Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Br J Cancer. 2011 Aug 9;105(4):523-33. doi: 10.1038/bjc.2011.263. Epub 2011 Jul 26.
We sought to investigate the role of ErbB3-mediated signalling on the interaction between pancreatic cancer-associated fibroblasts (CAF) and carcinoma cells in an effort to disrupt tumourigenic pancreatic ductal adenocarcinoma (PDAC) stromal-epithelial cross-communication.
Primary CAF cultures were established from human PDAC surgical specimens. AsPC-1 pancreatic cancer cell murine subcutaneous xenografts were developed in the presence and absence of CAF and were subsequently treated with epidermal growth factor receptor (EGFR) inhibitors (erlotinib) and ErbB3 inhibitors (MM-121, monoclonal ErbB3 antibody).
Cancer-associated fibroblasts were found to secrete neuregulin-1 (NRG-1), which promoted proliferation via phosphorylation of ErbB3 and AKT in AsPC-1 PDAC cells. This signalling cascade was effectively inhibited both in vitro and in vivo by specific ErbB3 blockade with MM-121, with greater degree of tumourigenesis inhibition when combined with erlotinib. The CAF-AsPC-1 pancreatic cancer xenografts reached significantly greater tumour volume than those xenografts lacking CAF and were resistant to the anti-tumour effects of EGFR inhibition with erlotinib.
Cancer-associated fibroblasts-derived NRG-1 promote PDAC tumourigenesis via ErbB3-AKT signalling and overcomes single-agent EGFR inhibition. Disruption of this stromally mediated tumourigenic mechanism is best obtained through combined EGFR-ErbB3 inhibition with both erlotinib and MM-121. We have identified the NRG-1/ErbB3 axis as an attractive molecular target for the interruption of tumourigenic stromal-epithelial interactions within the PDAC microenvironment.
我们试图研究 ErbB3 介导的信号在胰腺癌相关成纤维细胞（CAF）与癌细胞之间相互作用中的作用，以破坏致瘤性胰腺导管腺癌（PDAC）基质-上皮交叉通讯。
从人 PDAC 手术标本中建立原代 CAF 培养物。在存在和不存在 CAF 的情况下，开发了 AsPC-1 胰腺癌细胞鼠皮下异种移植物，并随后用表皮生长因子受体（EGFR）抑制剂（厄洛替尼）和 ErbB3 抑制剂（MM-121，单克隆 ErbB3 抗体）进行治疗。
发现 CAF 分泌神经调节蛋白-1（NRG-1），通过 AsPC-1 PDAC 细胞中 ErbB3 和 AKT 的磷酸化促进增殖。通过特异性 ErbB3 阻断 MM-121，无论是在体外还是体内，这种信号级联反应都得到了有效抑制，与厄洛替尼联合使用时，肿瘤发生抑制程度更大。CAF-AsPC-1 胰腺癌细胞异种移植物的肿瘤体积明显大于缺乏 CAF 的异种移植物，并且对厄洛替尼的 EGFR 抑制的抗肿瘤作用具有抗性。
CAF 衍生的 NRG-1 通过 ErbB3-AKT 信号促进 PDAC 肿瘤发生，并克服了单药 EGFR 抑制。通过联合使用厄洛替尼和 MM-121 破坏这种基质介导的致瘤机制是最佳的。我们已经确定了 NRG-1/ErbB3 轴作为中断 PDAC 微环境中致瘤性基质-上皮相互作用的有吸引力的分子靶标。
