Yao Yu, Wang Xiaomei, Jin Kunlin, Zhu Jianhong, Wang Yin, Xiong Sidong, Mao Ying, Zhou Liangfu
Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Road 12#, Shanghai, 200040, China.
J Neurooncol. 2008 Sep;89(2):121-9. doi: 10.1007/s11060-008-9601-x. Epub 2008 May 14.
B7-H4, a newly discovered member of B7 family that negatively regulates T cell-mediated immunity, may facilitate tumor progression by undermining host immunity. Recent studies show that brain tumor stem-like cells (TSCs) contribute to tumorigenesis. However, the relationship between B7-H4 and the clinical behavior of brain TSCs remains unclear. In this study, we found that B7-H4 was expressed in cultured tumor cells from human gliomas (n = 5) and medulloblastomas (n = 3). Double immunostaining indicated that B7-H4 was primarily restricted to non-dividing (Ki67(-)) cultured tumor cells. Tumor cells cultured under medium conditions favoring the growth of neural stem cells were able to form primary and secondary spheres, along with expression of neural stem/progenitor cell markers. These cells differentiated into different neural lineages when cultured in differentiation medium, indicating that these cells have TSCs characteristics. Double immunostaining showed that TSCs consisted of proliferative (Ki67(+)) and quiescent (Ki67(-)) cells. We also found that B7-H4 was expressed in a small population of CD133(+) cells sorted by flow cytometry. Interestingly, both CD133(+) and CD133(-) cells were tumorigenic in SCID mice in vivo. However, CD133(+) cells-initiated glioblastomas showed a higher proliferation index, compared to CD133(-) cells-induced glioblastomas in vivo. Secondary glioma cells derived from CD133(+) or CD133(-) cell xenografts expressed B7-H4 as well. Our data suggest B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subpopulation of brain TSCs, and CD133(-) tumor cells also have the capacity to initiate brain formation in vivo.
B7-H4是B7家族新发现的成员，对T细胞介导的免疫起负向调节作用，它可能通过削弱宿主免疫力促进肿瘤进展。最近的研究表明，脑肿瘤干细胞（TSCs）参与肿瘤发生。然而，B7-H4与脑TSCs临床行为之间的关系仍不清楚。在本研究中，我们发现B7-H4在人胶质瘤（n = 5）和髓母细胞瘤（n = 3）的培养肿瘤细胞中表达。双重免疫染色表明，B7-H4主要局限于不分裂（Ki67(-)）的培养肿瘤细胞。在有利于神经干细胞生长的培养基条件下培养的肿瘤细胞能够形成原代和传代球体，并表达神经干/祖细胞标志物。当在分化培养基中培养时，这些细胞分化为不同的神经谱系，表明这些细胞具有TSCs特征。双重免疫染色显示，TSCs由增殖性（Ki67(+)）和静止性（Ki67(-)）细胞组成。我们还发现，B7-H4在通过流式细胞术分选的一小部分CD133(+)细胞中表达。有趣的是，CD133(+)和CD133(-)细胞在体内SCID小鼠中均具有致瘤性。然而，与体内CD133(-)细胞诱导的胶质母细胞瘤相比，CD133(+)细胞引发的胶质母细胞瘤显示出更高的增殖指数。源自CD133(+)或CD133(-)细胞异种移植的继发性胶质瘤细胞也表达B7-H4。我们的数据表明，B7-H4优先在不分裂的脑肿瘤细胞和脑TSCs亚群中表达，并且CD133(-)肿瘤细胞在体内也具有引发脑肿瘤形成的能力。
