Application of PPG Technology and Previous Results to Human Breast Tumors

在上一次供资期间的项目4中，具体目标2和3--导致发现 大鼠和小鼠乳腺肿瘤的侵袭特征。因此，花费了大量的努力来定义 侵袭特征与转移癌趋化迁移行为的特殊相关性 小鼠乳腺肿瘤侵袭和渗入过程中的细胞。我们发现编码这些基因的 导致ZBP1/mRNA靶向、Cofilin、Mena/Capping蛋白和N-WASP/Arp2/3的途径 侵袭过程中调节EMT和β-肌动蛋白聚合的途径，以及细胞的方向性 在趋化EGF的过程中，突起和收缩是协调调节的。协调监管 这些基因与肿瘤微环境对转移的贡献特别相关，因为 对血管的趋化作用参与了癌细胞从原发性乳腺肿瘤中逃逸的过程。这个 在项目4的帮助下，研究了来自PI3K的ZBP1、Cofilin、MENA和N-WASP途径 所有核心，因为它们有能力改变转移结果，结果证实了 乳腺肿瘤转移中的侵袭征象。这一确认激发了对这些问题的详细分析 肿瘤细胞的趋化和侵袭途径，这些研究产生了对 转移过程中趋化作用的分子机制。侵袭征兆还包含一个转移 抑制通路，ZBP1/mRNA靶向通路，有助于钙粘连蛋白连接的稳定性 抑制EMT。从这些研究中得出的一个主要见解是，PI3K是起点 这些途径表明其在肿瘤细胞迁移中的关键作用 这一竞争性更新的当前项目4。 项目5也是从这项工作演变而来的。项目5的主题是扩展新技术和 前一资助期大鼠和小鼠对人类乳腺肿瘤的发现以确定是否 人类肿瘤中存在的微环境与之前在大鼠和小鼠身上发现的微环境相似 资助期，以及它们是否可以作为与生物标记物相关的里程碑来预测结果。 将多光子定义的地标和分子病理学研究与源自 前一资助期的侵袭特征，将确定主控基因的预后价值 治疗人类乳腺癌。此外，我们有兴趣确定是否存在入侵签名 人类，这与大鼠和小鼠相似，含有可用作生物标志物的主基因 预测人类患者的预后。

In Project 4 during the previous funding period, specific aims 2 and 3- led to the discovery of an Invasion Signature in rat and mouse mammary tumors. As a result, significant effort was expended to define the particular relevance of the Invasion Signature to the chemotactic migratory behavior of metastatic cancer cells during invasion and intravasation in mouse mammary tumors. We found that the genes coding for pathways leading to the ZBP1/mRNA targeting, cofilin, Mena/capping protein and N-WASP/Arp2/3 pathways, that regulate EMT and beta-actin polymerization during invasion, and the directionality of cell protrusion and contractility during chemotaxis to EGF, are coordinately regulated. Coordinate regulation of these genes is particularly relevant to the contribution of the tumor microenvironment to metastasis because chemotaxis to blood vessels is involved in the escape of cancer cells from primary mammary tumors. The ZBP1, cofilin, Mena and N-WASP pathways, emanating from PI3K, were studied in Project 4, with the help of all Cores, for their ability to alter metastatic outcome and the results confirmed the importance of the Invasion Signature in metastasis in mammary tumors. This confirmation stimulated detailed analysis of these pathways in chemotaxis and invasion of tumor cells and these studies have generated new insights into the molecular mechanisms of chemotaxis during metastasis. The Invasion Signature also contains a metastasis suppressor pathway, the ZBP1/mRNA targeting pathway, which contributes to cadheren junction stability and suppression of EMT. A major insight to emerge from these studies was that PI3K is the starting point from which these pathways emanate indicating its critical importance in tumor cell migration leading to the current Project 4 of this competing renewal. Project 5 also evolved from this work. The theme of Project 5 is to extend the new technologies and findings of the previous funding period in rats and mice to human breast tumors to determine if microenvironments exist in human tumors similar to those discovered in rats and mice during the previous funding period and if they can be used as landmarks in correlation with biomarkers to predict outcome. Combining multiphoton defined landmarks and molecular pathology studies with biomarkers derived from the Invasion Signature of the previous funding period, the prognostic value of master genes will be determined for human breast cancer. In addition, we are interested in determining if an invasion signature exists in humans, that is similar to that in rats and mice, containing master genes that can be used as biomarkers to predict outcome in human patients.