Regulation of Proliferation-Survival Decisions during Tumor Cell Hypoxia

ABSTRACT

Hypoxia may influence tumor biology in paradoxically opposing ways: it is lethal as a direct stress trigger, yet hypoxic zones in solid tumors harbor viable cells which are particularly resistant to treatment and contribute importantly to disease relapse. To examine mechanisms underlying growth-survival decisions during hypoxia, we have compared genetically related transformed and untransformed fibroblast cells in vitro for proliferation, survival, clonogenicity, cell cycle, and p53 expression. Hypoxia induces G₀/G₁ arrest in primary fibroblasts but triggers apoptosis in oncogene-transformed derivatives. Unexpectedly, the mechanism of apoptosis is seen to require accumulated acidosis and is rescued by enhanced buffering. The direct effect of hypoxia under nonacidotic conditions is unique to transformed cells in that they override the hypoxic G₀/G₁ arrest of primary cells. Moreover, when uncoupled from acidosis, hypoxia enhances tumor cell viability and clonogenicity relative to normoxia. p53 is correspondingly upregulated in response to hypoxia-induced acidosis but downregulated during hypoxia without acidosis. Hypoxia may thus produce both treatment resistance and a growth advantage. Given strong evidence that hypoxic regions in solid tumors are often nonacidotic (G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3:177–182, 1997), this behavior may influence relapse and implicates such cells as potentially important therapeutic targets.

ACKNOWLEDGMENTS

We thank G. McGill for providing Myc/Ras-transformed REF and S. Lowe, T. Jacks and D. Housman for the E1a/Ras-transfected MEF cell lines. We also thank L. Hlatky, E. Bump, N. Coleman, and M. Dewhirst for assistance with the hypoxic chambers and the hypoxic incubator as well as useful discussions and comments.

C.S. is the recipient of a scholarship from the Deutsche Forschungsgemeinschaft (Schm 1200/1-1). This work was supported by NIH grant CA 69531 (to D.E.F.). D.E.F. is a Nirenberg Fellow at Dana Farber Cancer Institute and is a Fellow of the Pew Foundation and the James S. McDonnell Foundation.