Abstract 3399: STAT3 promotes metastasis to the brain: Demonstrated by protein, gene, and functional analysis

Abstract

Abstract Brain metastasis affects an estimated 10% of cancer patients with metastatic disease, a major cause of morbidity and mortality in these patients. The most common primary tumors causing brain metastasis are adenocarcinoma of the lung or breast. While recent studies have demonstrated the genetic basis of such metastases, the molecular cause(s) of brain metastases remains largely elusive. Signal transducer and activator of transcription 3 (STAT3) has been shown to control various cellular functions and regulates the immune response. STAT3 is activated in various aggressive carcinomas. We hypothesize that STAT3 may play a role in metastatic brain tumors. Metastatic brain tumors were analyzed for expression of activated STAT3Tyr705 by immunohistochemical analysis. Gene expression profiling (17,000 gene chip) was performed in metastatic tumor samples, and STAT3 regulated genes were evaluated. Functional analysis such as cell motility and proliferation were investigated by chemotactic migration and MTT assay, respectively. The results of this study showed that a significant number of metastatic tumors to brain (75%) demonstrated nuclear expression of pSTAT3Tyr705. A significant number of these tumors also expressed mutant-p53 and activated MAPK. Gene expression analysis demonstrated that 32 STAT3-associated genes were significantly altered. Upregulated genes included stathmin-1 and stathmin-like 3 that control mictotubule dynamics in migrating cells and are associated with STAT3-related migration. The upregulation of stathmin-like 3 (also called SCG10-like-protein or SCLIP) also interacts with STAT3 in the maintenance of cellular dynamics involved in cell-cell attachment. The gp130-related interleukin 6 signal transducer gene, which is generally involved in STAT3-dependent glial fibrillary acidic protein (GFAP) induction during nerve regeneration, was inhibited. The suppression of STAT3-regulated gene oncostatin M receptor, which regulates metastasis, was observed. Furthermore, protein inhibitor of activated STAT3 (PIAS3), that suppresses activated STAT3 levels, was downregulated. Functional analysis revealed that cell proliferation of breast cancer cells (MCF7 cells) was enhanced in an astrocytic environment. Chemotactic analysis showed that breast cancer cells migrated toward astrocytic media. In addition, co-culture analysis demonstrated that astrocytes and tumor cells have an affinity for each other and make genuine cell-cell contact. These results indicate that STAT3 activation plays a significant role in brain metastasis by itself as well as by altering downstream target genes that regulate various cellular functions. Furthermore, the astrocytic milieu promotes the metastatic potential of tumor cells. Therefore, the activation of STAT3 promotes metastasis to brain, and may serve as a target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3399.