Authors' Affiliations: Department of Neurological Surgery, The Childhood Brain Tumor Project; Department of Pediatrics; Division of Hematology-Medical Oncology; Pediatric Brain Tumor Research, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medical College; Departments of Pathology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and National Eye Institute, NIH, Bethesda, Maryland.
Cancer Res. 2014 Feb 15;74(4):1011-21. doi: 10.1158/0008-5472.CAN-13-1072. Epub 2013 Dec 26.
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.
增强的血小板衍生生长因子 (PDGF) 信号在神经胶质瘤的发生和发展中起关键作用。在这项研究中，我们定义了源自基质的 PDGF 信号在维持神经胶质瘤微环境中肿瘤内稳态的独特作用。在高级别神经胶质瘤的浸润前沿，发现了大量由少突胶质细胞前体细胞 (OPC) 衍生的 PDGF 受体-α (PDGFRα) 表达基质细胞，它们表现出独特的血管周围分布。在 PDGFRα 缺陷型宿主小鼠中，由于原位 Gl261 肿瘤的生长减少，我们发现肿瘤相关血管的管腔更小，血管形态正常化，用血管成像剂钆注射的宿主动物中的肿瘤也较少被 MRI 增强。值得注意的是，神经胶质瘤相关的 OPC 通过消除血管周星形胶质细胞对血管内皮连接的抑制作用，促进内皮发芽和小管形成。基质衍生的 PDGF-CC 对于 OPC 的募集和激活至关重要，因为在 PDGF-CC 基因缺陷型小鼠中观察到的神经胶质瘤/血管缺陷与 PDGFRα 缺陷型小鼠相似。临床上，我们发现神经胶质瘤标本中 PDGF-CC 水平较高与疾病复发更快和总体生存较差相关。我们的研究结果定义了神经胶质瘤基质微环境中的 PDGFRα/PDGF-CC 信号轴，该信号轴有助于血管重塑和大脑中异常的肿瘤血管生成。
