Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels (Cancer Cell, 2012, 22:235-249)

報告日期: 2012/10/19
報告時間: 16:00/16:50
報告學生: 沈宛柔
講評老師: 王育民
附件下載: 下載[1233-1348725668-1.pdf] 

 

Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels

Cancer Cell 21,488-503, Apr 17, 2012

SpeakerWan-Jou Shen (沈宛柔)   Date/Time2012/10/15 16:00-16:50

CommentatorJu-Ming Wang, Ph.D. (王育民)             PlaceRoom 602

 

Abstract

Tumor vasculature is usually abnormal. This property is mainly attributed to the impaired maturation process of the tumor vessels. It also reduces the sensitivity of the tumors to ionic irradiation and aborts the delivery of chemotherapeutic agents1. Vascular endothelial growth factor (VEGF)-targeted cancer therapies are used to inhibit tumor angiogenesis and normalize the tumor vasculature, thereby improving the delivery of chemotherapy. Recent reports had verified that these therapies also lead to tumor invasiveness and distant metastasis in mice2. An antiangiogenic activity of a small GTPase, R-Ras, is dissimilar from the prototypic Ras oncoproteins. It inhibits vascular cell proliferation, invasion and promotes vascular quiescence. R-Ras is strongly expressed in maturation status of the vessels, suggesting it is essential for the vessel maturation. The authors hypothesized that R-Ras promotes maturation of regenerating adult vasculature and that chronically reduced R-Ras expression in tumor vessels causes the immaturity and poor functionality of these vessels. In this study, the authors verified R-Ras is downregulated in human tumor vasculature. R-Ras deficiency severely impaired coverage by collagen IV, a major constituent of normal endothelial basement membrane in the VE-cadherin-mediated vessel stabilization. They also detected the highly expressed immature vessels markersVEGFR2 and αV integrin in R-Ras knockout mice, immature phenotype demonstrating that R-Ras is required for maturation of tumor blood vessess. Moreover, they corroborated R-Ras signaling normalized pathologically regenerating blood vessels, controlling vessel sprouting and maturation. It can also suppress VE-cadherin to enhance endothelial barrier function and enhance vessel integrity. Finally, the authors established that R-Ras activation in pericytes induces normal capillary-like vessel morphogenesis. These findings suggest the significance of R-Ras to clinical challenges from cancer to therapeutic angiogenesis and tissue engineering.

 

References

1.     Jain, R.K. (2005). Science 307, 58–62.

2.     Pa` ez-Ribes, et. al. (2009). Cancer Cell 15, 220–231.