The Incidence, Correlation with Tumor-Infiltrating Inflammation, and Prognosis of Phosphorylated STAT3 Expression in Human Gliomas

Abstract

Purpose: The signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in most cancers, propagates tumorigenesis, and is a key regulator of immune suppression in cancer patients. We sought to determine the incidence of phosphorylated STAT3 (p-STAT3) expression in malignant gliomas of different pathologic types, whether p-STAT3 expression is a negative prognostic factor, and whether p-STAT3 expression influences the inflammatory response within gliomas. Methods: Using immunohistochemical analysis, we measured the incidence of p-STAT3 expression in 129 patients with gliomas of various pathologic types in a glioma tissue microarray. We categorized our results according to the total number of p-STAT3^expressing cells within the gliomas and correlated this number with the number of infiltrating T cells and T regulatory cells. We then evaluated the association between p-STAT3 expression and median survival time using univariate and multivariate analyses. Results: We did not detect p-STAT3 expression in normal brain tissues or low-grade astrocytomas. We observed significant differences in the incidence of p-STAT3 expression between the different grades of astrocytomas and different pathologic glioma types. p-STAT3 expression was associated with the population of tumor-infiltrating immune cells but not with that of T regulatory cells. On univariate analysis, we found that p-STAT3 expression within anaplastic astrocytomas was a negative prognostic factor. Conclusions: p-STAT3 expression is common within gliomas of both the astrocytic and oligodendroglial lineages and portends poor survival in patients with anaplastic astrocytomas. p-STAT3 expression differs significantly between gliomas of different pathologic types and grades and correlated with the degree of immune infiltration.A key transcription factor, signal transducer and activator of transcription (STAT3), has been shown to drive the fundamental components of tumorigenesis and metastasis by preventing apoptosis (by increasing survivin, BCL-XL, and MCL1 expression) and enhancing proliferation (by increasing c-Myc and cyclin D1/D2 expression; ref. 1), angiogenesis (by increasing vascular endothelial growth factor and hypoxia-inducible factor-1a expression), invasion (by increasing matrix metalloproteinase-2 and matrix metalloproteinase-9 expression), and metastasis (2, 3). Growth factors and cytokines, including interleukin (IL)-6, can activate Janus kinase 2, which subsequently activates STAT3 by phosphorylating the tyrosine residue in the STAT3 transactivation domain (4). Phosphorylated STAT3 (p-STAT3) then translocates into the nucleus and induces the expression of a variety of target genes. IL-6, which is expressed in the central nervous system (CNS) under a variety of conditions, such as hypoxia (5), traumatic and metabolic injury (6), and inflammation (7), has been shown to attract T cells to the CNS (8). Specifically, IL-6 signaling by means of STAT3 is tightly linked to the homing and migrational capacity of T cells (8)...

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