Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine

Abstract

Primary solid tumors originate close to pre-existing tissue vasculature, initially growing along such tissue blood vessels, and this phenomenon is important for the metastatic potential which frequently occurs in highly vascularized tissues. Unfortunately, preclinic and clinic anti-angiogenic approaches have not been very successful, and multiple factors have been found to contribute to toxicity and tumor resistance. Moreover, tumors can highlight intrinsic or acquired resistances, or show adaptation to the VEGF-targeted therapies. Furthermore, different mechanisms of vascularization, activation of alternative signaling pathways, and increased tumor aggressiveness make this context even more complex. On the other hand, it has to be considered that the transitional restoration of normal, not fenestrated, microvessels allows the drug to reach the tumor and act with the maximum efficiency. However, these effects are time-limited and different, depending on the various types of cancer, and clearly define a specific "normalization window." So, new horizons in the therapeutic approaches consist on the treatment of the tumor with pro- (instead of anti-) angiogenic therapies, which could strengthen a network of well-structured blood vessels that facilitate the transport of the drug.

Keywords: anti-angiogenic therapy; hypoxia detection; microvascular architecture; pericytes; tumor angiogenesis; tumor endothelial cells (TECs); vascular normalization.

FIGURE 1

Proposed mechanisms of microvessel responses to anti-angiogenic therapy. (A) Tumors may initially respond to anti-angiogenic therapy in different ways, and this response depends on the integrity of microcirculation. (a) Because of the presence of fenestrated vessels with a poor pericyte coverage, chemotherapeutic drug cannot reach the targeted tumor site. Consequently, tumor stabilizes or progresses. (b) The association of an anti-angiogenic drug with an anti-tumor drug in a proper timing window restores a balance between pro- and anti-angiogenic factors, leading to the normalization of blood vessels: the chemotherapeutic drug can reach the targeted tumor site. These effects are limited spatially and temporally, and are different in different types of cancers, particularly in the case of little vascularized tumors. (B) The predictive detection of microvessel architectural parameters is necessary for the selection of a precision and personal therapy, aimed to the vascular normalization, being these parameters based on Magnetic Resonance Imaging (MRI), Vessel Architectural Imaging (VAI), Microvascular Density (MVD), Positron Emission Tomography (PET).