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 G 0 /G 1 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 G 0 /G 1 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.

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

“…Resistance to hypoxia-induced apoptosis, in particular, is an important factor in the progression of human neoplasias and in the development of resistance to chemotherapy (Harris, 2002). This is because selective elimination of apoptosis-sensitive cells leads to expansion of cells that are more resistant to treatment and thus contribute to tumour relapse (Schmaltz et al, 1998). In contrast to solid tumours, little is known about how the cells of haematopoietic tumours escape apoptosis induced by hypoxic stress.…”

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

“…p53 accumulated under hypoxia and was required for induction of apoptosis. However, although reduced, hypoxia-induced apoptotic death was also detected in p53 null cells, indicating the presence of p53-independent pathways (Graeber et al, 1996;Kim et al, 1997;Schmaltz et al, 1998). Involvement of Apaf-1, caspase-9, and genes of the bcl-2 family has also been reported (Shimizu et al, 1995;Soengas et al, 1999).…”

“…Firstly, hypoxic cells slow down or even arrest their rate of progression through the cell division cycle (Durand and Raleigh, 1998). Experiments conducted in mammalian cells of different origin showed that prolonged hypoxia causes accumulation in the G 1 -phase of the cell cycle and inhibition of DNA replication, effects reversible upon reoxygenation (Amellem and Pettersen, 1991;Giaccia, 1996;Krtolica and Ludlow, 1996;Schmaltz et al, 1998). In experimental tumors, the fraction of proliferating cells and/or the rate of cell proliferation decreased as the distance from the vasculature increased (Tannock, 1968;Minchinton et al, 1990;Rodriguez et al, 1994).…”

Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

“…Still, it has been proposed that hypoxic areas in solid tumors may select more aggressive tumor clones which can survive under stress conditions (Sowter et al, 2003;Giatromanolaki et al, 2004). The rationale behind this hypothesis rests on the facts that: (a) hypoxia increases the mutational rate in the cells and (b) cells which gained a survival advantage by resisting apoptosis under hypoxic conditions also became more resistant to cancer therapy (Graeber et al, 1996;Reynolds et al, 1996;Schmaltz et al, 1998).…”