Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas.
Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas.
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DOI：
10.1158/0008-5472.can-13-0012
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发表时间：
2013-09-01
期刊：
影响因子：
11.2
通讯作者：
Moses HL
中科院分区：
文献类型：
--
作者：
Pickup MW;Laklai H;Acerbi I;Owens P;Gorska AE;Chytil A;Aakre M;Weaver VM;Moses HL
肿瘤间质环境可以决定肿瘤进展的许多方面。全面了解驱动基质激活的因素及其在肿瘤转移中的作用对于进一步研究治疗干预的目标至关重要。缺乏II型TGF-ß受体（PyMTmgko）的多瘤中t诱导乳腺癌与对照pymt诱导的癌（PyMTfl/fl）相比具有高转移性。我们假设PyMTmgko激活的基质与癌细胞相互作用，促进癌细胞的侵袭和转移。我们发现，与PyMTfl/fl乳腺癌相比，与PyMTfl/fl乳腺癌相关的细胞外基质更硬，具有更多的纤维性胶原，胶原交联酶赖氨酸氧化酶（LOX）的表达增加。抑制PyMTmgko小鼠LOX活性对肿瘤潜伏期和肿瘤大小没有影响，但通过抑制肿瘤细胞内渗漏显著降低肿瘤转移。这种表型与LOX抑制后PyMTmgko肿瘤中角蛋白14阳性肌上皮细胞的减少以及局灶粘连形成的减少有关。有趣的是，LOX的主要来源被发现是活化的成纤维细胞。LOX在这些成纤维细胞中的表达可由骨髓细胞来源的TGF-ß驱动，这与人类乳腺癌有显著关联。总的来说，PyMTmgko肿瘤的间质扩张可能是通过调节免疫细胞浸润促进成纤维细胞激活引起的。这反馈到上皮细胞，通过调节基底细胞的表型特征促进转移。我们的数据表明，上皮诱导的微环境变化在肿瘤发生中起重要作用，减弱这些变化可以抑制转移。
The tumor stromal environment can dictate many aspects of tumor progression. A complete understanding of factors driving stromal activation and their role in tumor metastasis is critical to furthering research with the goal of therapeutic intervention. Polyoma middle T-induced mammary carcinomas lacking the type II TGF-ß receptor (PyMTmgko) are highly metastatic compared to control PyMT-induced carcinomas (PyMTfl/fl). We hypothesized that the PyMTmgko activated stroma interacts with carcinoma cells to promote invasion and metastasis. We show that the extracellular matrix associated with PyMTmgko tumors is stiffer, has more fibrillar collagen, and increased expression of the collagen crosslinking enzyme lysyl oxidase (LOX) compared to PyMTfl/fl mammary carcinomas. Inhibition of LOX activity in PyMTmgko mice had no effect on tumor latency and size, but significantly decreased tumor metastasis through inhibition of tumor cell intravasation. This phenotype was associated with a decrease in keratin 14 positive myoepithelial cells in PyMTmgko tumors following LOX inhibition as well as a decrease in focal adhesion formation. Interestingly, the primary source of LOX was found to be activated fibroblasts. LOX expression in these fibroblasts can be driven by myeloid cell-derived TGF-ß, which is significantly linked to human breast cancer. Overall, stromal expansion in PyMTmgko tumors is likely caused through the modulation of immune cell infiltrates to promote fibroblast activation. This feeds back to the epithelium to promote metastasis by modulating phenotypic characteristics of basal cells. Our data indicate that epithelial induction of microenvironmental changes can play a significant role in tumorigenesis and attenuating these changes can inhibit metastasis.