THE ORIGIN OF THE MYOFIBROBLASTS IN BREAST-CANCER - RECAPITULATION OF TUMOR ENVIRONMENT IN CULTURE UNRAVELS DIVERSITY AND IMPLICATES CONVERTED FIBROBLASTS AND RECRUITED SMOOTH
THE ORIGIN OF THE MYOFIBROBLASTS IN BREAST-CANCER - RECAPITULATION OF TUMOR ENVIRONMENT IN CULTURE UNRAVELS DIVERSITY AND IMPLICATES CONVERTED FIBROBLASTS AND RECRUITED SMOOTH
复制标题
DOI：
10.1172/jci117736
复制
发表时间：
1995-02-01
影响因子：
15.9
通讯作者：
BISSELL, MJ
中科院分区：
文献类型：
--
作者：
RONNOVJESSEN, L;PETERSEN, OW;BISSELL, MJ
间质肌成纤维细胞的起源。反应一直是一个有争议的话题。为了明确地解决这个问题，我们开发了主要基质细胞类型的纯化和表征技术。我们定义了一组标记物，这些标记物可以通过免疫细胞化学、等电聚焦、免疫印迹和二维凝胶电泳明确区分这些细胞类型。然后，我们设计了一种测定法，在培养物中，在孵育的两周内，概括体内微环境的关键方面，包括典型的组织组织学和基质反应。当在该测定中面对肿瘤细胞时，成纤维细胞容易转化成肌源性分化的分级模式，在紧邻肿瘤细胞处最强。血管平滑肌细胞（VSMC），相反，没有明显变化，并保持协调的平滑肌分化。中毛细血管周细胞仅表现出轻微的肌源性分化倾向。对10例原发性肿瘤的分析涉及基质反应中的转化成纤维细胞（10/10）、血管平滑肌细胞（4/10）和周细胞（1/10）。肿瘤细胞在培养和体内均显示特异性剥脱小静脉，解释了基质中的VSMC表型。该测定法的建立和这些细胞来源的澄清为进一步分析转化机制以及这种异质性的诊断和治疗后果铺平了道路。
The origin of myofibroblasts in stromal. reaction has been a subject of controversy. To address this question definitively, we developed techniques for purification and characterization of major stromal cell types. We defined a panel of markers that could, in combination, unequivocally distinguish these cell types by immunocytochemistry, iso-electric focusing, immunoblotting, and two-dimensional gel electrophoresis. We then devised an assay to recapitulate in culture, within two weeks of incubation, critical aspects of the microenvironment in vivo including the typical tissue histology and stromal reaction. When confronted with tumor cells in this assay, fibroblasts readily converted into a graded pattern of myogenic differentiation, strongest in the immediate vicinity of tumor cells. Vascular smooth muscle cells (VSMC), in contrast, did not change appreciably and remained coordinately smooth muscle differentiated. Midcapillary pericytes showed only a slight propensity for myogenic differentiation. Analysis of ten primary tumors implicated converted fibroblasts (10/10), vascular smooth muscle cells (4/10), and pericytes (1/10) in the stromal reaction. Tumor cells were shown to specifically denude the venules both in culture and in vivo, explaining the VSMC phenotype in the stroma. The establishment of this assay and clarification of the origin of these cells pave the way for further analysis of the mechanisms of conversion, and of the consequence of such heterogeneity for diagnosis and treatment.