PLoS ONE：肿瘤周围组织存在抑制三阴性乳腺癌转移物质

近日，科学家在肿瘤周围组织中发现的一种天然物质可能抑制三阴乳腺癌转移。发表在PLOS ONE杂志上的一项临床前研究证实，有抑制肿瘤生长功效的核心蛋白聚糖能诱导三阴性乳腺癌肿瘤周围组织中一系列肿瘤抑制基因的表达，导致肿瘤转移受到抑制。

三阴乳腺癌特指雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER-2）均阴性的乳腺癌患者。托马斯·杰斐逊大学解剖学和细胞生物学Renato V. Iozzo医学博士说：这一最新研究发现最终可能有助于三阴乳腺癌的临床评估和预后判断。

Iozzo博士说：起初，我们认为核心蛋白聚糖是影响肿瘤细胞本身的，但令人惊讶的是，核心蛋白聚糖是能影响肿瘤微环境的。在这项研究中，核心蛋白聚糖能导致357个基因表达增加，但更有趣的是，研究人员发现三个肿瘤抑制基因是与三阴性乳腺癌相关联的，这些抑癌基因是Bmp2K、Zc3hav1和PEG3。

核心蛋白聚糖是蛋白聚糖(proteoglycan，PG)的一种，是一种多效性分子。在调节细胞粘附、迁徙、增殖、胶原纤维形成及调节TGF-β活性中起重要作用。研究人员还发现核心蛋白聚糖能调控p21蛋白的生成，p21蛋白能抑制肿瘤细胞生长。然而，核心蛋白聚糖背后的抗乳腺癌特性和机制仍然不甚明了。
 
在这项研究中，研究人员旨在探讨核心蛋白聚糖对三阴性乳腺癌肿瘤小鼠模型体内肿瘤细胞系的影响，以及分析肿瘤微环境基因表达情况。

小鼠给予蛋白聚糖治疗23天后，肿瘤体积体积缩小达50％。然后，研究人员利用先进的芯片技术分析了小鼠肿瘤微环境中基因表达情况，发现357个基因表达增加了，其中3个是肿瘤抑制基因。这些结果表明核心蛋白聚糖有助减少或预防肿瘤转移，改善转移性乳腺癌的治疗。

Decorin Protein Core Affects the Global Gene Expression Profile of the Tumor Microenvironment in a Triple-Negative Orthotopic Breast Carcinoma Xenograft Model.

Simone Buraschi, Thomas Neill, Rick T. Owens, Leonardo A. Iniguez, George Purkins, Rajanikanth Vadigepalli, Barry Evans, Liliana Schaefer, Stephen C. Peiper, Zi-Xuan Wang, Renato V. Iozzo.

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.