer morphogenesis are regulated by morphogenetic fields. The importance of morphogenetic fields is illustrated by transplantation of metastatic melanoma cells into the chick-embryo; the tumor cells adapt morphologies that resemble normal cells and function normally in the host. A morphogen gradient is a simple form of morphogenetic field. Morphogens such as those of the transforming growth factor (TGF)-beta family inhibit and stimulate basic cell proliferation at high and low concentrations respectively. Along a signaling gradient of declining TGF-beta concentration, with increasing distance from the gradient source, cell proliferation is first gradually less inhibited, and then gradually stimulated, thus generating a concave curved structure. In 3D cell cultures, TGF-beta concentration determines the diameter of the tubules it induces. TGF-beta1 can modulate mitochondrial OXPHOS via adenine nucleotide translocase (ANT) or uncoupling protein (UCP) via COX-2 and prostaglandin (PG) E2. Thus, gradients of TGF-beta can regulate the radius of curvature of tissues by modulating mitochondrial ATP generation. Derailment of morphogen control of mitochondrial ATP synthesis can lead to abnormal spatial variation in ATP supply, abnormal spatial distribution of cell proliferation, and cancer morphogenesis. Involvement of COX-2 in morphogen signaling is a mechanism whereby inflammation can promote carcinogenesis. Restoration of OXPHOS can reverse cancer morphogenesis and restore normal tissue morphology. Avoiding exposure to environmental mitochondrial toxins and toxic food ingredients should reduce the risk of cancer.