Department of Biomedical Engineering, 153 Weill Hall, Cornell University, Ithaca, NY 14853, USA.
Phys Biol. 2011 Feb;8(1):015008. doi: 10.1088/1478-3975/8/1/015008. Epub 2011 Feb 7.
Increased stiffness represents a hallmark of breast cancer that has been attributed to the altered physicochemical properties of the extracellular matrix (ECM). However, the role of fibronectin (Fn) in modulating the composition and mechanical properties of the tumor-associated ECM remains unclear. We have utilized a combination of biochemical and physical science tools to evaluate whether paracrine signaling between breast cancer cells and adipose progenitor cells regulates Fn matrix assembly and stiffness enhancement in the tumor stroma. In particular, we utilized fluorescence resonance energy transfer imaging to map the molecular conformation and stiffness of Fn that has been assembled by 3T3-L1 preadipocytes in response to conditioned media from MDA-MB231 breast cancer cells. Our results reveal that soluble factors secreted by tumor cells promote Fn expression, unfolding, and stiffening by adipose progenitor cells and that transforming growth factor-β serves as a soluble cue underlying these changes. In vivo experiments using orthotopic co-transplantation of primary human adipose-derived stem cells and MDA-MB231 into SCID mice support the pathological relevance of our results. Insights gained by these studies advance our understanding of the role of Fn in mammary tumorigenesis and may ultimately lead to improved anti-cancer therapies.
硬度增加是乳腺癌的一个标志，其归因于细胞外基质（ECM）的理化性质发生改变。然而，纤连蛋白（Fn）在调节肿瘤相关 ECM 的组成和力学性能方面的作用仍不清楚。我们已经结合生物化学和物理科学工具来评估乳腺癌细胞和脂肪祖细胞之间的旁分泌信号是否调节 Fn 基质组装和肿瘤基质中的硬度增强。特别是，我们利用荧光共振能量转移成像来绘制 3T3-L1 脂肪前体细胞响应 MDA-MB231 乳腺癌细胞条件培养基组装的 Fn 的分子构象和硬度。我们的结果表明，肿瘤细胞分泌的可溶性因子促进脂肪祖细胞中 Fn 的表达、展开和变硬，而转化生长因子-β 是这些变化的潜在可溶性线索。使用原发性人脂肪来源干细胞和 MDA-MB231 共移植到 SCID 小鼠的原位实验支持我们研究结果的病理学相关性。这些研究的深入了解推进了我们对 Fn 在乳腺肿瘤发生中的作用的认识，并可能最终导致改进的抗癌治疗方法。
