Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness
Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness
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DOI：
10.1172/jci87734
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发表时间：
2016-11-01
影响因子：
15.9
通讯作者：
Tomasini, Richard
中科院分区：
文献类型：
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作者：
Leca, Julie;Martinez, Sebastien;Tomasini, Richard
肿瘤内微环境或间质在胰腺导管腺癌（PDA）的病理生物学中具有重要意义，间质中的特定条件可能促进癌症侵袭性增加。我们假设，这种异质性和不断发展的隔室极大地影响肿瘤细胞的能力，这反过来又通过细胞外囊泡（EV）介导的串扰影响PDA的侵袭性。在这里，我们分析了PDA蛋白质组基质签名，并确定了肿瘤细胞串扰的膜联蛋白A6/LDL受体相关蛋白1/血小板反应蛋白1（ANXA 6/LRP 1/TSP 1）复合物的贡献。ANXA 6/LRP 1/TSP 1复合物的形成仅限于癌症相关成纤维细胞（CAF），并且需要改善肿瘤细胞存活和迁移的病理生理培养条件。增加的PDA侵袭性依赖于肿瘤细胞介导的对携带ANXA 6/LRP 1/TSP 1复合物的CAF衍生的ANXA 6（+）EV的摄取。CAF中ANXA 6的缺失损害了复合物的形成，随后损害了PDA和转移的发生，而CAF衍生的ANXA 6（+）EV的注射增强了肿瘤发生。我们发现血清中ANXA 6（+）EV的存在仅限于PDA患者，并且代表PDA等级的潜在生物标志物。这些发现表明，ANXA 6（+）EV支持的CAF-肿瘤细胞串扰可预测PDA侵袭性，突出了PDA的治疗靶点和潜在生物标志物。
The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6(+) EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6(+) EVs enhanced tumorigenesis. We found that the presence of ANXA6(+) EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6(+) EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.