In 2004 Avastin was approved as the first anti-angiogenic drug for human use. Additional anti-angiogenic compounds were approved since, and clinical use has demonstrated that they provide survival advantage
to metastatic renal cancer and, in combination with chemotherapy, to advanced colorectal, breast, and non-small lung cancers. Many clinical trials testing new molecules, new indications and new combinations are
in progress, including in gynecological cancers, including ovarian cancer. Compared to the benefits expected based on preclinical models, patient benefits in term of long-term survival, however, remained modest. Recent
experimental results have demonstrated that tumors treated with antiangiogenic therapies, contrary to initial assumptions, can develop evasive resistance and rapidly progress to become invasive and metastatic. Thus,
in spite of the undisputed success of this new therapeutic approach some old questions on tumor angiogenesis have remained unanswered and new ones have emerged. They include the understanding about how antiangiogenic therapy and chemotherapy synergize, the characterization of the biological consequences of sustained suppression of angiogenesis on tumor biology and normal tissue homeostasis, and the mechanisms
of tumor escape from anti-angiogenesis. Bone marrow-derived and tumor-mobilized cells recruited at tumor sites are emerging as critical determinant of resistance to anti-angiogenic therapy and may represent
novel therapeutic targets. Furthermore, although it has been suggested that biomarkers of angiogenesis would greatly facilitate the clinical development of anti-angiogenic therapies, so far there are no validated biomarkers
of angiogenesis and surrogate biomarkers of anti-angiogenesis. In order to improve the clinical use of available anti-angiogenic drugs and the development of new ones it will be important to challenge some of the
basic concepts of tumor angiogenesis biology and the relationship between tumor vessels and tumor cells. In this lecture I will review some of the emerging critical issues in tumor angiogenesis and discuss their impact on
the development of anti-angiogenic therapies.