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Abstract：
Increased remodeling of the extracellular matrix in malignant tumors has been shown to correlate with tumor aggressiveness and a poor prognosis. This remodeling involves degradation of the original extracellular matrix (ECM) and deposition of a new tumor-supporting ECM. The main constituent of the ECM is collagen and collagen turnover mainly occurs in a sequential manner, where initial proteolytic cleavage of the insoluble fibers is followed by cellular internalization of large well-defined collagen fragments for lysosomal degradation. However, despite extensive research in the field, a lack of consensus on which cell types within the tumor microenvironment express the involved proteases still exists. Furthermore, the relative contribution of different cell types to collagen internalization is not well-established. Here, we developed quantitative ex vivo collagen degradation assays and show that the proteases responsible for the initial collagen cleavage in two murine syngeneic tumor models are matrix metalloproteinases produced by cancer-associated fibroblasts and that collagen degradation fragments are endocytosed primarily by tumor-associated macrophages and cancer-associated fibroblasts from the tumor stroma. Using tumors from mannose receptor-deficient mice, we show that this receptor is essential for collagen-internalization by tumor-associated macrophages. Together, these findings identify the cell types responsible for the entire collagen degradation pathway, from initial cleavage to endocytosis of fragments for intracellular degradation.
摘要：
已显示，恶性肿瘤中细胞外基质的重塑增加与肿瘤侵袭性和不良预后相关。这种重塑涉及原始细胞外基质（ECM）的降解和新的支持肿瘤的ECM的沉积。ECM的主要成分是胶原蛋白，胶原蛋白周转主要以顺序方式发生，其中不溶性纤维的初始蛋白水解裂解随后是大的明确定义的胶原片段的细胞内化以用于溶酶体降解。然而,尽管在该领域进行了广泛的研究，关于肿瘤微环境中哪些细胞类型表达相关蛋白酶的共识仍然存在。此外，不同细胞类型对胶原内化的相对贡献尚不明确.这里,我们开发了定量的离体胶原降解试验,并显示在两个小鼠同系肿瘤模型中,负责胶原初始裂解的蛋白酶是由癌症相关成纤维细胞产生的基质金属蛋白酶,并且胶原降解片段主要被来自肿瘤基质的肿瘤相关巨噬细胞和癌症相关成纤维细胞胞吞.利用甘露糖受体缺陷小鼠的肿瘤，我们表明，这种受体对于肿瘤相关巨噬细胞的胶原内化至关重要。一起,这些发现确定了负责整个胶原蛋白降解途径的细胞类型，从最初的裂解到细胞内降解片段的内吞。
