The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites
The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites
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DOI：
10.3390/cancers12051270
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发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Solorio, Luis
中科院分区：
文献类型：
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作者：
Libring, Sarah;Shinde, Aparna;Solorio, Luis
在乳腺癌 (BC) 中，纤连蛋白 (FN) 和胶原蛋白积累导致的组织硬化与原发肿瘤和转移部位的晚期疾病进展相关。在这里，我们评估了 15 种 BC 细胞系中 FN 的产生，这些细胞系代表了各种亚型、表型、转移潜能和化疗敏感性。我们证明，细胞内和可溶性 FN 最初在致瘤转化过程中丢失，但在所有具有上皮间质可塑性 (EMP) 的细胞系中都得到了挽救。重要的是，我们确定没有 BC 细胞系能够独立组织强大的 FN 矩阵。未转化的乳腺上皮细胞也无法沉积 FN 基质，除非转谷氨酰胺酶 2（一种 FN 交联酶）过度表达。相反，BC 细胞以表型依赖性方式操纵成纤维细胞的 FN 基质产生。此外，根据成纤维细胞是否被调节以模拟转移生态位的旁分泌信号或内分泌信号，可以看到不同的积累水平。在前者中，用高 EMP 的 BC 培养物调节的成纤维细胞导致最大的 FN 基质积累。相比之下，间充质 BC 细胞产生细胞外囊泡 (EV)，导致条件成纤维细胞形成最高水平的基质。总体而言，我们证明了肿瘤微环境中肿瘤和基质细胞之间的动态关系，其中细胞外基质中 FN 的水平和纤维化在疾病进展的特定阶段受到调节。
In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic potentials, and chemotherapeutic sensitivities. We demonstrate that intracellular and soluble FN is initially lost during tumorigenic transformation but is rescued in all lines with epithelial-mesenchymal plasticity (EMP). Importantly, we establish that no BC cell line was able to independently organize a robust FN matrix. Non-transformed mammary epithelial cells were also unable to deposit FN matrices unless transglutaminase 2, a FN crosslinking enzyme, was overexpressed. Instead, BC cells manipulated the FN matrix production of fibroblasts in a phenotypic-dependent manner. In addition, varied accumulation levels were seen depending if the fibroblasts were conditioned to model paracrine signaling or endocrine signaling of the metastatic niche. In the former, fibroblasts conditioned by BC cultures with high EMP resulted in the largest FN matrix accumulation. In contrast, mesenchymal BC cells produced extracellular vesicles (EV) that resulted in the highest levels of matrix formation by conditioned fibroblasts. Overall, we demonstrate a dynamic relationship between tumor and stromal cells within the tumor microenvironment, in which the levels and fibrillarization of FN in the extracellular matrix are modulated during the particular stages of disease progression.