Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis
Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis
复制标题
肿瘤相关成纤维细胞表达endoglin调节结直肠癌侵袭和转移
DOI：
10.1158/1078-0432.ccr-18-0329
复制
发表时间：
2018-12-15
影响因子：
11.5
通讯作者：
Hawinkels, Lukas J. A. C.
中科院分区：
文献类型：
--
作者：
Paauwe, Madelon;Schoonderwoerd, Mark J. A.;Hawinkels, Lukas J. A. C.
目的：癌相关成纤维细胞（CAF）是结直肠癌肿瘤微环境的主要组成部分。CAFs在肿瘤的进展和转移中起重要作用，部分通过TGF-β信号通路。我们调查是否TGF-β家族辅助受体endoglin参与CAF-mediated invasion and metastasis.Experimental Design：CAF-specific endoglin的表达进行了研究，在结直肠癌切除标本使用IHC和相关的无瘤生存。通过transwell侵袭，使用原发性结直肠癌来源的CAF在体外评估内皮素介导的侵袭。CAF特异性内皮糖蛋白表达对肿瘤细胞侵袭的影响进行了研究，在结直肠癌斑马鱼模型，而肝转移进行了评估，在小鼠model.Results：CAF特异性在结直肠癌的侵袭性边界表达内皮糖蛋白和增加的表达强度与增加疾病阶段。在淋巴结和肝转移灶中也检测到表达内皮素的CAF，表明其在结直肠癌转移形成中的作用。在II期结直肠癌中，浸润边缘的CAF特异性内皮糖蛋白表达与无转移生存率相关。体外实验表明，内皮糖蛋白是骨形态发生蛋白（BMP）-9诱导的信号传导和CAF存活所必需的。使用中和抗体TRC 105靶向内皮糖蛋白抑制体外CAF侵袭。在斑马鱼中，表达内皮素的成纤维细胞增强了结肠直肠肿瘤细胞向肝脏的浸润并降低了存活率。最后，CAF特异性endoglin靶向TRC 105降低了结直肠癌细胞向小鼠liver.Conclusions的转移扩散：Endoglin表达CAFs有助于结直肠癌的进展和转移。TRC 105治疗抑制CAF侵袭和肿瘤转移，表明在血管生成内皮之外的另外的靶点，可能有助于在临床评价期间报告的有益效果。(C)2018年AACR。
Purpose: Cancer-associated fibroblasts (CAF) are a major component of the colorectal cancer tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through TGF-beta signaling pathway. We investigated whether the TGF-beta family coreceptor endoglin is involved in CAF-mediated invasion and metastasis.Experimental Design: CAF-specific endoglin expression was studied in colorectal cancer resection specimens using IHC and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary colorectal cancer-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a colorectal cancer zebrafish model, whereas liver metastases were assessed in a mouse model.Results: CAFs specifically at invasive borders of colorectal cancer express endoglin and increased expression intensity correlated with increased disease stage. Endoglin-expressing CAFs were also detected in lymph node and liver metastases, suggesting a role in colorectal cancer metastasis formation. In stage II colorectal cancer, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. In vitro experiments revealed that endoglin is indispensable for bone morphogenetic protein (BMP)-9-induced signaling and CAF survival. Targeting endoglin using the neutralizing antibody TRC105 inhibited CAF invasion in vitro. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, CAF-specific endoglin targeting with TRC105 decreased metastatic spread of colorectal cancer cells to the mouse liver.Conclusions: Endoglin-expressing CAFs contribute to colorectal cancer progression and metastasis. TRC105 treatment inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations. (C) 2018 AACR.