The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma.
The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma.
复制标题
癌症相关的成纤维细胞与肿瘤相关的巨噬细胞之间的相互作用通过肝细胞癌肿瘤微环境中的骨桥蛋白途径相关。
DOI：
10.18632/oncotarget.27881
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发表时间：
2021-02-16
期刊：
影响因子：
--
通讯作者：
Shimada M
中科院分区：
文献类型：
--
作者：
Tokuda K;Morine Y;Miyazaki K;Yamada S;Saito Y;Nishi M;Tokunaga T;Ikemoto T;Imura S;Shimada M
背景资料：癌-肿瘤相关巨噬细胞（TAM）-癌相关成纤维细胞（CAF）相互作用是影响肝细胞癌肿瘤微环境的重要因素。材料和方法：将肝星状细胞（HSC）与癌细胞条件培养基（Ca. CM）、TAM-CM和CAF-CM，RT-PCR检测CAF标志物的表达。用Ca. CM，TAM-CM和CAF-CM有助于增强癌细胞的恶性利用增殖，侵袭和迁移测定。此外，这三种类型的CM之间的差异进行了评估，使用细胞因子阵列。结果：用Ca. CM、TAM-CM和CAF-CM均能显著增加αSMA、FAP和IL-6的mRNA表达。与每种CM一起培养的所有HSC均表现出癌细胞的增殖、侵袭和迁移显著增加。与其他CAF-CM相比，与TAM-CM一起培养的HSC中骨桥蛋白浓度显著更高。骨桥蛋白抑制剂显著减少了与TAM-CM一起培养的HSC的骨桥蛋白分泌，并抑制了与TAM-CM一起培养的HSC增强的癌细胞的增殖和侵袭。结论：我们观察到TAM的骨桥蛋白分泌增强，并且这种骨桥蛋白的增加进一步促进了与TAM-CM一起培养的HSC的骨桥蛋白分泌，导致恶性肿瘤的增加。我们首次证明了肿瘤-TAM-CAF通过骨桥蛋白相互作用在肝细胞癌中的重要性。
Background: Cancer-tumor associated macrophage (TAM)-cancer associated fibroblast (CAF) interactions are an important factor in the tumor microenvironment of hepatocellular carcinoma. Materials and Methods: Hepatic stellate cells (HSCs) were cultured with cancer cell-conditioned medium (Ca.-CM), TAM-CM and CAF-CM, and the expression of CAF markers were evaluated by RT-PCR. Whether HSCs cultured with Ca.-CM, TAM-CM and CAF-CM contributed to the enhanced malignancy of cancer cells was examined using proliferation, invasion and migration assays. Furthermore, the differences between these three types of CM were evaluated using cytokine arrays. Results: HSCs cultured with Ca.-CM, TAM-CM and CAF-CM showed significantly increased mRNA expression of αSMA, FAP and IL-6. All HSCs cultured with each CM exhibited significantly increased proliferation, invasion and migration of cancer cells. The osteopontin concentration was significantly higher in HSCs cultured with TAM-CM than the other CAF-CMs. Osteopontin inhibition significantly reduced osteopontin secretion from HSCs cultured with TAM-CM and suppressed the proliferation and invasion of cancer cells enhanced by HSCs cultured with TAM-CM. Conclusions: We observed enhanced osteopontin secretion from TAMs, and this increased osteopontin further promoted osteopontin secretion from HSCs cultured with TAM-CM, leading to increased malignancy. For the first time, we demonstrated the importance of cancer-TAM-CAF interactions via osteopontin in hepatocellular carcinoma.