Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Institute of Pathology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
Mol Cancer Res. 2020 Jun;18(6):926-937. doi: 10.1158/1541-7786.MCR-19-0395. Epub 2020 Mar 13.
Tumor-host interactions play a major role in malignancies' initiation and progression. We have reported in the past that tumor cells attenuate genotoxic stress-induced p53 activation in neighboring stromal cells. Herein, we aim to further elucidate cancer cells' impact on signaling within lung cancer stroma. Primary cancer-associated fibroblasts were grown from resected human lung tumors. Lung cancer lines as well as fresh cultures of resected human lung cancers were used to produce conditioned medium (CM) or cocultured with stromal cells. Invasiveness of cancer cells was evaluated by transwell assays, and tumor growth was tested in Athymic nude mice. We found CM of a large variety of cancer cell lines as well as -cultured lung cancers to rapidly induce protein levels of stromal-MDM2. CM of nontransformed cells had no such effect. Mdm2 induction occurred through enhanced translation, was mTORC1-dependent, and correlated with activation of AKT and p70 S6 Kinase. or knockdown in fibroblasts reduced the invasion of neighboring cancer cells, independently of stromal-p53. overexpression in fibroblasts enhanced cancer cells' invasion and growth of inoculated tumors in mice. Our results indicate that stromal-MDM2 participates in a p53-independent cancer-host feedback mechanism. Soluble cancer-originated signals induce enhanced translation of stromal-MDM2 through AKT/mTORC1 signaling, which in turn enhances the neighboring cancer cells' invasion ability. The role of these tumor-host interactions needs to be further explored. IMPLICATIONS: We uncovered a novel tumor-stroma signaling loop, which is a potentially new therapeutic target in lung cancer and possibly in additional types of cancer.
肿瘤-宿主相互作用在恶性肿瘤的发生和发展中起着重要作用。我们过去曾报道过，肿瘤细胞会减弱相邻基质细胞中因遗传毒性应激而引发的 p53 激活。在此，我们旨在进一步阐明癌细胞对肺癌基质中信号转导的影响。从切除的人肺肿瘤中培养原代癌相关成纤维细胞。使用肺癌系以及切除的人肺癌的新鲜培养物来产生条件培养基（CM）或与基质细胞共培养。通过 Transwell 测定评估癌细胞的侵袭性，并用无胸腺裸鼠测试肿瘤生长。我们发现，各种癌细胞系的 CM 以及培养的肺癌迅速诱导基质-MDM2 的蛋白水平。非转化细胞的 CM 没有这种作用。MDM2 诱导通过增强翻译发生，依赖于 mTORC1，与 AKT 和 p70 S6 激酶的激活相关。成纤维细胞中的 或 敲低独立于基质-p53 降低了相邻癌细胞的侵袭。成纤维细胞中 过表达增强了相邻癌细胞的侵袭能力，并增强了接种肿瘤在小鼠中的生长。我们的结果表明，基质-MDM2 参与了一种不依赖于 p53 的肿瘤-宿主反馈机制。源自肿瘤的可溶性信号通过 AKT/mTORC1 信号增强基质-MDM2 的翻译，进而增强相邻癌细胞的侵袭能力。这些肿瘤-宿主相互作用的作用需要进一步探索。意义：我们揭示了一个新的肿瘤-基质信号环路，这可能是肺癌以及其他类型癌症的一个潜在新的治疗靶点。
