In patients with colorectal cancer (CRC), local and systemic inflammatory responses have been extensively reported to be associated with cancer survival. However, the specific signalling pathways responsible for inflammatory responses are not clear. The Src family kinases (SFKs) are plausible candidates as they can play a role in mediating inflammation via STAT3 and MMP9 and have been associated with cancer progression. This study therefore examined the relationship between tumor SFK416/STAT3705/MMP-9 expression, inflammatory responses and survival in patients with CRC.
Immunohistochemical assessment of SFK416, STAT3705 and MMP9 was performed using a CRC patient tissue microarray. Tumor cell expression of SFK416, STAT3705 and MMP9 were assessed using the weighted histoscore at the membrane, cytoplasm and nucleus. Low and high expression was then divided using the median and only patients with a score for all three proteins included in analysis. Analysis was performed with SPSS, using the Chi-squared test to assess relationships with clinicopathological characteristics, Kaplan Meier analysis for cancer-specific survival, log rank test for univariate analysis and cox regression for multivariate analysis. Significance was set at P<0.05.
In 204 CRC patients, high tumor cytoplasmic MMP9 expression was significantly associated with poorer CSS (13.0yrs v 9.9yrs, P = 0.001) and this association was further strengthened when cytoplasmic MMP-9 was combined into a four-point prognostic score with phosphorylation of nuclear SFK416 and nuclear STAT3705 (13.6yrs v 13.0yrs v 9.8yrs v 8.8yrs, P<0.001). The four-point score was also significantly associated with higher TNM stage (P = 0.009), poorer differentiation (P = 0.005), venous invasion (P<0.001), lower immunoscore (P = 0.009), weaker Klintrup Makinen grade (P = 0.007), and higher Glasgow microenvironment score (GMS, P = 0.004). When cytoplasmic MMP-9 and the four-point score where entered into multivariate survival analysis with significant clinicopathological and inflammatory characteristics, only the four-point score was independently prognostic in these CRC patients (P = 0.046).
In CRC patients, tumor-specific MMP-9 expression was significantly associated with poorer CSS, particularly when combined with phosphorylation of nuclear SFK416 and STAT3705 to give a four-point prognostic score. The four-point score significantly associated with all measures of the local inflammatory response. This suggests that activation of SFKs phosphorylates STAT3705 to up-regulate MMP9 expression and in turn down regulate local inflammation within the tumor microenvironment. Further work is now needed to identify the specific SFK responsible.
Citation Format: Antonia Kathryn Roseweir, Arfon GNT Powell, James Park, Donald C. McMillan, Joanne Edwards. Src family kinases modulate local inflammatory responses via STAT3 and MMP9 in colorectal cancer patients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A106.