Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression
Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression
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DOI：
10.1158/0008-5472.can-18-2931
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发表时间：
2019-07-15
期刊：
影响因子：
11.2
通讯作者：
Hurley, Paula J.
中科院分区：
文献类型：
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作者：
Hughes, Robert M.;Simons, Brian W.;Hurley, Paula J.
肿瘤进展到转移不是癌细胞自主的，而是涉及肿瘤微环境内多种细胞类型的相互作用。在这里，我们确定asporin（ASPN）作为一种新的，分泌的间充质基质细胞（MSC）因子的肿瘤微环境，调节转移的发展。MSC表达高水平的ASPN，其随着谱系分化而降低。ASPN丢失损害MSC自我更新，促进终末细胞分化。从机制上讲，分泌的ASPN结合BMP-4和限制BMP-4诱导的MSC分化之前的谱系承诺。ASPN表达在MSC和癌相关成纤维细胞（CAF）之间明显保守。肿瘤微环境中的ASPN表达广泛影响多种细胞类型。ASPN缺失小鼠的前列腺肿瘤同种异体移植物中肿瘤相关MSC数量减少，癌症干细胞减少，肿瘤血管减少，浸润CD 8（+）T细胞百分比增加。与野生型小鼠相比，ASPN缺失小鼠的肺转移也显著减少。这些数据建立了ASPN作为一个重要的MSC因子，广泛影响肿瘤微环境和诱导转移progress.Significance：这些研究结果表明，asporin调节间充质基质细胞的关键特性，包括自我更新和多能性，和asporin表达反应性基质细胞改变肿瘤微环境，促进转移进展。
Tumor progression to metastasis is not cancer cell autonomous, but rather involves the interplay of multiple cell types within the tumor microenvironment. Here we identify asporin (ASPN) as a novel, secreted mesenchymal stromal cell (MSC) factor in the tumor microenvironment that regulates metastatic development. MSCs expressed high levels of ASPN, which decreased following lineage differentiation. ASPN loss impaired MSC self-renewal and promoted terminal cell differentiation. Mechanistically, secreted ASPN bound to BMP-4 and restricted BMP-4-induced MSC differentiation prior to lineage commitment. ASPN expression was distinctly conserved between MSC and cancer-associated fibroblasts (CAF). ASPN expression in the tumor microenvironment broadly impacted multiple cell types. Prostate tumor allografts in ASPN-null mice had a reduced number of tumor-associated MSCs, fewer cancer stem cells, decreased tumor vasculature, and an increased percentage of infiltratingCD8(+) T cells. ASPN-null mice also demonstrated a significant reduction in lung metastases compared with wild-type mice. These data establish a role for ASPN as a critical MSC factor that extensively affects the tumor microenvironment and induces metastatic progression.Significance: These findings show that asporin regulates key properties of mesenchymal stromal cells, including self-renewal and multipotency, and asporin expression by reactive stromal cells alters the tumor microenvironment and promotes metastatic progression.