Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Cell Tissue Res. 2011 Nov;346(2):223-36. doi: 10.1007/s00441-011-1254-y. Epub 2011 Oct 11.
During cancer cell growth many tumors exhibit various grades of desmoplasia, unorganized production of fibrous or connective tissue, composed mainly of collagen fibers and myofibroblasts. The accumulation of an extracellular matrix (ECM) surrounding tumors directly affects cancer cell proliferation, migration and spread; therefore the study of desmoplasia is of vital importance. Stromal fibroblasts surrounding tumors are activated to myofibroblasts and become the primary producers of ECM during desmoplasia. The composition, density and organization of this ECM accumulation play a major role on the influence desmoplasia has upon tumor cells. In this study, we analyzed desmoplasia in vivo in human colorectal carcinoma tissue, detecting an up-regulation of collagen I, collagen IV and collagen V in human colorectal cancer desmoplastic reaction. These components were then analyzed in vitro co-cultivating colorectal cancer cells (Caco-2 and HCT116) and fibroblasts utilizing various co-culture techniques. Our findings demonstrate that direct cell-cell contact between fibroblasts and colorectal cancer cells evokes an increase in ECM density, composed of unorganized collagens (I, III, IV and V) and proteoglycans (biglycan, fibromodulin, perlecan and versican). The desmoplastic collagen fibers were thick, with an altered orientation, as well as deposited as bundles. This increased ECM density inhibited the migration and invasion of the colorectal tumor cells in both 2D and 3D co-culture systems. Therefore this study sheds light on a possible restricting role desmoplasia could play in colorectal cancer invasion.
在癌细胞生长过程中，许多肿瘤表现出不同程度的纤维母细胞性间质反应，即纤维组织或结缔组织的无序产生，主要由胶原纤维和肌成纤维细胞组成。肿瘤周围细胞外基质（ECM）的积累直接影响癌细胞的增殖、迁移和扩散；因此，对纤维母细胞性间质反应的研究至关重要。肿瘤周围的基质成纤维细胞被激活为肌成纤维细胞，并在纤维母细胞性间质反应中成为 ECM 的主要产生细胞。这种 ECM 积累的组成、密度和组织在纤维母细胞性间质反应对肿瘤细胞的影响中起着重要作用。在本研究中，我们分析了人结直肠癌组织中的纤维母细胞性间质反应，检测到人结直肠癌纤维母细胞性间质反应中胶原 I、胶原 IV 和胶原 V 的上调。然后，我们利用各种共培养技术，在体外共培养结直肠癌细胞（Caco-2 和 HCT116）和成纤维细胞，对这些成分进行了分析。我们的研究结果表明，成纤维细胞与结直肠癌细胞之间的直接细胞-细胞接触会引起 ECM 密度的增加，包括无序的胶原（I、III、IV 和 V）和蛋白聚糖（biglycan、fibromodulin、perlecan 和 versican）。纤维母细胞性间质反应中的胶原纤维变厚，取向改变，并呈束状沉积。这种 ECM 密度的增加抑制了结直肠肿瘤细胞在 2D 和 3D 共培养系统中的迁移和侵袭。因此，本研究揭示了纤维母细胞性间质反应可能在结直肠癌侵袭中发挥限制作用。
