Chondroitin Sulfate Proteoglycans Potently Inhibit Invasion and Serve as a Central Organizer of the Brain Tumor Microenvironment
Chondroitin Sulfate Proteoglycans Potently Inhibit Invasion and Serve as a Central Organizer of the Brain Tumor Microenvironment
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DOI：
10.1523/jneurosci.3004-12.2013
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发表时间：
2013-09-25
影响因子：
5.3
通讯作者：
Steindler, Dennis A.
中科院分区：
文献类型：
--
作者：
Silver, Daniel J.;Siebzehnrubl, Florian A.;Steindler, Dennis A.
胶质母细胞瘤（GBM）仍然是所有脑恶性肿瘤中最普遍和最致命的。造成这种不良预后的一个因素是肿瘤的高度侵袭性。GBM的特点是肿瘤细胞在显微镜下浸润整个大脑，而非神经转移，以及选择较低级别的胶质瘤，发展为独立的和明确描绘的病变。通过啮齿类异种移植肿瘤模型和病理人类患者标本，我们提出证据表明，侵袭性和非侵袭性两种不同病理之间的一个基本转换是通过肿瘤细胞外基质介导的。具体来说，非侵袭性病变与含有大量糖基化硫酸软骨素蛋白聚糖（CSPGs）的丰富基质相关，而糖基化的CSPGs在弥漫性浸润性肿瘤中基本不存在。CSPGs作为肿瘤微环境的中心组织者，极大地影响了驻留的反应性星形胶质细胞，诱导它们离开肿瘤肿块，并导致非侵入性病变的包封。此外，CSPGs诱导肿瘤相关小胶质细胞的激活。我们发现星形胶质胶质瘤囊可以直接抑制肿瘤的侵袭，而它在GBM中的缺失为弥漫性浸润提供了有利的环境。我们还发现白细胞共同抗原相关磷酸酶受体（PTPRF）可能是细胞外糖基化CSPGs和非侵袭性肿瘤细胞之间的中介。总之，我们认为CSPGs是脑肿瘤组织病理学的关键调节因子，并有助于阐明肿瘤微环境在脑肿瘤侵袭中的作用。
Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies-invasion and noninvasion-is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion.