Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression

Abstract

Carcinogenesis is a complex, multistep, multipath process often described as "somatic evolution." Conventional models of cancer progression are typically based on the genetic and epigenetic changes observed in malignant and premalignant tumors. We have explored an alternative approach that emphasizes the selection forces within adaptive landscapes governing growth and evolution in insitu, microinvasive, and metastatic cancers. In each environment, specific barriers to proliferation act as strong selection forces that determine the optimal phenotypic properties that permit tumor growth and invasion. Thus, the phenotypic properties or "hallmarks" of cancer can be viewed as successful adaptations to these microenvironmental selection forces. In turn, these selection pressures are not static but will dynamically change as a result of tumor population growth and evolution.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.

Interfering with pH regulation in tumours as a therapeutic strategy

“…Oncogenic metabolism also generates an excess of protons and carbon dioxide, which are kept in equilibrium with carbonic acid by the enzyme carbonic anhydrase [3][4][5][6][7][8][9] . Thus, increased glucose metabolism in tumour cells leads to enhanced acidification of the extracellular milieu, which is frequently accompanied by various levels of hypoxia.…”

“…They eliminate acidic catabolites by ion transporters and pumps to preserve a slightly alkaline intracellular pH (pH i ), which is optimal for cell proliferation and tumour survival [3][4][5][6][7][8][9][10] . Acid export leads to a reduction in the extracellular pH (pH e ) to values as low as 6.0 (the usual pH e in tumours is in the range of 6.5-7.0) 3 , which is a salient feature of the tumour microenvironment [3][4][5][6][7][8][9] . As well as triggering the overexpression of many proteins involved in glucose metabolism -such as the glucose transporter GLUT1 (also known as SLC2A1) and pH-regulating proteins such as carbonic anhydrase 9 (CA9) 3,4,10 -hypoxia also constitutes a detrimental feature for radiotherapy, as oxygen is needed to oxidize the radiation-induced DNA free radicals that subsequently lead to tumour cell death 4 .…”

“…In tumour cells, these processes are even more complex owing to the internal compartment being slightly more alkaline (pH 7.4 or more) and the external compartment being more acidic than in normal cells [4][5][6][7][8][9] . A variation in the pH i /pH e ratio as low as 0.1 pH units may disrupt important biochemical and/or biological processes such as ATP synthesis, enzyme function and the proliferation, migration, invasion and metastasis of tumour cells 5 ; consequently, a tight regulation of these processes has evolved [5][6][7][8][9] . Changes in the pH i as low as 0.1-0.2 pH units also trigger mechanisms of alternative splicing of extracellular matrix components that generate different isoforms of tenascin and fibronectin, which are typical of tumour cells and not normal cells 11,12 .…”

“…Several sophisticated molecular mechanisms are responsible for maintaining the alkaline pH i and the acidic pH e in tumour cells [5][6][7][8][9][10] . These include proteins that import weak bases (such as the HCO 3 -ion) into the cells and proteins that export the weak acids generated during metabolism -such as carbon dioxide, carbonic acid or lactic acid -out of the cells 4 .…”

“…These include proteins that import weak bases (such as the HCO 3 -ion) into the cells and proteins that export the weak acids generated during metabolism -such as carbon dioxide, carbonic acid or lactic acid -out of the cells 4 . In addition, H + ions are directly extruded from the cells, either in exchange for other cations (such as Na + ) or by means of the vacuolar ATPase (V-ATPase) [5][6][7][8][9]13,14 .…”