| Project Overview: | Hypoxia resistance and inherent tolerability to hypovascular environments have been observed in some cancer types. Furthermore, the selection of hypoxia resistant cancer cells with the ability to thrive in a therapy induced low oxygen environment has previously been reported and inactivating p53 mutations have been identified to contribute to hypoxia resistance. A large scalesiRNA screen of hypoxia resistance genes in C. elegans highlighted the complexity of this process, identifying almost 200 genes from a variety of functional gene groups such as signaling molecules, metabolic genes and genes controlling protein translation that influence survival under hypoxic conditions. Knockdown of several of these genes also led to hypoxia resistance in human cancer cell lines. This indicates that hypoxia sensitivity is strongly determined by the genetic background through distinct and complex cellular pathways. Unpublished data generated by the PREDICT consortium demonstrates that some RCC cell lines are highly sensitive to cytostatic hypoxia effects (0.2% O2) whereas others continue to proliferate showing that hypoxia sensitivity is variable in RCC cells. Importantly, the hypoxia sensitivity is not associated with either p53 or VHL status in the small panel of RCC cell lines studied to date. Thus, hypoxia resistance is likely to contribute to VEGF-targeted therapeutic resistance. Furthermore, hypoxia can induce genetic instability in cancer cells and the steady proliferation of hypoxia resistant cancer cell clones could foster the acquisition of additional mutations that may permit the tumour to re-establish a resistant vasculature (e.g. through activation of alternative pro-angiogenic pathways and factor secretion). |
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| Screener: | Claudio Santos (Swanton Lab). Extension:3462, Rm 115 |
| Project Status: | Published |
| Project Start Date: | Jan 2011 |
| Keywords: | Hypoxia Kidney cancer Viability |
| Libraries Screened: |
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