Epithelial cells lining the adult human colon do not normally express
gastrin-releasing peptide (GRP) or its receptor (GRPR). In contrast, approximately one-third of human
colon cancers and
cancer cell lines have been shown to express GRP-binding sites. Because GRPR activation causes the proliferation of many
cancer cell lines, GRP has been presumed to act as a clinically significant
growth factor. Yet GRP has not been shown to be expressed by
colon cancers in humans nor has the effect of GRP and/or GRPR coexpression on
tumor behavior been investigated. We therefore determined GRP and GRPR expression by immunohistochemistry in 50 randomly selected
colon cancers resected between 1980 and 1997, all 37 associated lymph node and liver
metastases, and 20
polyps.
Tumor sections studied were those that contained the margin and adjacent nonmalignant epithelium. Overall, 84% of
cancers aberrantly expressed GRP or GRPR, with 62% expressing both
ligand and receptor, whereas expression was not observed in adjacent normal epithelium. Consistent with the previously established mitogenic capabilities of GRP, tissues coexpressing GRP and GRPR were more likely to express
proliferating cell nuclear antigen than tissues not expressing both
ligand and receptor. Yet GRP/GRPR coexpression was seen with equal frequency in stage A as in stage D
cancers and was only detected in 1 in 37
metastases. Furthermore, Kaplan-Meier analysis did not reveal any difference in patient survival between those whose
tumors did or did not express GRP/GRPR. In contrast, GRP/GRPR coexpression was found in all well-differentiated
tumor regions, whereas poorly differentiated tissues never coexpressed GRP/GRPR. Overall, these data indicate that, although GRP is a
mitogen, it is not a clinically significant
growth factor in human
colon cancers. Rather, the strong association of GRP/GRPR coexpression with
tumor differentiation raises the possibility that these
proteins primarily act in vivo as morphogens.