Stromal matrix metalloproteinase 2 regulates collagen expression and promotes the outgrowth of experimental metastases.
Stromal matrix metalloproteinase 2 regulates collagen expression and promotes the outgrowth of experimental metastases.
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DOI：
10.1002/path.4493
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发表时间：
2015-04
影响因子：
7.3
通讯作者：
Fingleton, Barbara
中科院分区：
文献类型：
--
作者：
Bates, Andreia L.;Pickup, Michael W.;Hallett, Miranda A.;Dozier, E. Ashley;Thomas, Stacy;Fingleton, Barbara
乳腺癌的存活率从局部疾病患者的99%下降到远处转移患者的25%。基质金属蛋白酶（MMP），包括MMP 2，与转移进展相关。我们发现，宿主MMP 2的丢失减少了肺中实验性转移瘤的增殖，并确定了荷瘤肺中的成纤维细胞是MMP 2的主要来源。在体外，球形乳腺肿瘤的生长增加与控制成纤维细胞分离的荷瘤肺，但不使用时，成纤维细胞与稳定的Mmp 2敲低共培养。这一结果促使我们评估MMP 2是否负责肿瘤增殖，活化成纤维细胞表型。为了验证这一点，我们评估了（i）来自野生型荷瘤肺的成纤维细胞，有或没有shRNA介导的MMP 2敲除，以及（ii）从WT或Mmp 2 −/−小鼠中分离的正常静止成纤维细胞。定量PCR显示，Mmp 2敲低减弱了两种活化标志物（α-平滑肌肌动蛋白和波形蛋白）的表达，但正如预期的那样，在静止的WT或Mmp 2 −/−成纤维细胞中表达最低。将静止的成纤维细胞置于活化条件下导致WT中活化相关转录物的增加，但不导致Mmp 2 −/−成纤维细胞的增加。此外，Mmp 2敲低的成纤维细胞显示基质转录物胶原蛋白I、胶原蛋白IV和纤连蛋白的表达显著降低。加入活性TGFβ足以拯救MMP 2依赖的胶原I和IV表达，而加入TGFβ-1中和抗体则阻断MMP 2诱导的胶原表达。人乳腺癌基质细胞中的基因表达数据揭示，MMP 2表达也与活化和基质转录物正相关。因此，我们提出了一个模型，其中MMP 2在肿瘤成纤维细胞的生产是重要的TGFβ-1活性和随后的活化成纤维细胞的基质生产，增殖支持表型。总体而言，我们的研究结果揭示了MMP 2在成纤维细胞介导的转移性生长中的先前未定义的作用，并扩展了MMP促进肿瘤进展的机制。
Breast cancer survival rates decrease from 99% for patients with local disease to 25% for those with distant metastases. Matrix metalloproteinases (MMPs), including MMP2, are associated with metastatic progression. We found that loss of host MMP2 reduces the proliferation of experimental metastases in the lungs and identified fibroblasts in tumour-bearing lungs as the major source of MMP2. In vitro, spheroidal mammary tumour growth was increased by co-culture with control fibroblasts isolated from tumour-bearing lungs but not when fibroblasts with stable Mmp2 knockdown were used. This result prompted us to assess whether MMP2 was responsible for a tumour-proliferative, activated fibroblast phenotype. To test this, we evaluated (i) fibroblasts from wild-type tumour-bearing lungs with or without shRNA-mediated MMP2 knockdown and (ii) normal, quiescent fibroblasts isolated from either WT or Mmp2−/− mice. Quantitative PCR revealed that Mmp2 knockdown attenuated expression of two markers of activation (α-smooth muscle actin and vimentin), but there was minimal expression in quiescent WT or Mmp2−/− fibroblasts, as expected. Placing quiescent fibroblasts under activating conditions led to increases in activation-associated transcripts in WT but not Mmp2−/− fibroblasts. Additionally, Mmp2 knockdown fibroblasts showed significantly decreased expression of the matrix transcripts collagen I, collagen IV and fibronectin. Addition of active TGFβ was sufficient to rescue the MMP2-dependent collagen I and IV expression, while MMP2-induced collagen expression was blocked with addition of TGFβ-1 neutralizing antibody. Gene expression data in stromal cells of human breast cancers reveals that MMP2 expression is also positively correlated with activation and matrix transcripts. Thus, we present a model whereby MMP2 production in tumour fibroblasts is important for TGFβ-1 activity and subsequent activation of fibroblasts to a matrix-producing, proliferation-supportive phenotype. Overall, our results reveal a previously undefined role for MMP2 in metastatic outgrowth mediated by fibroblasts, and extend the mechanisms by which MMPs contribute to tumour progression.
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DOI：
10.1146/annurev-pathol-020712-163930
发表时间：
2013-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Duffield JS;Lupher M;Thannickal VJ;Wynn TA
通讯作者：
Wynn TA
影响因子：
3.3
作者：
Liu, Shangxi;Xu Shi-wen;Leask, Andrew
通讯作者：
Leask, Andrew
影响因子：
6.4
作者：
Jensen, BV;Johansen, JS;Teisner, B
通讯作者：
Teisner, B
影响因子：
8.8
作者：
Ito, A;Nakajima, S;Sasaguri, Y;Nagase, H;Mori, Y
通讯作者：
Mori, Y
影响因子：
3.8
作者：
Knudsen, Erik S.;Ertel, Adam;Witkiewicz, Agnieszka K.
通讯作者：
Witkiewicz, Agnieszka K.