Circulating Tumor Cells and the role of hypoxia in the metastatic process

Research on breast cancer has underscored a critical interaction between breast cancer circulating tumor cells (CTCs) and hypoxia in leading cancer progression. Originating from the primary tumor as single or clustered cells, CTCs enter the bloodstream and migrate through a metastatic cascade to colonize different organs, including the brain, contributing to poor clinical outcomes. Hypoxia influences this process by inducing a series of modification at the transcriptional and proteomic level that increase CTC malignancy as well as their ability to survive, proliferate and metastasize. Researchers aimed to have a better insight on the multiple aspects of this interaction to develop new therapies that could be more targeted. At first, they observed that clustered rather than single CTCs are mostly hypoxic, and that intra-tumor hypoxia results in a higher CTC cluster shedding rate and metastasis formation. In this context, pro-angiogenic treatments may inhibit the release of CTCs in concomitance with conventional chemotherapeutic approaches to counteract primary tumor growth. Next, in consideration of breast CTC tropism to the brain, scientists observed that HIF1α overexpression correlates with enhanced proliferation in the brain and a worse prognosis, and that HIF1α downmodulation specifically impairs brain tumor growth, pointing to relevant therapeutic implications. Researchers then discovered that hypoxia exerts a prolonged effect to promote metastasis. Indeed, it induces an immunosuppressive signaling that remains sustained even after returning to normoxic conditions, determining a ‘hypoxic memory’ that enhances the metastatic propensity of cancer cells. Lastly, they found that the histone deacetylase inhibitor Entinostat is able to erase this ‘hypoxic memory’. Overall, these data highlight the multiple mechanism by which hypoxia affects the metastatic ability of breast cancer CTC, paving the way for innovative therapeutic approaches.