Bone Marrow-derived Myofibroblasts Are the Providers of Pro-invasive Matrix Metalloproteinase 13 in Primary Tumor
Bone Marrow-derived Myofibroblasts Are the Providers of Pro-invasive Matrix Metalloproteinase 13 in Primary Tumor
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DOI：
10.1593/neo.121092
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发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Noel, Agnes
中科院分区：
文献类型：
--
作者：
Lecomte, Julie;Masset, Anne;Noel, Agnes
癌相关成纤维细胞是调节癌进展的肿瘤微环境的关键贡献者。它们由具有不同起源、表型和功能的异质细胞群组成。在本报告中，我们探讨了骨髓（BM）来源的细胞产生不同的成纤维细胞亚群的贡献，这些成纤维细胞亚群可产生基质金属蛋白酶13（MMP 13）并影响癌细胞的侵袭。将小鼠皮肤癌模型应用于小鼠，照射，并用从绿色荧光蛋白（GFP）转基因小鼠中分离的BM移植。我们提供的证据表明，三分之一的BM来源的GFP（+）细胞浸润肿瘤表达硫酸软骨素蛋白聚糖NG 2（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），而几乎90%的Thy 1（+）成纤维细胞来自常驻GFP阴性细胞。产生MMP 13的细胞仅为α-SMA（+）细胞，并且来源于GFP（+）BM细胞。为了研究它们对肿瘤侵袭的影响，我们从野生型和MMP 13缺陷小鼠的BM中分离出间充质干细胞（MSC）。在球体测定中，野生型MSC促进癌细胞侵袭，而从MMP 13缺陷小鼠获得的MSC则不能。我们的数据支持成纤维细胞亚群特化的概念，BM衍生的α-SMA（+）细胞是MMP 13的主要来源，MMP 13是癌细胞侵袭的基质介质。
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) transgenicmice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or alpha-smooth muscle actin (alpha-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13-producing cells were exclusively alpha-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stemcells (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 alpha-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion.