Herrera Victoria L, Decano Julius L, Tan Glaiza A, Moran Ann M, Pasion Khristine A, Matsubara Yuichi, Ruiz-Opazo Nelson
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
PLoS One. 2014 Jan 21;9(1):e85821. doi: 10.1371/journal.pone.0085821. eCollection 2014.
A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.
先验地，一种在肿瘤微血管、癌细胞和癌症干细胞样细胞（CSCs）中诱导产生的共同受体，参与肿瘤血管生成、侵袭以及癌症干细胞的失巢凋亡抗性和存活，可能是这些事件同步协调的基础，而非随机发生。在此我们表明，对双内皮素1/VEGF信号肽受体DEspR（以前称为Dear，位于4号染色体q31.2）的功能分析支持了在胰腺癌（PDAC）和胶质母细胞瘤（GBM）中的假定共同受体模式，这两种肿瘤因其侵袭性、CD133 +癌症干细胞以及极化血管生成特征而被选中。与正常组织不同，在从PDAC - Panc1和GBM - U87细胞中分离出的PDAC和GBM微血管、肿瘤细胞及癌症干细胞中检测到了DEspR。在体外，DEspR抑制降低了血管生成、侵袭性、癌症干细胞存活及失巢凋亡抗性，并且在裸（nu/nu）大鼠中降低了Panc1 - CSC和U87 - CSC异种移植肿瘤的生长、血管生成及侵袭性，这表明DEspR激活会协调这些肿瘤进展事件。作为一种可及的细胞表面“共同受体协调因子”，DEspR抑制为胰腺癌和胶质母细胞瘤定义了一种新的靶向治疗模式。
