Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis.

Erika López-Arribillaga,Silvia Menéndez,Yolanda Guillén,Anna Bigas,Mar Iglesias,Montserrat Andreu,Bing Yan,Lluís Espinosa,Teresa Lobo-Jarne

doi:10.3390/cells10112928

Abstract

Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: We performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan–Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: Our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited.

Highlights

Colorectal cancer (CRC) is the second leading cause of death by cancer in the industrialized countries
Paneth cells are responsible for providing intestinal stem cells (ISC) with the signals required to activate the Notch and Wnt/β-catenin pathways [2] that are essential for stem cell homeostasis
A Subset of Colorectal Adenomas Accumulates Paneth Cells That Are c-Kit and Paneth cells are mostly located at the bottom of the small intestinal crypts in both mouse and humans

Summary

Introduction

Colorectal cancer (CRC) is the second leading cause of death by cancer in the industrialized countries. There is a rare population of Goblet cells that express the stem cell factor receptor c-Kit and exert this ISC niche function in the absence of Paneth cells [9]. Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation.

Methods

Results

Conclusion