Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel.
Cancer Biology, the Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
Lab Invest. 2020 Dec;100(12):1517-1531. doi: 10.1038/s41374-020-0458-8. Epub 2020 Jul 1.
Primary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs' pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.
原发性和转移性黑色素瘤的进展得到局部微环境的支持，包括癌相关成纤维细胞（CAF）等。我们之前在同基因/同基因小鼠模型中报告称，基质外切酶 CD38 参与黑色素瘤的生长和转移。这里提出的结果表明，CD38 是 CAF 促肿瘤功能的新调节剂。与表达 CD38 的成纤维细胞相比，CD38 缺陷型成纤维细胞和 B16F10 黑色素瘤细胞的原位共植入限制了肿瘤大小。本质上，CAF-CD38 促进原代成纤维细胞向黑色素瘤细胞的迁移。此外，CAF-CD38 的体外旁分泌作用促进了肿瘤细胞的迁移和侵袭以及内皮细胞管形成。从机制上讲，我们报告 CAF-CD38 驱动血管生成/促转移特征的蛋白表达，其中包括 VEGF-A、FGF-2、CXCL-12、MMP-9 和 HGF。数据表明，CAF-CD38 通过促进促进细胞侵袭、迁移和血管生成的促肿瘤因子的产生来促进肿瘤发生。
