Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.
Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.
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胰腺癌中的化学抗性由基质衍生的胰岛素样生长因子驱动。
DOI：
10.1158/0008-5472.can-16-1201
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发表时间：
2016-12-01
期刊：
影响因子：
11.2
通讯作者：
Mielgo A
中科院分区：
文献类型：
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作者：
Ireland L;Santos A;Ahmed MS;Rainer C;Nielsen SR;Quaranta V;Weyer-Czernilofsky U;Engle DD;Perez-Mancera PA;Coupland SE;Taktak A;Bogenrieder T;Tuveson DA;Campbell F;Schmid MC;Mielgo A
肿瘤相关巨噬细胞（TAM）和肌成纤维细胞是许多癌症中与耐药相关的癌症的关键驱动因素，包括胰腺导管腺癌（PDAC）。然而，我们对TAM和成纤维细胞促进化学耐药的分子机制的理解尚不清楚。在本研究中，我们发现TAM和肌成纤维细胞通过分泌胰岛素样生长因子（IGF） 1和2，激活胰腺癌细胞上的胰岛素/IGF受体，直接支持胰腺癌细胞的化疗抵抗。胰腺癌患者活检的免疫组化分析显示，72%的患者肿瘤细胞上表达活化的胰岛素/IGF受体，这与CD163+ TAM浸润增加呈正相关。在体内，我们发现TAM和肌成纤维细胞是产生IGF的主要来源，IGF的药物阻断使胰腺肿瘤对吉西他滨敏感。这些发现表明，抑制IGF联合化疗可能使PDAC患者受益，并且胰岛素/IGF1R激活可能用作识别此类治疗干预患者的生物标志物。
Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention.