The human colorectal epithelium is maintained by multipotent stem cells that give rise to absorptive, mucous, and endocrine lineages. Recent evidence suggests that human
colorectal cancers are likewise maintained by a minority population of so-called cancer stem cells. We have previously established a human
colorectal cancer cell line with multipotent characteristics (HRA-19) and developed a serum-free medium that induces endocrine, mucous and absorptive lineage commitment by HRA-19 cells in vitro. In this study, we investigate the role of the
beta1 integrin family of cell surface
extracellular matrix receptors in multilineage differentiation by these multipotent human
colorectal cancer cells. We show that endocrine and mucous lineage commitment is blocked in the presence of function-
blocking antibodies to
beta1 integrin. Function-
blocking antibodies to
alpha2 integrin also blocked both HRA-19 endocrine lineage commitment and enterocytic differentiation by Caco-2 human
colon cancer cells; both effects being abrogated by the
MEK inhibitor,
PD98059, suggesting a role for ERK signaling in alpha2-mediated regulation of
colorectal cancer cell differentiation. To further explore the role of
alpha2 integrin in multilineage differentiation, we established multipotent cells expressing high levels of wild-type
alpha2 integrin or a non-signaling chimeric
alpha2 integrin. Overexpression of wild-type
alpha2 integrin in HRA-19 cells significantly enhanced endocrine and mucous lineage commitment, while cells expressing the non-signaling chimeric
alpha2 integrin had negligible ability for either endocrine or mucous lineage commitment. This study indicates that the
collagen receptor alpha2beta1 integrin is a regulator of cell fate in human multipotent
colorectal cancer cells.