Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1.
Glioblastoma endothelium drives bevacizumab-induced infiltrative growth via modulation of PLXDC1.
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DOI：
10.1002/ijc.31983
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发表时间：
2019-03-15
影响因子：
6.4
通讯作者：
Pallini R
中科院分区：
文献类型：
--
作者：
Falchetti ML;D'Alessandris QG;Pacioni S;Buccarelli M;Morgante L;Giannetti S;Lulli V;Martini M;Larocca LM;Vakana E;Stancato L;Ricci-Vitiani L;Pallini R
贝伐珠单抗是一种靶向VEGF的单克隆抗体，可能会触发胶质母细胞瘤的浸润性生长模式。我们使用人类标本和大鼠模型研究了这种模式。在人体标本中，相当一部分浸润性肿瘤细胞位于沿着血管周围间隙，与内皮细胞关系密切。用贝伐单抗处理的U87 MG细胞的脑异种移植物小于对照（p = 0.0055; Student t检验），然而，肿瘤细胞带在脑中扩散得比对照更远（p < 0.001; Student t检验）。浸润性肿瘤细胞表现出对血管结构的向性，并倾向于与内皮细胞形成小管和壁龛。分子上，贝伐珠单抗引发了上皮细胞向间充质细胞的转化，受体丛状蛋白结构域1（PLXDC 1）过度表达。这些结果使用患者来源的胶质瘤干细胞样细胞的脑异种移植物进行了验证。PLXDC 1在U87 MG细胞中的增强表达促进沿血管周围间隙的脑浸润沿着。重要的是，PLXDC 1抑制可防止血管周围浸润，并显著增加贝伐珠单抗治疗大鼠的存活率。我们的研究表明，贝伐单抗诱导的脑浸润是由血管内皮驱动的，并取决于肿瘤细胞的PLXDC 1激活。 有什么新消息吗？ 贝伐珠单抗是一种靶向VEGF的单克隆抗体，已观察到可触发胶质母细胞瘤的浸润性生长模式，作为一种逃逸机制。然而，这种神经胶质瘤样生长模式的机制仍不清楚。在这里，作者发现浸润性生长模式主要发生在沿着血管周围空间，并依赖于肿瘤细胞对PLXDC 1的过度表达和血脑屏障内皮成分的恢复。总之，数据显示贝伐珠单抗诱导的脑浸润主要由血管内皮驱动。重要的是，PLXDC 1的抑制可防止贝伐珠单抗诱导的浸润性生长，导致存活率显著增加。
Bevacizumab, a VEGF‐targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p = 0.0055; Student t‐test), however, bands of tumor cells spread through the brain farther than controls (p < 0.001; Student t‐test). Infiltrating tumor Cells exhibited tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over‐expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient‐derived glioma stem‐like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab‐treated rats. Our study indicates that bevacizumab‐induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells. What's new? Bevacizumab, a VEGF‐targeting monoclonal antibody, has been observed to trigger an infiltrative growth pattern in glioblastoma as an escape mechanism. The mechanisms underlying this gliomatosis‐like growth pattern, however, remain unclear. Here, the authors found that the infiltrative growth pattern occurs mostly along perivascular spaces and relies on the over‐expression of PLXDC1 by tumor cells and on the restoration of the endothelial component of blood brain barrier. Altogether, the data show that the brain infiltration induced by bevacizumab is mainly driven by the vascular endothelium. Importantly, inhibition of PLXDC1 prevents bevacizumab‐induced infiltrative growth, resulting in significant increase of survival.
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影响因子：
15.9
作者：
Gomez-Manzano, Candelaria;Holash, Jocelyn;Yung, W. K. Alfred
通讯作者：
Yung, W. K. Alfred
影响因子：
64.8
作者：
Miller TE;Liau BB;Wallace LC;Morton AR;Xie Q;Dixit D;Factor DC;Kim LJY;Morrow JJ;Wu Q;Mack SC;Hubert CG;Gillespie SM;Flavahan WA;Hoffmann T;Thummalapalli R;Hemann MT;Paddison PJ;Horbinski CM;Zuber J;Scacheri PC;Bernstein BE;Tesar PJ;Rich JN
通讯作者：
Rich JN
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Moutal, Aubin;Honnorat, Jerome;Thomasset, Nicole
通讯作者：
Thomasset, Nicole
影响因子：
3.3
作者：
Granholm, ACE;Curtis, M;Rose, GM
通讯作者：
Rose, GM