Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types
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DOI：
10.1158/0008-5472.can-15-0561
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发表时间：
2016-02-01
期刊：
影响因子：
11.2
通讯作者：
Gurney, Austin
中科院分区：
文献类型：
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作者：
Chartier, Cecile;Raval, Janak;Gurney, Austin
长期以来，β-连环蛋白信号的失调与癌症有关。该通路的细胞内组分，包括轴蛋白、APC和β-连环蛋白，在一系列人类肿瘤中经常发生突变，但通过该信号传导轴促进癌症发展的特异性细胞外配体的贡献仍不清楚。我们在一组人类肿瘤中进行了基于荧光素的筛选，以鉴定刺激β-连环蛋白信号传导的分泌因子。通过这种筛选和进一步的分子表征，我们发现R-spondin（RSPO）蛋白与Wnt蛋白协同激活β-连环蛋白。RSPO家族成员在代表多种恶性肿瘤的几种人类肿瘤中表达，包括卵巢癌、胰腺癌、结肠癌、乳腺癌和肺癌。我们产生了RSPO家族成员的特异性单克隆抗体拮抗剂，并发现抗RSPO治疗显著抑制了人类患者来源的肿瘤异种移植模型中的肿瘤生长，无论是作为单一药物还是与化疗联合。此外，基于系列移植研究，阻断RSPO信号传导降低了癌细胞的致瘤性。此外，基因表达分析显示，抗RSPO治疗反应性肿瘤强烈抑制已知与癌症和正常干细胞相关的β-连环蛋白靶基因。总的来说，我们的研究结果表明，RSPO家族是许多人类肿瘤中β-连环蛋白活性的重要刺激物，并突出了治疗调节这一基本信号传导轴的新的有效方法。(C)2015年AACR。
Deregulation of the beta-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and beta-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate beta-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate beta-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited beta-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of beta-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. (C) 2015 AACR.