Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment
Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment
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DOI：
10.1172/jci200523424
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发表时间：
2005-05-01
影响因子：
15.9
通讯作者：
Scherer, PE
中科院分区：
文献类型：
--
作者：
Iyengar, P;Espina, V;Scherer, PE
转化细胞与周围基质细胞的相互作用对肿瘤的进展和转移具有重要意义。脂肪细胞衍生因子与乳腺癌细胞存活和生长的相关性被确立。然而，目前尚不清楚哪些特定的脂肪细胞衍生因子在这一过程中最为关键。胶原VI在脂肪细胞中大量表达。胶原蛋白（-/-）小鼠在小鼠乳腺肿瘤病毒/多瘤病毒中T癌基因（MMTV-PyMT）背景下的乳腺癌模型显示，早期增生和原发性肿瘤生长率显著降低。VI型胶原通过表达在恶性导管上皮细胞表面的NG2/硫酸软骨素蛋白聚糖受体，依次激活Akt和β -catenin，稳定cyclin D1，从而促进其促生长和促生存作用。胶原VI α 3的羧基末端结构域（全长分子的蛋白水解产物）水平在小鼠和人类乳腺癌病变中显著上调。同样的片段在体外对MCF-7细胞有强大的生长刺激作用。因此，脂肪细胞在确定正常和肿瘤源性导管上皮细胞的ECM环境中起着至关重要的作用，并通过分泌和加工胶原VI在早期阶段显著促进肿瘤生长。
The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is wen established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen(-/-) mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and beta-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VI alpha 3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.