HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

Abstract

Hypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles

“…Meanwhile, cobalt prevented the interaction between hydroxylated HIF-a and pVHL, which suppressed subsequent ubiquitination as well as degradation of HIF-a and stabilized the expression of HIFa. The major regulator of the hypoxic response is the transcription factor hypoxia-inducible factor-1a (HIF-1a), and a previous study has shown that HIF-1a accumulates rapidly during CoCl 2 -stimulated hypoxia to induce a hypoxic-like response in tumor cells (Harrison et al, 2018). Meanwhile, Sinnberg et al have reported that CoCl 2 was used as an inducer for HIF-1a to evaluate the cytotoxic effects of ascorbate on cancer cells (Sinnberg et al, 2014).…”

Cancer stem cells: Culprits in endocrine resistance and racial disparities in breast cancer outcomes

“…Interestingly, ER + breast cancer cells are less sensitive to ET when hypoxic, while HIF2α levels are increased in endocrine-resistant cells [46]. ET exposure further increases HIF2α expression in these endocrine resistant cells.…”

Hypoxia‐induced secretion stimulates breast cancer stem cell regulatory signalling pathways

“…Our group has previously shown that reduced oxygen levels have an opposing, direct estrogen receptor (ER)-a-dependent effect on breast cancer stem cell (BCSC) populations (Harrison et al, 2013). Given that many reports highlight secretion as a mean for tumour cells to communicate within the tumour microenvironment, we hypothesized that hypoxic regions secrete factors to nearby cells and thereby influence cellular plasticity and expansion or reduction of stem cell properties (Harrison et al, 2018;Hu et al, 2009;Tyan et al, 2011).…”