Wang Karin, Wu Fei, Seo Bo Ri, Fischbach Claudia, Chen Weisi, Hsu Lauren, Gourdon Delphine
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA; Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14583, USA.
Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA.
Matrix Biol. 2017 Jul;60-61:86-95. doi: 10.1016/j.matbio.2016.08.001. Epub 2016 Aug 6.
Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel their extracellular matrix (ECM) and promote invasive tumor growth. Two major ECM components, fibronectin (Fn) and collagen I (Col I), are known to interact with each other to regulate cellular behavior. In this study, we seek to understand how Fn and Col I interplay and promote a dysregulated signaling pathway to facilitate tumor progression. Specifically, we investigated the evolution of tumor-conditioned stromal ECM composition, structure, and relaxation. Furthermore, we assessed how evolving Fn-Col I interactions gradually affected pro-angiogenic signaling. Our data first indicate that CAFs initially assembled a strained, viscous, and unfolded Fn matrix. This early altered Fn matrix was later remodeled into a thick Col I-rich matrix that was characteristic of a dense tumor mass. Next, our results suggest that this ECM remodeling was primarily mediated by matrix metalloproteinases (MMPs). This MMP activity caused profound structural and mechanical changes in the developing ECM, which then modified vascular endothelial growth factor (VEGF) secretion by CAFs and matrix sequestration. Collectively, these findings enhance our understanding of the mechanisms by which Fn and Col I synergistically interplay in promoting a sustained altered signaling cascade to remodel the breast tumor stroma for invasive breast tumor growth.
乳腺癌细胞募集周围的基质细胞，如癌症相关成纤维细胞（CAFs），以重塑其细胞外基质（ECM）并促进肿瘤侵袭性生长。已知两种主要的ECM成分，纤连蛋白（Fn）和I型胶原蛋白（Col I），会相互作用以调节细胞行为。在本研究中，我们试图了解Fn和Col I如何相互作用并促进失调的信号通路，以促进肿瘤进展。具体而言，我们研究了肿瘤条件下基质ECM组成、结构和松弛的演变。此外，我们评估了不断演变的Fn-Col I相互作用如何逐渐影响促血管生成信号。我们的数据首先表明，CAFs最初组装了一种紧张、粘稠且未折叠的Fn基质。这种早期改变的Fn基质后来被重塑为富含Col I的厚基质，这是致密肿瘤块的特征。接下来，我们的结果表明，这种ECM重塑主要由基质金属蛋白酶（MMPs）介导。这种MMP活性在发育中的ECM中引起了深刻的结构和力学变化，进而改变了CAFs分泌血管内皮生长因子（VEGF）和基质隔离。总的来说，这些发现加深了我们对Fn和Col I协同相互作用促进持续改变的信号级联反应以重塑乳腺肿瘤基质促进侵袭性乳腺肿瘤生长机制的理解。
