Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.
Neoplasia. 2012 Oct;14(10):943-51. doi: 10.1593/neo.121092.
Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM)-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13) and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or α-smooth muscle actin (α-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively α-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs) from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13-deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived α-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion.
癌相关成纤维细胞是肿瘤微环境的主要贡献者，调节着癌的进展。它们由具有不同起源、表型和功能的异质性细胞群体组成。在本报告中，我们探讨了骨髓（BM）来源的细胞对产生不同成纤维细胞亚群的贡献，这些亚群可能产生基质金属蛋白酶 13（MMP13）并影响癌细胞浸润。我们应用了一种皮肤癌的小鼠模型，对小鼠进行照射，并移植了来自绿色荧光蛋白（GFP）转基因小鼠的 BM。我们提供的证据表明，浸润肿瘤的三分之一 BM 来源的 GFP（+）细胞表达软骨素硫酸蛋白聚糖 NG2（周细胞标志物）或α-平滑肌肌动蛋白（α-SMA，肌成纤维细胞标志物），而近 90%的 Thy1（+）成纤维细胞来源于常驻 GFP 阴性细胞。产生 MMP13 的细胞是唯一的α-SMA（+）细胞，来源于 GFP（+）BM 细胞。为了研究它们对肿瘤浸润的影响，我们从野生型和 MMP13 缺陷型小鼠的 BM 中分离间充质干细胞（MSCs）。野生型 MSC 在球体测定中促进了癌细胞的浸润，而 MMP13 缺陷型 MSC 则不能。我们的数据支持成纤维细胞亚群特化的概念，即 BM 来源的α-SMA（+）细胞是 MMP13 的主要来源，MMP13 是癌细胞浸润的间质介质。
