In vivo mitogenic effects of estradiol on colon cancers: role of gastrin and gastrin receptors.
We have previously reported mitogenic effects of gastrin on a mouse colon cancer (MC-26) cell line in vivo. The present studies were undertaken to determine if gonadal hormones can influence the mitogenic response of MC-26 cells to gastrin. The female gonadal hormone, estradiol (E2), was determined to be as mitogenic as pentagastrin (PG) for the growth of MC-26 tumors in mice; the mitogenic effects of E2 and PG were not additive. Female gonadal hormones were furthermore as effective as PG in maximally up-regulating gastrin receptor (GR) concentrations on MC-26 tumor membranes, which was confirmed in autoradiographic studies. Since PG and E2 had similar and non-additive trophic effects it was hypothesized that gastrin may be mediating the trophic effects of E2. Serum gastrin concentrations were significantly increased in E2 treated ovariectomized mice that correlated with an increase in tumor weights; E2 however was ineffective in stimulating the release of gastrin from perfused rat stomachs indicating that the increase in serum gastrin concentration on long-term treatment with E2 was mediated by some other mechanism. Saturable high-affinity E2 binding sites were not measured in MC-26 cells and tumors, supporting the possibility that mitogenic effects of E2 were probably mediated via indirect mechanisms. In summary our results indicate that both E2 and PG are equally mitogenic for colon cancer cells in vivo which may explain the sex- and age-related discrepancy in the incidence of human colon cancers.
Singh
P
P
Department of Surgery, University of Texas Medical Branch, Galveston 77550.
Reubi
J C
JC
Rajakumar
G
G
Guo
Y S
YS
Prioux
H
H
Chicone
L
L
D000818:Animals; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000473:pathology*; D004958:Estradiol / Q000502:physiology*; D005260:Female; D005755:Gastrins / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010052:Ovariectomy; D010418:Pentagastrin / Q000494:pharmacology; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000502:physiology*; D012727:Sex Characteristics; D014407:Tumor Cells, Cultured
D005755:Gastrins; D011949:Receptors, Cholecystokinin; D004958:Estradiol; D010418:Pentagastrin