Little is known about the factors involved in regulating the appearance, or differentiation, of solid
tumors including those arising from the colon. We herein demonstrate that the
mitogen gastrin-releasing peptide (GRP) is a morphogen, critically important in regulating the differentiation of murine
colon cancer. Although epithelial cells lining the mouse colon do not normally express GRP and its receptor (GRP-R), both are aberrantly expressed by all better differentiated
cancers in wild-type C57BL/6J mice treated with the
carcinogen azoxymethane. Whereas small
tumors in both wild-type and GRP-R-deficient (i.e., GRP-R-/-) mice are histologically similar, larger
tumors become better differentiated in the former but degenerate into more poorly differentiated
mucinous adenocarcinomas in the latter. This alteration in phenotype is attributable to GRP increasing
focal adhesion kinase expression in GRP-R-expressing
tumors. Consistent with GRP acting as a
mitogen, GRP/GRP-R coexpressing
tumors in wild-type animals also contain more proliferating cells than those occurring in GRP-R-/- mice. Yet
tumors are similarly sized in animals of either genotype receiving
azoxymethane for identical times, a finding attributable to the significantly higher number of apoptotic cells detected in GRP/GRP-R coexpressing
cancers. Thus, these findings indicate that although GRP is a
mitogen, aberrant expression does not result in increased
tumor growth. Rather, the mitogenic properties of GRP are subordinate to it acting as a morphogen, where it and its receptor are critically involved in regulating
colon cancer histological progression by promoting a well-differentiated phenotype.