Evidence Showing That Tumors Can Grow Without Angiogenesis and Can Switch Between Angiogenic and Nonangiogenic Phenotypes

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....All these results have therefore established the study of non-angiogenic tumors as a new field in cancer biology, but so far we have only just scratched the surface. So what now are the most pressing questions we face? 

One is: what is the biology underlying the non-angiogenic phenotype, and what are the mechanisms that allow a cancer cell to switch between angiogenic and non-angiogenic phenotypes? 

Second, how do the cancer cells interact with and co-opt the pre-existing vessels? Data published so far suggests that this is an active process (26,29). Moreover, how does this process change in different organs? 

Third, does vessel co-option also facilitate resistance to other classes of anti-angiogenic drugs, such as the VEGF-neutralizing antibody bevacizumab?

Fourth, given that vessel co-option occurs in many human cancers, including some of the most prevalent (eg, malignancies from breast, colon, rectum, and lung), is vessel co-option also a mechanism of resistance to anti-angiogenic therapy in humans and not just in animal models? 

Last, but not least, can vessel co-option be inhibited with drugs? The data of Kuczynski and colleagues shows that the response to sorafenib in HCC might be more durable if sorafenib were to be combined with a drug that targets vessel co-option. However, there are currently no drugs designed to target vessel co-option in humans. In our opinion, this represents a major deficiency in the current portfolio of oncology drugs and needs to be addressed urgently. 

Hopefully, this new field of cancer biology will lead to novel therapeutic interventions designed according to the relationship observed between neoplastic cells and vessels in tumor lesions, in the knowledge that tumors can also grow without inducing angiogenesis.