title: Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells.
abstract: VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain. One of possible mechanisms for the resistance may be the direct effect of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGF-R). We investigated here the direct effect of chronic VEGF inhibition on phenotype changes in cancer cells. To chronically inhibit cancer cell-derived VEGF, human colon cancer HCT116 cells were chronically exposed (3 months) to anti-VEGF neutralizing monoclonal antibody (HCT/mAb cells, blockade of VEGF alone) or VEGF-R tyrosine kinase inhibitor foretinib (HCT/fore cells, blockade of all VEGF family). HCT/mAb cells redundantly increased VEGF family member (VEGF, PlGF, VEGF-B, VEGF-R1 and VEGF-R2) and induced a resistance to hypoxia-induced apoptosis. By contrast, HCT/fore cells did not show the redundant increase in VEGF family member, but significantly increased a VEGF-independent pro-angiogenic factor FGF-2. HCT/fore cells showed increased migration and invasion activities in addition to a resistance to hypoxia-induced apoptosis. The resistance to apoptosis was significantly suppressed by inhibition of hypoxia-inducible factor-1α in HCT/mAb cells, but not in HCT/fore cells. These findings suggest that chronic inhibition of VEGF/VEGF-R accelerates malignant phenotypes of colon cancer cells. J. Med. Invest. 62: 75-79, February, 2015.
authors: Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School.
authors: Chisato
authors: C
authors: Tomida
authors: Naoko
authors: N
authors: Yamagishi
authors: Kana
authors: K
authors: Aibara
authors: Chiaki
authors: C
authors: Yano
authors: Takayuki
authors: T
authors: Uchida
authors: Tomoki
authors: T
authors: Abe
authors: Ayako
authors: A
authors: Ohno
authors: Katsuya
authors: K
authors: Hirasaka
authors: Takeshi
authors: T
authors: Nikawa
authors: Shigetada
authors: S
authors: Teshima-Kondo
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D010641:Phenotype; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000813:Anilides; D057134:Antibodies, Neutralizing; C544831:GSK 1363089; D011804:Quinolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor