Anti-Angiogenics: Their Value in Colorectal Cancer Therapy

Abstract

Angiogenesis is a hallmark of cancer and is regulated by a balance of pro- and anti-angiogenic factors; among them, the vascular endothelial growth factor (VEGF) is the key angiogenic factor. VEGF plays an important role in colorectal cancer (CRC) biology, and its inhibition by using bevacizumab, an anti-VEGF antibody, proved for the first time to be effective and became indispensable for the treatment of metastatic CRC (mCRC). Several large phase III studies showed also relevant responses and tolerability of other anti-angiogenic drugs such as ramucirumab, aflibercept, and regorafenib, and led to the approval of these therapeutics. Nevertheless, the efficacy of anti-angiogenic therapies is rather limited and the high expectations raised by preclinical studies were not fulfilled in the clinics. Furthermore, to date, no predictive biomarkers for anti-angiogenic agents could be identified and validated. Thus, new mechanisms of action are discussed, such as tumor vasculature normalization to improve the accessibility of tumor tissue by drugs or to promote tumor infiltration by host immune cells. Cellular and molecular studies will be necessary to characterize the dynamic changes of the tumor microenvironment and the vascular architecture in individual patients in order to predict responsiveness to anti-angiogenic therapies. In this review, we tried to highlight the standard of care of using anti-angiogenics in mCRC patients and to provide an outlook on potential new substances and strategies.

Tumor-secreted dickkopf2 accelerates aerobic glycolysis and promotes angiogenesis in colorectal cancer

“…Bevacizumab, an anti-VEGF antibody, which is indispensable for the treatment of mCRC, is proved to be effective at first but tolerant in the later treatment. Other anti-angiogenic drugs including ramucirumab, aflibercept and regorafenib also showed similar responses in several studies on late phase CRC patients 31. In this study, we focused on differentially expressed genes in eight pairs of nmCRC and mCRC tissues aiming to found out new tumor markers and mechanisms behind CRC metastasis.…”

Comprehensive review of targeted therapy for colorectal cancer

“…Increased VEGF levels were observed in very early stages of colorectal neoplasia, e.g., adenoma, and were even higher in later stages of cancer, especially in the metastatic stage. 177,178 VEGF regulation is complex in CRC. Mutated K-RAS and p53, expression of COX-2, and hypoxia inducible factor 1 (HIF-1) induced by hypoxia from high tumor cell density might all contribute to VEGF-VEGFR activity alteration, resulting in cancer growth and migration.…”

Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors

“…VEGF is one of the key angiogenic factors that largely contribute to development of disorganized and highly leaky tumor vessels 11,12 . Treatment of tumors with VEGF blockades including neutralizing antibodies and its soluble receptors could restore a healthy vascular phenotype 10,13,14 . Currently, most clinically available AADs contain inhibitory components that target VEGF, VEGFR, and their downstream signaling 15 .…”