As described above, host immune cells such as TANs and TAMs contribute to some of the proposed mechanisms of anti-VEGF therapy resistance [47,48,52,145]. the VEGF pathway. These mechanisms are involved in the development of resistance to anti-VEGF therapies in cancer patients. gene  (Physique 1). Among these, VEGF121 and VEGF165 are the two major isoforms. VEGF121 binds solely to VEGFR1 and VEGFR2, whereas VEGF165 binds to the co-receptors neuropilin (NRP)-1 and -2 via its basic sequence encoded in exon 7, which enhances the binding of VEGF165 to VEGFR2 and promotes its bioactivity . As for the receptors, VEGFR2 is usually expressed on endothelial cells whereas VEGFR1 is usually expressed on endothelial cells and other cell types, such as smooth muscle cells, fibroblasts, myeloid progenitors, macrophages, and various types of cancer cells . Although the angiogenic effect of VEGFA is usually predominantly mediated by VEGFR2, VEGFR1 signaling plays a role in tumor cell survival and growth [9,10,11]. Open in a separate window Physique 1 Schematic representation of the VEGFA isoforms. Each number indicates the exon composition and the isoforms consist of splicing variants of these exons from the gene. In 1993, a monoclonal neutralizing antibody against VEGFA was reported to inhibit tumor growth in the in vivo xenograft model . This idea led to the development of bevacizumab (Avastin), a recombinant humanized monoclonal antibody specific to VEGFA. In 2004, bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (CRC) . In addition, various other inhibitors of the VEGF signaling pathway have been developed. The RTK inhibitors (RTKIs) sunitinib (Sutent) , sorafenib (Nexavar) , and pazopanib (Votrient)  are currently approved for the treatment of various types of cancers. Aflibercept (Zaltrap), a soluble recombinant fusion protein that consists of the extracellular domains of VEGFR1 and VEGR2 fused to the Fc portion of human IgG1, neutralizes VEGFA, VEGFB, and placental growth factor (PlGF), and was approved in 2012 by the FDA for the treatment of metastatic CRC . Ramucirumab (Cyramza) is also a monoclonal antibody that binds VEGFR2 to block the VEGF signaling pathway and has been approved by the FDA for the treatment of several types of solid cancers . GSK 2830371 Despite a large amount of promising data from animal experiments, simply blocking the VEGF signaling pathway by an anti-VEGF monotherapy appears to be ineffective for advanced cases in the clinical setting . This primary or de novo treatment resistance is a common problem in the treatment of cancer patients, even with the most recent sophisticated drugs. Resistance to anti-VEGF therapy often occurs owing to the escape mechanisms of the angiogenic process through the activation of signaling pathways other than the VEGF pathway. Moreover, it has been proposed that this inhibition of VEGFR by RTKI or an antibody promotes tumor invasiveness and Rabbit Polyclonal to PTGDR metastasis [20,21]. In this review, we summarize the proposed alternative pathways that are involved in the emergence of resistance to anti-VEGF therapy in cancer. 2. Alternative Angiogenic Pathways to the VEGF Pathway That Influence Anti-VEGF Treatment Although the GSK 2830371 VEGF pathway induces the most profound angiogenesis during tumor formation, the prediction of the presence of alternative angiogenic pathways is relevant as we observe various anti-VEGF resistant cancers. In this section, we discuss the potential angiogenic factors that are proposed to contribute to the escape from anti-VEGF treatment (Physique 2, right). Open in a separate window Physique 2 Alternative angiogenic factors are listed on the right side and phenotypical tumor changes are listed on the left side. 2.1. Angiopoietin-2 (Ang2) AngiopoietinCTie signaling is a vascular-specific RTK pathway that is GSK 2830371 essential for blood vessel development, remodeling, and regulation of vascular permeability. Angiopoietin-1 (Ang1) was initially identified as an agonist of the Tie2 receptor, activating this pathway; GSK 2830371 angiopoietin-2 (Ang2) was identified as an antagonist of the Tie2 receptor . Ang1 affords maturation or stabilization of blood vessels through Tie2, which can be blocked by Ang2, while such inhibition by Ang2 results in the remodeling or initiation of vascular sprouts in the.