Berger Liron, Shamai Yeela, Skorecki Karl L, Tzukerman Maty
Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
Rambam Medical Center, Haifa, Israel.
Stem Cells. 2016 Apr;34(4):1011-26. doi: 10.1002/stem.2269. Epub 2015 Dec 31.
Non-neoplastic stromal cells harvested from patient tumors were identified as tumor-derived mesenchymal stem cells (MSCs) by their multipotential capacity to differentiate into adipocytes, osteoblasts, and chondrocytes and by the expression of MSC specific cell surface markers. These procedures yielded also epithelial cancer cells and their counterpart MSC from gastric carcinoma (GSC1) and lung carcinoma (LC2). While the LC2 cancer cell growth is independent of their LC-MSC, the GSC1 cancer cell growth is critically dependent on the presence of their counterpart GSC-MSC or their conditioned medium (CM). The fact that none of the various other tumor-derived MSCs was able to restore the specific effect of GSC-MSC on GSC1 cancer cell growth suggests specificity of tumor-derived MSC, which are specifically recruited and "educated"/reprogrammed by the cancer cells to support tumor growth. Using cytokine array analysis, we were able to demonstrate that GSC1 cell growth is mediated through hepatocyte growth factor (HGF)/c-MET signaling pathway which is activated exclusively by HGF secreted from GSC-MSC. An innovative approach demonstrates GSC1-mediated specific tropism of "naïve" MSC from the adjacent tissue in a tumor specific manner to support tumor progression. The results suggest that specific tumor tropic "naïve" MSC are reprogrammed in a tumor-specific manner to support gastric tumor progression. Understanding the mechanisms involved in the interactions of the tumor cancer cells and tumor-derived MSC will constitute the basis for developing multimodal anticancer therapeutic strategies that will also take into account the specific tumor tropism properties of MSC and their reprogramming.
从患者肿瘤中获取的非肿瘤性基质细胞，因其具有分化为脂肪细胞、成骨细胞和软骨细胞的多能能力以及间充质干细胞（MSC）特异性细胞表面标志物的表达，而被鉴定为肿瘤来源的间充质干细胞。这些操作还从胃癌（GSC1）和肺癌（LC2）中获得了上皮癌细胞及其对应的MSC。虽然LC2癌细胞的生长不依赖于其LC-MSC，但GSC1癌细胞的生长严重依赖于其对应的GSC-MSC或其条件培养基（CM）的存在。其他各种肿瘤来源的MSC均无法恢复GSC-MSC对GSC1癌细胞生长的特定作用，这一事实表明肿瘤来源的MSC具有特异性，它们被癌细胞特异性招募并“驯化”/重编程以支持肿瘤生长。通过细胞因子阵列分析，我们能够证明GSC1细胞的生长是通过肝细胞生长因子（HGF）/c-MET信号通路介导的，该通路仅由GSC-MSC分泌的HGF激活。一种创新方法表明，GSC1以肿瘤特异性方式介导来自相邻组织的“未分化”MSC的特异性趋向性以支持肿瘤进展。结果表明，特定的肿瘤趋向性“未分化”MSC以肿瘤特异性方式重编程以支持胃癌进展。了解肿瘤癌细胞与肿瘤来源的MSC相互作用所涉及的机制，将构成开发多模式抗癌治疗策略的基础，该策略还将考虑MSC的特定肿瘤趋向性特性及其重编程。
