ADAM-9 is a novel mediator of tenascin-C-stimulated invasiveness of brain tumor–initiating cells

Autor: Donna L. Senger, Franz J. Zemp, V. Wee Yong, Susobhan Sarkar, Stephen M. Robbins
Rok vydání: 2015
Předmět:
Zdroj: Neuro-Oncology. 17:1095-1105
ISSN: 1523-5866
1522-8517
Popis: Malignant gliomas are intracranial tumors that account for 3%–8% of all cancer-related death. Despite several clinical advances, malignant gliomas remain largely untreatable and median survival time for the high-grade glioblastoma does not exceed 15 months. A major reason for the poor prognosis is the invasive nature of gliomas within the CNS, thereby generating multiple foci of transformed growth. The neoplastic growth of malignant gliomas is thought to be maintained by a rare population of cells that proliferate and undergo self-renewal and that seed and generate more differentiated glioma progenies. These self-renewing transformed precursors have been variously referred to as glioma stem cells or brain tumor–initiating cells (BTICs),1–3 and are thought to be important in mediating treatment resistance and recurrence. Notably, as few as 10 BTICs deposited into the striatum of mice are sufficient to form intracranial tumors.4 BTICs are highly invasive cells, and the multiple foci of new transformed growth is a major factor for the poor prognosis of patients with high-grade gliomas. Thus, mechanisms that regulate invasiveness are reasonable targets for improved therapeutics. Glioma invasiveness is mediated in part by the interaction of glioma cells with the extracellular matrix (ECM), followed by the proteolytic cleavage of ECM by tumor cell–derived proteases.5–7 The family of matrix metalloproteinases (MMPs) is implicated in glioma invasiveness, with high expression of several MMP members in resected glioma specimens inversely correlating with the survival of patients. Further, inhibitors of MMPs reduce the invasiveness of glioma cell lines in vitro and attenuate the growth of glioma xenografts in mice.4–7 While MMP members are implicated in glioma invasiveness, the role of the related a disintegrin and metalloproteinase (ADAM) family of metzincin metalloproteinases in invasiveness of differentiated glioma cells has only recently emerged.8–10 Currently, there is only one report11 of ADAMs (ADAM-10 and -17) in BTIC biology, principally in regulating their self-renewal. The microenvironment of tumors includes the ECM around cells. For most tumor types, the availability of ECM proteins is a critical factor for growth12,13 because they bind and/or activate integrins on the cell surface to trigger survival and proliferative signaling, and because the ECM is a rich source of growth factors. The ECM in malignant gliomas includes vitronectin, proteoglycans, collagens I and IV, osteopontin, and tenascin-C (TNC).14,15 Of these, perhaps the most prominent glioma ECM component is TNC, with expression correlated with glioma grades.16,17 Further, antibodies that block TNC reduce the invasiveness of differentiated glioma cells in culture18 and suppress the growth of gliomas in mice.19 These preclinical results have evolved to clinical trials of glioma patients using locally introduced small interfering (si)RNA to TNC,20 or iodine-131–labeled anti-TNC antibody,21 where the survival results have been encouraging. We reported that TNC is a permissive substrate for the invasiveness of conventional glioma cell lines (U251 or U87) in culture, through regulating MMP-1222 and protein kinase C.23 Herein, we have addressed the impact and mechanisms of TNC on invasiveness of BTICs.
Databáze: OpenAIRE
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