Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions.
Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions.
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DOI：
10.1016/j.matbio.2016.08.001
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Gourdon D
中科院分区：
文献类型：
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作者：
Wang K;Wu F;Seo BR;Fischbach C;Chen W;Hsu L;Gourdon D
乳腺癌细胞招募周围的间质细胞，如癌症相关成纤维细胞(CAF)，以重塑其细胞外基质(ECM)，促进侵袭性肿瘤生长。两个主要的细胞外基质成分，纤维连接蛋白(FN)和I型胶原(Col I)，已知相互作用来调节细胞行为。在这项研究中，我们试图了解FN和Col I是如何相互作用并促进失调的信号通路来促进肿瘤进展的。具体地说，我们研究了肿瘤条件下间质ECM的成分、结构和松弛的演变。此外，我们评估了FN-Col I相互作用的演变是如何逐渐影响促血管生成信号的。我们的数据首先表明，CAF最初组装了一个应变的、粘性的和展开的FN矩阵。这个早期改变的FN基质后来被改造成一个厚厚的富含Col I的基质，这是致密的肿瘤肿块的特征。其次，我们的结果表明，这种ECM重塑主要是由基质金属蛋白酶(MMPs)介导的。这种基质金属蛋白酶的活性导致发育中的细胞外基质发生了深刻的结构和机械变化，进而改变了血管内皮生长因子(VEGF)的分泌和基质隔离。总而言之，这些发现增强了我们对FN和Col I协同作用的机制的理解，通过这些机制，FN和Col I相互作用，促进了持续变化的信号级联，以重塑乳腺肿瘤间质，以适应乳腺肿瘤的侵袭性生长。
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.