Inhibition of MACC1-Induced Metastasis in Esophageal and Gastric Adenocarcinomas

SIMPLE SUMMARY: Esophageal and Gastric Adenocarcinomas (AGE/S) are characterized by early metastasis and poor survival. MACC1 (Metastasis Associated in Colon Cancer 1) acts in colon cancer as a metastasis inducer and is linked to reduced survival. In this study, we analyzed the prognostic role of MACC1 in a large AGE/S cohort and the potential of MACC1 inhibition in vitro and in vivo. MACC1 is an independent negative prognostic marker in our cohort. In vitro, migration was enhanced by MACC1 in overexpressing cells. This MACC1-related effect could be inhibited by using selumetinib in vitro. In vivo, MACC1 induced faster and larger metastasis development, which could be inhibited by selumetinib. In conclusion, MACC1 is a strong negative prognostic factor in AGE/S and is a potential target for therapy with selumetinib. ABSTRACT: Esophageal and Gastric Adenocarcinomas (AGE/S) are characterized by early metastasis and poor survival. MACC1 (Metastasis Associated in Colon Cancer 1) acts in colon cancer as a metastasis inducer and is linked to reduced survival. This project illuminates the role and potential for the inhibition of MACC1 in AGE/S. Using 266 of 360 TMAs and survival data of AGE/S patients, we confirm the value of MACC1 as an independent negative prognostic marker in AGE/S patients. MACC1 gene expression is correlated with survival and morphological characteristics. In vitro analysis of lentivirally MACC1-manipulated subclones of FLO-1 and OE33 showed enhanced migration induced by MACC1 in both cell line models, which could be inhibited by the MEK1 inhibitor selumetinib. In vivo, the efficacy of selumetinib on tumor growths and metastases of MACC1-overexpressing FLO-1 cells xenografted intrasplenically in NOG mice was tested. Mice with high-MACC1-expressing cells developed faster and larger distant metastases. Treatment with selumetinib led to a significant reduction in metastasis exclusively in the MACC1-positive xenografts. MACC1 is an enhancer of tumor aggressiveness and a predictor of poor survival in AGE/S. This effect can be inhibited by selumetinib.