Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression

Here, we emphasize the role of hypoxia and acidosis in the progression of tumor from in situ to invasive cancer. This is a consequence of early tumor cell proliferation on epithelial surfaces, which are separated from the underlying blood supply by the intact basement membrane. As tumor cells proliferate further away from the basement membrane, the diffusion-reaction kinetics of substrate and metabolite flow to and from the blood vessels result in regional hypoxia and acidosis. Cellular adaptation to the former include upregulation of glcyolysis and to the latter include upregulation of Na+/H+ exchangers (NHE1) and other acid-regulating proteins such as carbonic anhydrase. We propose this phenotype is critical for subsequent malignant growth of primary and metastatic cancers.