Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis.
Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis.
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DOI：
10.1186/1476-4598-9-122
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发表时间：
2010-05-26
期刊：
影响因子：
37.3
通讯作者：
Reiss M
中科院分区：
文献类型：
--
作者：
Ganapathy V;Ge R;Grazioli A;Xie W;Banach-Petrosky W;Kang Y;Lonning S;McPherson J;Yingling JM;Biswas S;Mundy GR;Reiss M
转化生长因子β（Transforming growth Factor β，TGF-β）在肿瘤的侵袭和转移中起重要作用。我们着手研究TGF-β拮抗剂在人转移性基底样乳腺癌模型中的可能临床效用。我们检查了两种类型的TGF-β途径拮抗剂的作用（1D 11，一种小鼠单克隆泛TGF-β中和抗体和LY 2109761，一种TGF-β I型和II型受体激酶的化学抑制剂）对优先转移到肺的基底细胞样MDA-MB-231人乳腺癌细胞亚系的作用（4175 TR，4173）或骨（SCP 2 TR，SCP 25 TR，2860 TR，3847 TR）。在体外，1D 11和LY 2109761均有效地阻断了所有MDA-MB-231亚克隆中TGF-β诱导的受体相关Smads的磷酸化。此外，两种拮抗剂均抑制TGF-β刺激的MDA-MB-231亚克隆的体外迁移和侵袭，表明这些过程部分由TGF-β驱动。此外，这两种拮抗剂显着降低了体内肺或骨的转移负荷，似乎独立于个体肿瘤细胞克隆之间的内在差异。除了以肿瘤细胞自主方式抑制转移外，TGF-β拮抗剂还抑制与肺转移相关的血管生成以及与溶解性骨转移相关的破骨细胞数量和活性。总之，这些研究支持TGF-β在基底细胞样乳腺癌的骨转移和肺转移中起重要作用的观点，并且抑制TGF-β信号传导导致独立于转移细胞的组织嗜性的治疗效果。靶向TGF-β通路有望成为转移性基底细胞样乳腺癌的新治疗方法。总之，这些研究支持TGF-β在基底细胞样乳腺癌的骨转移和肺转移中起重要作用的观点，并且抑制TGF-β信号传导导致独立于转移细胞的组织嗜性的治疗效果。靶向TGF-β通路有望成为转移性基底细胞样乳腺癌的新治疗方法。
Transforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-β antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody and LY2109761, a chemical inhibitor of TGF-β type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR). Both 1D11 and LY2109761 effectively blocked TGF-β-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-β stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-β. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-β antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.
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