Novel Interaction of MUC4 and Galectin: Potential Pathobiological Implications for Metastasis in Lethal Pancreatic Cancer

Abstract

Purpose: Several studies have reported aberrant expression of MUC4 in pancreatic cancer (PC), which is associated with tumorigenicity and metastasis. Mechanisms through which MUC4 promote metastasis of PC cells to distant organs are poorly defined.Experimental Design: Identification of MUC4-galectin-3 interaction and its effect on the adhesion of cancer cells to endothelial cells were done by immunoprecipitation and cell-cell adhesion assays, respectively. Serum galectin-3 level for normal and PC patients were evaluated through ELISA.Results: In the present study, we have provided clinical evidence that the level of galectin-3 is significantly elevated in the sera of PC patients with metastatic disease compared with patients without metastasis (P ¼ 0.04) and healthy controls (P ¼ 0.00001). Importantly, for the first time, we demonstrate that MUC4 present on the surface of circulating PC cells plays a significant role in the transient and reversible attachment (docking) of circulating tumor cells to the surface of endothelial cells. Further, exogenous galectin-3 at concentrations similar to that found in the sera of PC patients interacts with MUC4 via surface glycans such as T antigens, which results in the clustering of MUC4 on the cell surface and a stronger attachment (locking) of circulating tumor cells to the endothelium.Conclusions: Altogether, these findings suggest that PC cell-associated MUC4 helps in the docking of tumor cells on the endothelial surface. During cancer progression, MUC4-galectin-3 interaction-mediated clustering of MUC4 may expose the surface adhesion molecules, which in turn promotes a stronger attachment (locking) of tumor cells to the endothelial surface.

The expressions and clinical significances of tissue and serum galectin-3 in pancreatic carcinoma

“…Some scientists assumed that pancreatic carcinoma cell-associated MUC4, overexpressed in pancreatic carcinoma, helps in the docking of tumor cells on the endothelial surface. During cancer progression, MUC4-galectin-3 may expose the surface adhesion molecules, which in turn promotes a stronger attachment (locking) of tumor cells to the endothelial surface (Senapati et al 2011). Galectin-3-dependent mechanism modulated the regulation of MUC1/EGFR (epidermal (Zhao et al 2009).…”

Transmembrane Mucin Expression and Function in Embryo Implantation and Placentation

“…Multiple galectins have been detected in human endometrium and placental tissues with a wider variety found in placental tissues (Jeschke et al 2013 ). Several galectins can bind to TMs, including MUC1, MUC4, and MUC16 (Bancalari et al 1989 ;Seelenmeyer et al 2003 ;Yu et al 2007 ;Argueso et al 2009 ;Senapati et al 2011 ). Functional consequences of these interactions are suggested to include enhancement of the barrier function of TMs to activation of signal transduction cascades.…”

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

“…For instance, a specific and readily detectable 5-to 30-fold increase in the circulating levels of several galectins has been reported in the bloodstream of patients with various types of cancers, including breast [22], head and neck [23], bladder [24], melanoma [25], pancreatic [26,27], and colorectal [28][29][30] carcinomas. These observations have prompted the development of galectin-targeting drugs, some of which have been tested in clinical trials [31].…”