Resistance to Cell Death in Mucinous Colorectal Cancer-A Review

Abstract

Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10-15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-X_L, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

Keywords: apoptosis; chemo-resistance; colorectal; mucin.

Figure 1

Representative histological slides of: (a) mucinous colorectal adenocarcinoma displaying abundant extracellular mucin in a 61 year old male patient with a pT4N2 mucinous rectal tumor. (b) Non-mucinous colorectal adenocarcinoma in a 67 year old female patient with a pT3N1 rectal tumor. H&E-stained section, 10× magnification, imaged with Leica DM 4000B microscope (Leica Microsystems, Mannheim, Germany).

Figure 2

(a) Interaction of mucin glycoproteins with apoptosis proteins in colorectal cancer cells. (b) Cell survival mechanisms altered by expression of mucin glycoproteins in colorectal cancer cells.