Increased frequency of gastrin-releasing peptide receptor gene mutations during colon-adenocarcinoma progression.
Epithelial cells lining the mature human colon do not normally express receptors for gastrin-releasing peptide (GRPR). In contrast, we have shown that when aberrantly expressed in functional form in colon cancer, this protein acted as a morphogen where it caused tumor cells to adopt a better-differentiated phenotype. Importantly, GRPR mRNA is ubiquitously mutated in human colon cancer cell lines, with inactivating mutations detected in all cell lines not expressing functional receptor. Since colon cancers are heterogeneously differentiated, we set out to determine if the GRPR gene was mutated as a function of tumor cell differentiation in archived human colon cancers. We used laser capture microscopy to dissect out 67 regions of defined differentiation from 20 human colon cancers randomly selected from the UIC GI Tumor Bank. Except for two polymorphisms, the GRPR gene was not mutated in nonmalignant epithelial cells. In contrast, 42 distinct mutations were identified in malignant cells. Overall mutation number inversely correlated with the degree of tumor cell differentiation. Within any cancer, all GRPR mutations found within better-differentiated cells were conserved in more poorly-differentiated cells; while all poorly-differentiated cells contained mutations resulting in GRPR pharmacological inactivation. These data suggest that accumulation of mutations within the GRPR gene ultimately resulting in the production of nonfunctional receptors may represent a previously unappreciated mechanism allowing for the dedifferentiation of tumor cells within any particular colon cancer; and that poorly-differentiated tumor cells within any individual cancer may arise clonally from their better-differentiated precursors.
Department of Medicine, University of Illinois at Chicago and Chicago Veterans Affairs Medical Center, Chicago, Illinois 60612, USA.
Sarah C
SC
Glover
Maria S
MS
Tretiakova
Robert E
RE
Carroll
Richard V
RV
Benya
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D006224:Cricetinae; D004252:DNA Mutational Analysis; D018450:Disease Progression; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010641:Phenotype; D018004:Receptors, Bombesin / Q000235:genetics*; D014162:Transfection
D018004:Receptors, Bombesin