Michaelson Jennifer S, Cho Sandy, Browning Beth, Zheng Timothy S, Lincecum John M, Wang Monica Z, Hsu Yen-Ming, Burkly Linda C
Department of Exploratory Science, Biogen Idec, 12 Cambridge Center, Bio6-320, Cambridge MA, USA.
Oncogene. 2005 Apr 14;24(16):2613-24. doi: 10.1038/sj.onc.1208208.
Members of the tumor necrosis factor (TNF) superfamily regulate cell survival and proliferation and have been implicated in cancer. Tweak (TNF-related weak inducer of apoptosis) has pleiotropic biological functions including proapoptotic, proangiogenic and proinflammatory activities. We explored a role for Tweak in mammary gland transformation using a three-dimensional model culture system. Tweak stimulates a branching morphogenic phenotype, similar to that induced by pro-oncogenic factors, in Eph4 mammary epithelial cells cultured in matrigel. Increased proliferation and invasiveness are observed, with a concomitant inhibition of functional differentiation. Levels of matrix metalloproteinase-9 (MMP-9) are significantly increased following Tweak treatment. Notably, MMP inhibitors are sufficient to block the branching phenotype induced by Tweak. The capacity to promote proliferation, inhibit differentiation and induce invasion suggests a role for Tweak in mammary gland tumorigenesis. Consistent with this, we have observed elevated protein levels of the Tweak receptor, Fn14, in human breast tumor cell lines and xenograft models as well as in primary human breast tumors. Together, our results suggest that the Tweak/Fn14 pathway may be protumorigenic in human breast cancer.
肿瘤坏死因子（TNF）超家族成员调节细胞存活和增殖，并与癌症有关。Tweak（肿瘤坏死因子相关的凋亡弱诱导剂）具有多效性生物学功能，包括促凋亡、促血管生成和促炎活性。我们使用三维模型培养系统探讨了Tweak在乳腺转化中的作用。在基质胶中培养的Eph4乳腺上皮细胞中，Tweak刺激出一种分支形态发生表型，类似于由促癌因子诱导的表型。观察到增殖和侵袭增加，同时功能分化受到抑制。Tweak处理后基质金属蛋白酶-9（MMP-9）水平显著升高。值得注意的是，MMP抑制剂足以阻断Tweak诱导的分支表型。促进增殖、抑制分化和诱导侵袭的能力表明Tweak在乳腺肿瘤发生中起作用。与此一致的是，我们在人乳腺肿瘤细胞系、异种移植模型以及原发性人乳腺肿瘤中观察到Tweak受体Fn14的蛋白水平升高。总之，我们的结果表明Tweak/Fn14通路可能在人乳腺癌中具有促肿瘤作用。
