TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts.
TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts.
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DOI：
10.3390/cancers8110100
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发表时间：
2016-11-04
期刊：
影响因子：
5.2
通讯作者：
Owens P
中科院分区：
文献类型：
--
作者：
Jovanović B;Pickup MW;Chytil A;Gorska AE;Johnson KC;Moses HL;Owens P
TGF-β通路通过调节上皮细胞和基质细胞信号传导在肿瘤进展中起主要作用。该通路的功能障碍可导致癌进展和转移。为了深入了解TGF-β通路在乳腺癌中的基质作用，我们对乳腺癌患者和乳房缩小术患者进行了激光捕获显微切割（LCM）。显微切割的肿瘤间质和正常乳腺间质的基因表达进行了检查。与对照健康乳腺组织相比，肿瘤间质中TGF-β III型受体（TGFBR 3）的表达显著降低。这些结果表明，与对照组织相比，肿瘤间质中的TGFBR 3 mRNA降低了44倍。我们研究了公开可用的数据库，并已确定TGFBR 3 mRNA水平在肿瘤间质中降低。我们接下来研究了来自癌组织和正常乳腺组织的成纤维细胞系，发现除了mRNA水平外，TβRIII蛋白水平也显著降低。先前已经确定癌症相关成纤维细胞分泌更高水平的肿瘤促进细胞因子，我们研究了可溶性T βRIII（sTβRIII）对成纤维细胞的影响。分析成纤维细胞条件培养基中102种人分泌的细胞因子，观察到对sTβRIII的反应的明显变化。接下来，我们使用成纤维细胞条件培养基刺激人单核细胞系THP-1。这些结果表明，依赖于sTβRIII治疗和它是否来自正常或癌性乳腺组织的不同的转录反应。我们的结论是，TβRIII的作用不仅在癌症相关的成纤维细胞中具有独特的作用，而且sTβRIII在肿瘤微环境中具有独特的旁分泌功能。
The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-β type III receptor (TGFBR3) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, TβRIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-TβRIII (sTβRIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sTβRIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sTβRIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of TβRIII has distinct roles not only in cancer-associated fibroblasts but that sTβRIII has distinct paracrine functions in the tumor microenvironment.
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