The Mathematical Institute, University of Oxford, Eprints Archive

Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Gatenby, R. A. and Smallbone, K. and Maini, P. K. and Rose, F. and Averill, J. and Nagle, R. B. and Worrall, L. and Gillies, R. J. (2007) Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. British Journal of Cancer, 97 (5). pp. 646-653. ISSN 0007-0920

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Abstract

Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer.

Item Type:Article
Additional Information:n/a
Uncontrolled Keywords:carcinogenesis; aerobic glycolysis; GLUT-1; NHE; hypoxia; mathematical models
Subjects:A - C > Biology and other natural sciences
Research Groups:Centre for Mathematical Biology
ID Code:646
Deposited By:Philip Maini
Deposited On:03 Sep 2007
Last Modified:20 Jul 2009 14:23

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