Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells.

Abstract

Although vascular endothelial growth factor receptor (VEGF-R)-targeted antiangiogenic agents are important treatment for a number of human malignancies, there is accumulating evidence that the therapies may promote disease progression, such as invasion and metastasis. How tumors become to promote their evasiveness remains fully uncertain. One of possible mechanisms for the adaptation may be a direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. To elucidate a direct effect of VEGF-R-targeting drug (sunitinib), we established a human colorectal cancer cell model adapted to sunitinib. The sunitinib-conditioned cells showed a significant increase in cellular motility and migration activities, compared to the vehicle-treated control cells. Consistent with the phenotype, the sunitinib-conditioned cells decreased the expression levels of E-cadherin (an epithelial marker), while significantly increased the levels of Slug and Zeb1 (mesenchymal markers). Expression profiles of VEGF-R in the sunitinib-conditioned cells showed that only neuropilin-1 (NRP1) expression was significantly increased among all VEGF-R tested. Blockade of NRP1 using its antagonist clearly repressed the migration activation in sunitinib-conditioned cells, but not in the control cells. These results suggest that inhibition of VEGF-R on colorectal cancer cells can drive the epithelial-mesenchymal transition, leading to activation of cell motility in an NRP1-dependent manner. J. Med. Invest. 64: 250-254, August, 2017.

• Authors: Chisato Tomida, Naoko Yamagishi, Hikaru Nagano, Takayuki Uchida, Ayako Ohno, Katsuya Hirasaka, Takeshi Nikawa, Shigetada Teshima-Kondo
• Journal: The journal of medical investigation : JMI (J Med Invest) Vol. 64 Issue 3.4 Pg. 250-254 ( 2017) ISSN: 1349-6867 [Electronic] Japan
• PMID: 28954991 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Indoles
• Pyrroles
• Neuropilin-1
• Receptors, Vascular Endothelial Growth Factor
• Sunitinib

Topics

• Angiogenesis Inhibitors (pharmacology)
• Cell Movement (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• Epithelial-Mesenchymal Transition (drug effects)
• HCT116 Cells
• Humans
• Indoles (pharmacology)
• Neuropilin-1 (analysis)
• Pyrroles (pharmacology)
• Receptors, Vascular Endothelial Growth Factor (analysis, antagonists & inhibitors)
• Sunitinib
• Transcriptome