ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.
ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.
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DOI：
10.1158/1541-7786.mcr-11-0100
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Wewer UM
中科院分区：
文献类型：
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作者：
Fröhlich C;Nehammer C;Albrechtsen R;Kronqvist P;Kveiborg M;Sehara-Fujisawa A;Mercurio AM;Wewer UM
ADAM12在大多数正常组织中表达较低，但在许多人类癌症（包括乳腺癌）中显著增加。我们之前已经证明过表达ADAM12会加速乳腺癌小鼠模型（PyMT）中的肿瘤进展。在目前的研究中，我们发现ADAM12缺陷减少了PyMT模型中的乳腺肿瘤进展。然而，ADAM12的催化活性似乎与其促肿瘤作用无关。有趣的是，我们证明了在PyMT模型中肿瘤相关基质中内源性表达的ADAM12不会影响肿瘤进展，但肿瘤细胞的ADAM12表达是这些小鼠肿瘤进展所必需的。这一发现与我们的观察结果一致，即在人类乳腺癌中，ADAM 12几乎完全位于肿瘤细胞中，很少见于肿瘤相关基质中。然而，我们假设肿瘤相关基质可能刺激肿瘤细胞中的ADAM 12表达，这是基于TGF-β 1刺激ADAM 12表达的事实，并且TGF-β 1是一种众所周知的从肿瘤相关基质释放的生长因子。TGF-β 1刺激ADAM 12阴性刘易斯肺肿瘤细胞可诱导ADAM 12合成，这些细胞在体内生长可诱导ADAM 12表达增加200倍以上。我们的观察结果表明，与正常乳腺组织中发现的终末导管小叶单位（TDLUs）相比，人类乳腺癌附近的TDLUs中的ADAM 12表达显著较高，这支持了我们的假设，即肿瘤相关基质触发ADAM 12表达。
Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma ADAM12 is almost exclusively located in tumor cells and only rarely seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, based on the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced a >200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLUs) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.