Introduction Understanding the molecular processes mediating colorectal cancer (CRC) tumorigenesis will enable the development of targeted therapies that selectively disrupt the pathways responsible for tumour growth. The gastrin family of growth factors promote CRC growth, invasion and angiogenesis. Hypoxic microenvironments, caused by tumours outgrowing their local blood supply, stimulate aggressive tumour behaviour. However, the effect of hypoxia on gastrin expression in CRC is unknown.
Methods Expression of the gastrin gene in the CRC cell line LoVo was examined under conditions of normoxia and hypoxia. The effect of inhibiting expression of HIF-1α (the transcriptional master regulator of cellular responses to hypoxia) and of deleting HIF-binding sites in the gastrin promoter was investigated. The effect of inhibiting gastrin expression on CRC cell behaviour in vitro and on tumorigenesis in mouse xenografts was analysed.
Results Gastrin gene expression in CRC cells is stimulated by hypoxia by HIF-1α binding to the gastrin promoter. The viability of hypoxic (1% O2) gastrin knockdown cells in vitro is diminished due to loss of resistance against hypoxia-inducible apoptosis. In xenografts in mice exposed to hypoxia (10% O2) for 21 days, apoptosis is significantly increased by knocking down gastrin expression.
Conclusion This work provides evidence that gastrin expression is involved in the adaptation of CRCs to hypoxic microenvironments through resistance to apoptosis. Shrinkage of CRC liver metastases by the angiogenesis inhibitor bevacizumab is dependent on hypoxia-induced apoptosis. Therapies that target gastrin may enhance the therapeutic efficacy of bevacizumab and increase secondary resectability rates in patients with CRC liver metastases.
Disclosure of Interest None Declared.
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