Frazier K S, Grotendorst G R
Dept. of Cell Biology and Anatomy, University of Miami School of Medicine, FL 33136, USA.
Int J Biochem Cell Biol. 1997 Jan;29(1):153-61. doi: 10.1016/s1357-2725(96)00127-6.
Desmoplasia, the formation of highly cellular, excessive connective tissue stroma associated with some cancers, shares many features with the wound healing response. Since connective tissue growth factor (CTGF) has previously been demonstrated to play a role in wound repair, we wanted to determine if it might be involved in the pathogenesis of stromal demoplasia in mammary cancer. We assayed 11 human invasive mammary ductal carcinomas by Northern blot and 7 out of 11 were positive for both CTGF expression and transforming growth factor-beta 1 (TGF-beta 1, a principal CTGF inducer). One specimen was positive only for TGF-beta 1. The remaining 3 tumors lacked significant stromal involvement and were negative for either factor. In every case we assayed, in which there was marked connective tissue involvement, both CTGF and TGF-beta 1 messages were found. We also assayed 3 murine mammary tumor models. The GI-101 xenograft model had marked stroma and was positive for both factors in-vivo, but positive for only TGF-beta 1 mRNA expression in culture where fibroblasts were absent. The DMBA murine tumor lacked significant stroma and was negative for CTGF and TGF-beta 1 expression by Northern blot, while the stromal rich DMBA-MMTV tumor contained multifocal desmoplasia and was positive for both factors. We performed in-situ hybridization for CTGF and TGF-beta 1 on the GI-101 and DMBA-MMTV tumors. CTGF message was observed only in the fibroblasts of the stroma, while TGF-beta 1 mRNA hybridization was present in tumor epithelial cells and leukocytes. These results suggest that cancer stroma formation involves induction of similar fibroproliferative growth factors (TGF-beta 1 and CTGF) as wound repair.
促纤维增生反应，即与某些癌症相关的高度细胞化、过度的结缔组织基质的形成，与伤口愈合反应有许多共同特征。由于先前已证明结缔组织生长因子（CTGF）在伤口修复中起作用，我们想确定它是否可能参与乳腺癌基质促纤维增生反应的发病机制。我们通过Northern印迹法检测了11例人浸润性乳腺导管癌，其中11例中有7例CTGF表达和转化生长因子-β1（TGF-β1，一种主要的CTGF诱导剂）均为阳性。1个标本仅TGF-β1呈阳性。其余3个肿瘤缺乏明显的基质浸润，两种因子均为阴性。在我们检测的每一个有明显结缔组织浸润的病例中，均发现了CTGF和TGF-β1信息。我们还检测了3种小鼠乳腺肿瘤模型。GI-101异种移植模型有明显的基质，在体内两种因子均为阳性，但在无成纤维细胞的培养物中仅TGF-β1 mRNA表达呈阳性。DMBA小鼠肿瘤缺乏明显的基质，Northern印迹法检测CTGF和TGF-β1表达均为阴性，而富含基质的DMBA-MMTV肿瘤有多灶性促纤维增生反应，两种因子均为阳性。我们对GI-101和DMBA-MMTV肿瘤进行了CTGF和TGF-β1的原位杂交。仅在基质的成纤维细胞中观察到CTGF信息，而TGF-β1 mRNA杂交则存在于肿瘤上皮细胞和白细胞中。这些结果表明，癌症基质形成涉及诱导与伤口修复类似的纤维增生性生长因子（TGF-β1和CTGF）。
