Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment
Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment
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DOI：
10.1073/pnas.0704366104
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发表时间：
2007-06-26
影响因子：
11.1
通讯作者：
Deuel, Thomas F.
中科院分区：
文献类型：
--
作者：
Chang, Yunchao;Zuka, Masahiko;Deuel, Thomas F.
多效生长因子（PTN，Ptn）是一种在许多乳腺癌中表达的18 kDa分泌型细胞因子;然而，Ptn在乳腺癌中表达的意义尚未确定。我们现在已经测试了三种模型来确定Ptn的不适当表达在乳腺癌中的作用。在MMTV-多瘤病毒中T抗原（PyMT）-Ptn小鼠乳腺癌中表达的小鼠乳腺肿瘤病毒（MMTV）启动子驱动的Ptn首次显示诱导形态学鉴定的“硬癌”癌灶的快速生长，并广泛重塑微环境，包括增加肿瘤血管生成和小鼠原胶原I α 2、IV α 5和XI α 1以及弹性蛋白的显著增加。MCF-7（人乳腺癌）-Ptn细胞异种移植物中的异位Ptn表达也显示出显著增加MCF-7-Ptn细胞异种移植物在裸鼠中的生长;此外，它诱导了微环境和肿瘤血管生成的广泛重塑。在等量NIH 3 T3基质成纤维细胞和MCF-7-Ptn细胞的共培养模型中，MCF-7-Ptn细胞分泌的PTN随后显示诱导更恶性的MCF-7-Ptn乳腺癌细胞表型和MCF-7-Ptn/NIH 3 T3细胞微环境的广泛重塑;在MCF-7-Ptn和NIH 3 T3细胞中，它上调了侵袭性乳腺癌标志物的表达，包括PKCS和基质金属蛋白酶-9。MCF-7-Ptn细胞异种移植物和MCF-7-Ptn细胞/NIH 3 T3细胞共培养物的形态表型与MMTV-PyMT-Ptn小鼠中的乳腺癌非常相似。因此，Ptn的不适当表达促进了小鼠乳腺癌的进展;数据表明，通过单独刺激基质细胞微环境分泌PTN可能足以解释乳腺癌进展的显著特征。
Pleiotrophin (PTN, Ptn) is an 18-kDa secretory cytokine expressed in many breast cancers; however, the significance of Ptn expression in breast cancer has not been established. We have now tested three models to determine the role of inappropriate expression of Ptn in breast cancer. Mouse mammary tumor virus (MMTV) promoter-driven Ptn expressed in MMTV-polyoma virus middle T antigen (PyMT)-Ptn mouse breast cancers was first shown to induce rapid growth of morphologically identified foci of "scirrhous" carcinoma and to extensively remodel the microenvironment, including increased tumor angiogenesis and striking increases in mouse protocollagens I alpha 2, IV alpha 5, and XI alpha 1, and elastin. Ectopic Ptn expression in MCF-7 (human breast cancer)-Ptn cell xenografts also was shown to markedly increase MCF-7-Ptn cell xenograft growth in nude mice; furthermore, it induced extensive remodeling of the microenvironment and tumor angiogenesis. In a coculture model of equal numbers of NIH 3T3 stromal fibroblasts and MCF-7-Ptn cells, PTN secreted from MCF-7-Ptn cells was then shown to induce a more malignant MCF-7-Ptn breast cancer cell phenotype and extensive remodeling of the MCF-7-Ptn/NIH 3T3 cell microenvironment; it up-regulated expression of markers of aggressive breast cancers, including PKCS and matrix metalloproteinase-9 in both MCF-7-Ptn and NIH 3T3 cells. The morphological phenotypes of MCF-7-Ptn cell xenografts and MCF-7-Ptn cell/NIH 3T3 cell cocultures closely resembled breast cancers in MMTV-PyMT-Ptn mice. Inappropriate expression of Ptn thus promotes breast cancer progression in mice; the data suggest that secretion of PTN through stimulation of the stromal cell microenvironment alone may be sufficient to account for significant features of breast cancer progression.