Normalizing tumoral vessels to treat cancer: an out-of-the-box strategy involving TIE2 pathway

The idea of targeting vessels for cancer therapy, termed antiangiogenesis, was coined by Folkman in his pioneer report in 1971 (1,2). Folkman’s seminal contribution to cancer biology was the early description of what we now understand as the tumor microenvironment (2). In this manuscript, he postulated that tumor growth depends on vessel recruitment and that the growth of vascular and tumor cells are interdependent. Per instance, he stated that the maintenance of the mitotic index of the two cell populations depends on each other, and that the secretion of diffusible factors from tumor cells influences the formation of tumor capillaries (1). Furthermore, he described that the blockade of pro-angiogenic signals resulted in the regression of the new blood vessels. In addition, he hypothesized that central tumor necrosis is the consequence of poor perfusion due to increased internal pressure and decreased of the blood flow at the tumor site (1,2). This hypothesis was tested by Rakesh Jain who demonstrated that Folkman’s assumption was correct, and further suggested that increased interstitial fluid pressure might impede the delivery of large anticancer agents to tumors (2,3).