Tumor-associated fibroblasts predominantly come from local and not circulating precursors
Tumor-associated fibroblasts predominantly come from local and not circulating precursors
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DOI：
10.1073/pnas.1600363113
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发表时间：
2016-07-05
影响因子：
11.1
通讯作者：
Schreiber, Hans
中科院分区：
文献类型：
--
作者：
Arina, Ainhoa;Idel, Christian;Schreiber, Hans
成纤维细胞是癌症间质中常见的细胞类型，可产生癌细胞存活和生长所需的胶原蛋白。虽然一些癌症治疗策略针对肿瘤成纤维细胞，但其起源仍有争议。多篇出版物表明循环间充质前体是肿瘤相关成纤维细胞的来源。然而，我们通过三种独立的方法表明，肿瘤成纤维细胞主要来源于局部的、无根的前体。首先，在I型胶原（Col-I）启动子（COL-EGFP）控制下，在表达绿色荧光报告蛋白（EGFP）的小鼠体内发育的可移植肿瘤具有绿色基质，而在缺乏荧光报告子的异种共生伙伴体内发育的肿瘤中，我们没有发现COL-EGFP（+）细胞。在发生原位肠腺瘤的COL-EGFP小鼠和转基因小鼠的异种配对中，证实了循环中缺乏COL-EGFP（+）细胞进入肿瘤。其次，用COL-EGFP小鼠骨髓细胞重组的嵌合小鼠的可移植肿瘤很少显示表达EGFP的间质成纤维细胞。最后，在非报告性小鼠的全层COLEGFP皮肤移植物下注射的癌细胞发展成含有绿色基质细胞的肿瘤。使用多色体内共聚焦显微镜，我们发现表达col - i的成纤维细胞约占间质团的三分之一，并形成连续的膜包裹肿瘤血管。总之，肿瘤形成成纤维细胞基质主要来自局部肿瘤微环境中的前体，而骨髓来源的循环前体的贡献是罕见的。
Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP(+) cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP(+) cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COLEGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I-expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.