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The cancer stem‐like cell niche for dedifferentiation, drug resistance and aggressiveness: modulation of tumor angiogenesis normalization to develop potent anti‐cancer therapies.
In solid tumours hypoxia is a key regulator of growth and invasion. Hypoxic tumours tend to develop their own blood supply, by tumour angiogenesis, which facilitates metastatic spreading. An allosteric effector of haemoglobin, taken up by red blood cells (RBC), enhances oxygen release, counteracts the effects of hypoxia and inhibits angiogenesis in vitro. We show, in a mouse experimental model, that this treament reduces lung metastasis in mouse melanoma. Associated to chemotherapeutic agents: cisplatin and paclitaxel, it inhibited primary melanoma growth and lung metastases. The mechanism is the reduction of tumour neoangiogenesis and reorganisation of tumour vasculature, switching from anarchic to well‐organized, non‐leaky, mature vessels. This allows for the effective delivery of chemotherapeutic agents in the primary tumours and spread metastases leading to tumour reduction and metastases eradication. Treatments increases oxygen tension (pO2) and blood flow in tumours, causes long lasting suppression of hypoxia‐inducible factor HIF‐1α and the subsequent gene cascade. This, prevents the selection of high multi drug resistance‐expressing and metastatic cells by hostile hypoxic/acidic microenvironment and the dedifferentiation process of cancer stem like‐cells responsible for hindering antitumor treatments effectiveness. Treatments selectively counteracting tumor hypoxia, by vessel normalisation, open new ways to increase chemotherapy efficiency and to eliminate the consequences and sequels of tumour hypoxia. The knowledge of angiogenesis modulation miRNA brings a breakthrough in this strategy.