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The Role of Hypoxia-Inducible Factor-1 in Three-dimensional Tumor Growth, Apoptosis, and Regulation by the Insulin-Signaling Pathway

¹ Growth Factor Group, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom and ² School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom

Requests for reprints: Adrian L. Harris, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. Phone: 441-865-226184; Fax: 441-865-222431; E-mail: a.harris{at}cancer.org.uk.

The purpose of this study was to establish the effect of hypoxia-inducible factor-1 (HIF-1) directly on tumor growth, independently of angiogenesis. This was done by growing wild-type mouse hepatoma cells (HEPA-1) and their HIF-1–deficient counterpart C4 as multicellular tumor spheroids and quantifying differences in growth rates and proliferative and apoptotic indices. Insulin and insulin-like growth factor-I are key growth factors, also able to regulate hypoxia-responsive genes via HIF-1; thus, the effects of insulin on this model were also investigated. Two-dimensional growth was serum dependent and no difference was seen between wild-type HEPA-1 and C4 cell growth profiles, but major differences were seen in three-dimensional growth. HIF-1 supported spheroid growth under hypoxia as the HEPA-1 spheroids grew faster than the C4. Surprisingly, the HIF-1–deficient cells had a higher proliferation rate in three-dimensional growth (C4 mean S-phase index, 13.6%; HEPA-1 mean S-phase index, 9%; P = 0.009) that was associated with an inhibition of apoptosis. However, the apoptosis rate was much greater in these spheroids (C4 mean apoptotic index, 6.4; HEPA-1 mean apoptotic index, 0.78%; P = 0.0006). Addition of insulin increased proliferation and apoptosis in both HEPA-1 and C4 spheroids, demonstrating an HIF-1–independent effect of insulin signaling in three-dimensional growth. These results indicate that the enhancing effect of HIF-1 in three-dimensional tumor growth is a balance of both reduced proliferation and enhanced survival, the latter being proportionally greater.

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