Metastatic brain tumors are regulated by immuno-inflammatory signaling pathways governed by STAT3 and MAPK with tumor suppressor p53: possible therapeutic targets

Introduction: Brain metastasis (BM) affects approximately 10% of cancer patients with metastatic disease, representing a major cause of morbidity and mortality in these patients. Standard treatment includes neurosurgical resection, chemo/immunotherapy, and/or radiation. While recent studies demonstrate the genetic basis of such metastases, the molecular causes remain largely elusive. Signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinases, ERK1/2) are dysregulated in various cancers along with tumor suppressor p53. We hypothesize that STAT3 and MAPK with p53 play a critical role in BM.

Methods: Twenty-six tumors, with various primary malignancies, were obtained in accordance with Institutional Review Board guidelines. Immunohistochemical analysis was performed to determine pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and p53 expression. Gene expression analysis was performed on cDNA microarray utilizing hybridization against normal lung sample RNA. Human metastatic breast cancer cells (MDA-MB-231), with tendency for BM, were treated with STAT3 inhibitor (NSC74859) or MAPK inhibitor (U0126) in regular or astrocytic media to determine cell proliferation and migration by MTT assay and scratch wound, respectively. MAPK (ERK1/2) pathway activation was assessed by Western blotting.

Results: Phosphorylated STAT3 and ERK1/2 were expressed in BM tumor margins, and mutant p53 was uniformly expressed. Gene expression analysis identified alterations in 32 STAT3- and MAPK-associated genes, including upregulation of stathmin-1/stathmin-like 3, which control microtubule dynamics associated with STAT3-related cellular migration, and variations in cytokine-related genes, suggesting dysregulated immune responses. Expression of pERK1/2Thr202/Tyr204 was reduced following U0126 or NSC74859 treatments. Cell proliferation and migration were enhanced in an astrocytic environment, and suppressed with STAT3 or MAPK inhibitors.

Conclusion : Activation of STAT3 and ERK1/2 may promote BM, and serve as potential therapeutic targets in the era of precision medicine to provide further immunotherapeutic options, and improve management of BM patients.