The transcriptional regulators hypoxia-inducible factor 1α (HIF1α) and HIF2α are overexpressed in many cancers, and it has been sug-gested that the HIFs could be poten-tial anti-cancer therapeutic targets. Two studies from Celeste Simon and colleagues now describe differing roles of HIF2α in tumour develop-ment, indicating that therapeutically targeting this protein may not be straightforward and that context-dependent effects should be taken into account.

Tumour-associated macrophages (TAMs) migrate towards and accu-mulate in hypoxic regions of tumours and have been implicated in tumour progression, although their role is controversial as previous reports have described both beneficial and adverse effects of TAMs on tumour growth. As overexpression of HIF2α in TAMs has previously been correlated with high tumour grade and poor prognosis, Imtiyaz et al. examined the effects of myeloid-specific deletion of Hif2a in mouse models of inflammation-associated hepatocellular carcinoma or colitis-associated cancer. In both models, the authors observed that deletion of Hif2a in macrophages led to the decreased infiltration of TAMs into tumours, reduced tumour cell mitosis and delayed tumour growth, suggesting that HIF2α is needed for efficient TAM recruitment to tumours and that these inflammatory cells have a role in driving cancer progression.

The results of this first study are consistent with other studies that have indicated a tumour-promoting role for HIF2α; however, a study from Mazumdar et al. reports the surprising result that HIF2α can also have a tumour suppressive role. The authors deleted Hif2a in a KrasG12D mouse model of lung cancer and found that loss of HIF2α pro-moted tumour progression. What transcriptional targets of HIF2α might be responsible for its tumour suppressive effect? The authors identified several downregulated HIF2α target genes, including the putative tumour suppressor Scgb3a1. They extended their studies to human lung adenocarcinoma A549 cells that contain an activating KRAS mutation, and observed downregulation of SCGB3A1 after short hairpin RNA-mediated HIF2A knockdown and increased growth of these cells as tumour xenografts in immunocompromised mice. Restoration of HIF2A expression or ectopic expression of SCGB3A1 in the xenografted A549 cells led to the suppression of tumour growth. HIF2α directly binds to sites in the SCGB3A1 promoter, and levels of bound HIF2α are increased in hypoxic conditions. Moreover, the levels of HIF2A and SCGB3A1 transcripts correlate in human non-small-cell lung cancer samples, supporting the idea that HIF2α directly regulates SCGB3A1 transcription. SCGB3A1

has previously been reported to inhibit AKT signalling, and consist-ent with this, the authors observed increased levels of activated AKT after HIF2A knockdown, suggesting that AKT signalling is important for the increased proliferation of HIF2A-knockdown cells.

These authors suggest that although HIF2α overexpression can contribute to tumour progression, reduction of HIF2α below a crucial threshold level might have para-doxical tumour-promoting effects by reducing the expression of tumour suppressor genes, such as SCGB3A1, and this might have important conse-quences for HIF-targeted therapeutic strategies.

Meera Swami

ORIGINAL RESEARCH PAPERS Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 19 Jul 2010 (doi:10.1172/JCI39506) | Mazumdar, J. et al. HIF-2a deletion promotes Kras-driven lung tumor development. Proc. Natl Acad. Sci. USA 21 Jul 2010 (doi:10.1073/pnas.1001296107)

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The HIF2α puzzle

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NATuRe RevIeWS | CanCer voluMe 10 | SepTeMBeR 2010

Nature Reviews Cancer | Aop, published online 12 August 2010; doi:10.1038/nrc2921

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