Laboratory of Tumor and Developmental Biology, GIGA-Cancer, Institute of Pathology, University of Liège, Liège, Belgium.
Oncogene. 2012 Jan 26;31(4):480-93. doi: 10.1038/onc.2011.249. Epub 2011 Jun 27.
As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminal-like breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis.
当侵袭性乳腺癌细胞突破其基底膜时，它们会遇到由 I 型胶原组成的密集三维反应性基质。为了获得转移能力，侵袭性肿瘤细胞必须获得在这种新的微环境中迁移的能力。胶原通过诱导细胞凋亡来影响上皮细胞的命运。然而，侵袭性肿瘤细胞逃避胶原诱导凋亡所使用的机制仍有待确定。我们证明，膜型 1 基质金属蛋白酶（MT1-MMP/MMP-14）赋予乳腺癌细胞在胶原凝胶中嵌入以及在体内原位植入时逃避凋亡的能力。在缺乏 MMP-14 依赖性蛋白水解的情况下，I 型胶原通过诱导腔细胞样乳腺癌细胞中促凋亡的 Bcl-2 相互作用杀伤因子的表达来触发细胞凋亡。这些发现揭示了一种新的机制，即 MMP-14 活性通过绕过凋亡来促进肿瘤的进展。
