The role of hypoxic signaling in evasive tumor resistance against anti-angiogenic therapy

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TrompakOmelyan_2019_11_04.pdf (8.01 MB)

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2019

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DOI:
http://dx.doi.org/10.22029/jlupub-14744

Abstract

Rapidly growing tumors depend on supply of oxygen and nutrients and avascular neoplastic lesions do not grow larger than 1-2 mm in diameter. At a very early stage of tumor growth, a phenotypic shift occurs, referred to as angiogenic switch , during which hypoxia induces secretion of angiogenic factors by tumor cells driving the formation of new vessels, which is a critical milestone in tumor progression. Realization of this key feature of tumor biology led Judah Folkman in the 1970s to propose a novel therapeutic approach anti-angiogenic therapy, the rationale for which was based on blocking the growth of tumor vessels. At that time, it was believed that since tumor cells were not the primary target, no resistance mechanisms would be encountered. Yet, after the first clinical trials, it became obvious that tumors could indeed adapt to the therapy. One of the resistance mechanisms, which is the primary focus of the current thesis, is characterized by increased invasion and metastasis, preventing wider application of anti-angiogenic agents for the treatment of various carcinomas.Epithelial-to-mesenchymal transition (EMT), a process characterized by specific changes in epithelial cells leading to weakening of cell-to-cell contacts and increased motility, has been shown to regulate tumor cell migration and metastatic dissemination. Since hypoxia is a well characterized trigger of EMT, we hypothesized that enhanced tumor hypoxia generated by anti-angiogenic therapy could be the driver of this form of resistance. To explore this hypothesis, several in vivo models of treatment with anti-angiogenic drugs (sunitinib, sorafenib, or bevacizumab) were established, which revealed increased metastasis following therapy. Next, using human lung and breast cancer lines re-isolated from tumors of animals receiving antiangiogenic therapy with sunitinib, we could show that these cells acquire a stable EMT-phenotype with invasive and metastatic traits. Importantly, the cells isolated from tumors of animals receiving anti-angiogenic therapy were more responsive to hypoxia, showing increased levels of hypoxia inducible factor 2 alpha (HIF2alpha). We could further show that prolonged exposure to intermittent hypoxia is sufficient to induce an EMT phenotype in tumor cells. Moreover, loss of function experiments identified HIF2alpha as a factor required for maintenance and acquisition of the EMT phenotype. Finally, we identified DNA demethylation mediated by the Ten-Eleven Translocation 1 (TET1) methylcytosine dioxygenase as a mechanism by which intermittent hypoxia upregulates HIF2alpha expression.Taken together, our findings provide insight into the mechanisms underlying evasive resistance of tumors to anti-angiogenic therapy. In particular, we show that intermittent hypoxia induces a feed-forward loop involving HIF2alpha and TET1 which leads to epigenetic reprogramming of tumor cells promoting enhanced tumor response to hypoxia and increased invasion and metastasis. This work may contribute to a more rational approach to anti-angiogenic therapy, specifically combining anti-angiogenic and HIF2alpha-targeting approaches, which could potentially decrease the risk of tumor metastasis, and thus improve the clinical outcome of anti-angiogenic treatment.

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