Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine.

Winston Liauw,Samar Masoumi-Moghaddam,David L. Morris,Anahid Ehteda,Afshin Amini

doi:10.18632/oncotarget.5259

Abstract

Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin.

Highlights

Mucins are a diverse family of high molecular weight, heavily glycosylated proteins that are differentially expressed by specialized epithelial cells of mucosal and secretory surfaces throughout the body in a relatively organ- and cell type-specific manner [1]
Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology
A large body of evidence indicates that the prototypical membrane-associated and secreted mucins are implicated in the pathogenesis of human carcinomas

Summary

Introduction

Mucins are a diverse family of high molecular weight, heavily glycosylated proteins that are differentially expressed by specialized epithelial cells of mucosal and secretory surfaces throughout the body in a relatively organ- and cell type-specific manner [1]. The structural characteristics of mucin are primary indicators of its physiological function and changes to its composition have been identified in gastrointestinal pathologies, including gastric and colorectal cancer [2]. Mucins make individual contributions to the biology and clinical features of some peritoneal malignancies, including peritoneal carcinomatosis (PC) from mucinous gastrointestinal adenocarcinomas and pseudomyxoma peritonei (PMP) [4]. In order to maintain a diseasefree peritoneal surface after complete cytoreduction, additional efforts should be made to optimize, and even customize, HIPEC and to improve locoregional treatment. For this purpose, the efficacy of HIPEC needs to be enhanced by determining optimal agents, and duration and temperature of hyperthermia, and by developing novel locoregional treatments

Methods

Results

Conclusion