Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix
Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix
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DOI：
10.1002/ijc.31775
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发表时间：
2019-03-15
影响因子：
6.4
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
--
作者：
Okumura, Takashi;Ohuchida, Kenoki;Nakamura, Masafumi
虽然最近的研究表明，脂肪组织加速胰腺肿瘤的进展与过量的细胞外基质，在脂肪微环境中的结缔组织增生的关键球员仍然未知。在此，我们通过体外和体内实验研究脂肪组织来源的基质细胞（ASCs）在促结缔组织增生性病变和肿瘤进展中的作用。在使用来自CAG-EGFP小鼠的内脏脂肪的三维（3-D）器官型脂肪侵袭模型中，GFP阳性成纤维细胞向癌细胞浸润。当肿瘤细胞接种到移植的内脏脂肪垫在体内，肿瘤重量和基质成分增强相比，皮下和原位肿瘤细胞接种无脂肪垫。与癌症相关的成纤维细胞相比，在已建立的人ASC中α SMA的表达较低，并且在癌细胞条件培养基中培养的ASC产生的3-D胶原基质从松散结构变为影响癌细胞运动性的致密结构。微阵列分析显示S100 A4在ASC中上调，而在人胰腺癌的胰腺外侵袭部位观察到S100 A4阳性基质细胞。目前的研究结果表明，ASCs被招募到胰腺外浸润部位，并产生致密的胶原基质，导致肿瘤进展加快。ASCs募集和激活的抑制可能导致新的抗基质治疗。
Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of alpha SMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.