Goblet cell differentiation in colorectal cancer

Abstract

Colorectal stem cells give rise to three cell types in the colorectal crypt: enterocytes, enteroendocrince cells and goblet cells. In colorectal cancer this stem cell differentiation is dysregulated and absence of differentiation usually confers a worse prognosis for the patient. In order to understand goblet cell differentiation in colorectal cancer we first investigated novel goblet cell markers. REG4 was found as a marker through examination of our microarray data on 96 colorectal cell lines and confirmed through flow cytometry and immunohistochemistry. Dll4 was also examined as a potential goblet cell marker but instead stained a separate population of cells that may prove to either influence goblet cell differentiation or be goblet cell progenitors. We then examined the roles of goblet cell differentiation regulators such as Notch and the homeobox genes CDX1 and CDX2 in colorectal cell lines. Treatment of colorectal cell lines with inhibitors of the Notch pathway, including the γ-secretase inhibitor DBZ and anti-Dll4, increased the number of goblet cells. Knockdown of CDX1 and CDX2 decreased the number of goblet cells in goblet cell producing cell lines. Further research will elucidate the mechanisms by which these regulators influence differentiation, which could yield a treatment for colorectal cancer; inducing goblet cell differentiation and abating further tumor growth.</p