Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression.
Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression.
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发表时间：
2001-02
期刊：
影响因子：
11.2
通讯作者：
M. Shekhar;J. Werdell;S. Santner;R. Pauley;L. Tait
中科院分区：
文献类型：
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作者：
M. Shekhar;J. Werdell;S. Santner;R. Pauley;L. Tait
虽然生长因子和细胞外基质（ECM）被认为是乳腺上皮生长、形态发生、激素反应和肿瘤进展的重要贡献者，但乳腺基质和上皮细胞之间的功能相互作用对这些过程的影响尚未明确。利用一种新的三维细胞-细胞相互作用模型，我们比较了不同间充质细胞类型的能力，包括来自乳腺缩小成形术和肿瘤组织的乳腺成纤维细胞，以及人脐内皮细胞（HUVECs）诱导正常MCF10A和肿瘤前MCF10AT1-EIII8（简称EIII8）人乳腺上皮细胞的三维形态发生和生长。我们的数据表明，在上皮形态发生的诱导中需要器官特异性成纤维细胞。正常缩乳成形术中包含的成纤维细胞分别抑制或延缓MCF10A和EIII8细胞的形态转化和生长，而肿瘤来源的乳腺成纤维细胞可诱导MCF10A和EIII8细胞的导管-肺泡形态发生。即使在雌激素存在的情况下，正常成纤维细胞的生长和形态发生抑制作用仍然存在，因为它们能够抑制雌激素诱导的EIII8细胞的生长，而肿瘤成纤维细胞支持并维持EIII8细胞的雌激素反应性。肿瘤成纤维细胞对EIII8细胞的诱导形态发生作用被huvec的加入进一步增强，因为这些共培养经历了增殖和分支导管-肺泡形态发生的急剧增加，伴随着入侵、一致ECM降解和MMP-9表达的增加。因此，肿瘤成纤维细胞赋予上皮细胞形态发生和有丝分裂诱导，进一步促进生长和进展需要活跃的血管生成。这些数据说明了乳腺间质细胞和上皮细胞之间的结构和功能相互作用在乳腺上皮细胞生长和进展的调节中的重要性。
Although growth factors and extracellular matrix (ECM) are recognized as important contributors to breast epithelial growth, morphogenesis, hormone responsiveness, and neoplastic progression, the influence of functional interactions between breast stromal and epithelial cells on these processes has not been defined. Using a novel three-dimensional cell-cell interaction model, we have compared the abilities of different mesenchymal cell types, including breast fibroblasts derived from reduction mammoplasty and tumor tissues, and human umbilical endothelial cells (HUVECs) to induce three-dimensional morphogenesis and growth of normal MCF10A and preneoplastic MCF10AT1-EIII8 (referred as EIII8) human breast epithelial cells. Our data demonstrate a requirement for organspecific fibroblasts in the induction of epithelial morphogenesis. Whereas inclusion of normal reduction mammoplasty fibroblasts inhibit or retard morphological conversion and growth of MCF10A and EIII8 cells, respectively, tumor-derived breast fibroblasts evoke ductal-alveolar morphogenesis of both MCF10A and EIII8 cells. The growth and morphogenesis inhibitory effects of normal fibroblasts remain even in the presence of estrogen because they are able to suppress the estrogen-induced growth of EIII8 cells, whereas tumor fibroblasts support and maintain estrogen responsiveness of EIII8 cells. The inductive morphogenic effects of tumor fibroblasts on EIII8 cells is further augmented by the inclusion of HUVECs because these cocultures undergo a dramatic increase in proliferation and branching ductal-alveolar morphogenesis that is accompanied by an increase in invasion, degradation of coincident ECM, and expression of MMP-9. Therefore, tumor fibroblasts confer morphogenic and mitogenic induction of epithelial cells, and further enhancement of growth and progression requires active angiogenesis. These data illustrate the importance of structural and functional interactions between breast stromal and epithelial cells in the regulation of breast epithelial growth and progression.