Walters M J, Ebsworth K, Berahovich R D, Penfold M E T, Liu S-C, Al Omran R, Kioi M, Chernikova S B, Tseng D, Mulkearns-Hubert E E, Sinyuk M, Ransohoff R M, Lathia J D, Karamchandani J, Kohrt H E K, Zhang P, Powers J P, Jaen J C, Schall T J, Merchant M, Recht L, Brown J M
ChemoCentryx Inc., 850 Maude Ave, Mountain View, CA 94043, USA.
Department of Radiation Oncology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
Br J Cancer. 2014 Mar 4;110(5):1179-88. doi: 10.1038/bjc.2013.830. Epub 2014 Jan 14.
In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.
We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.
CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.
These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.
在多形性胶质母细胞瘤（GBM）的实验模型中，辐射（IR）诱导趋化因子CXCL12/SDF-1的局部表达，这会促进肿瘤复发。CXCL12的高亲和力受体CXCR7在肿瘤对IR的反应中的作用尚未得到研究。
我们在三种啮齿动物GBM模型中测试了CXCR7抑制剂对IR后肿瘤生长和/或动物存活的影响。我们使用免疫组织化学来确定CXCR7蛋白在肿瘤和人类GBM样本中的表达位置。我们使用人类GBM异种移植的神经球形成试验来确定CXCR7在体外对癌症干细胞（CSC）活性是否必要。
在啮齿动物模型和人类GBM中，在肿瘤细胞和/或肿瘤相关脉管系统中检测到CXCR7。在人类GBM中，CXCR7表达随胶质瘤分级增加，并且在空间上与CXCL12和CXCL11/I-TAC相关。在啮齿动物GBM模型中，IR后对CXCR7进行药理抑制导致肿瘤消退，阻止肿瘤复发，和/或显著延长生存期。人类GBM异种移植细胞上的CXCR7表达水平与神经球形成活性相关，并且CXCR7抑制剂可阻断分选的CSC形成球体。
这些结果表明，CXCR7抑制剂可能通过干扰CSC来阻断IR后GBM肿瘤的复发。
