BACKGROUND: During development, the homeobox gene Cdx2 exerts a homeotic function, providing the positional information necessary for correct specification of the midgut endoderm. This is illustrated by the non-neoplastic gastric-type heteroplasias present at birth in the pericaecal region of Cdx2(+/-) mice. Furthermore, intestinal expression of Cdx2 continues throughout life but diminishes in colorectal cancers compared with adjacent normal tissue, suggesting a role in tumorigenesis. AIM: To investigate the consequence of altered Cdx2 expression on colon tumour initiation and/or progression. METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane. RESULTS: Cdx2(+/-) mice did not spontaneously develop malignant tumours. After azoxymethane treatment, the gastric-like heteroplasias in the pericaecal region did not evolve into cancer indicating that they are not precancerous lesions. However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage. Histopathological and molecular analyses indicated that these tumours were invasive adenocarcinomas that recapitulated the malignant sequence observed in the majority of sporadic colorectal cancers in human. In addition, we found that the colonic epithelium was less sensitive to radiation induced apoptosis in Cdx2(+/-) than in wild-type mice. CONCLUSION: This study provides the first experimental evidence that Cdx2 is a tumour suppressor gene involved in cancer progression in the distal colon. This action in adults is functionally and geographically distinct from its homeotic role during gut development.
BACKGROUND: During development, the homeobox gene Cdx2 exerts a homeotic function, providing the positional information necessary for correct specification of the midgut endoderm. This is illustrated by the non-neoplastic gastric-type heteroplasias present at birth in the pericaecal region of Cdx2(+/-) mice. Furthermore, intestinal expression of Cdx2 continues throughout life but diminishes in colorectal cancers compared with adjacent normal tissue, suggesting a role in tumorigenesis. AIM: To investigate the consequence of altered Cdx2 expression on colon tumour initiation and/or progression. METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane. RESULTS:Cdx2(+/-) mice did not spontaneously develop malignant tumours. After azoxymethane treatment, the gastric-like heteroplasias in the pericaecal region did not evolve into cancer indicating that they are not precancerous lesions. However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage. Histopathological and molecular analyses indicated that these tumours were invasive adenocarcinomas that recapitulated the malignant sequence observed in the majority of sporadic colorectal cancers in human. In addition, we found that the colonic epithelium was less sensitive to radiation induced apoptosis in Cdx2(+/-) than in wild-type mice. CONCLUSION: This study provides the first experimental evidence that Cdx2 is a tumour suppressor gene involved in cancer progression in the distal colon. This action in adults is functionally and geographically distinct from its homeotic role during gut development.
Authors: T Hinoi; M Tani; P C Lucas; K Caca; R L Dunn; E Macri; M Loda; H D Appelman; K R Cho; E R Fearon Journal: Am J Pathol Date: 2001-12 Impact factor: 4.307
Authors: Minjung J Kim; Robert D Cardiff; Nishita Desai; Whitney A Banach-Petrosky; Ramon Parsons; Michael M Shen; Cory Abate-Shen Journal: Proc Natl Acad Sci U S A Date: 2002-02-19 Impact factor: 11.205
Authors: Debra G Silberg; Jessica Sullivan; Eugene Kang; Gary P Swain; Jennifer Moffett; Newman J Sund; Sara D Sackett; Klaus H Kaestner Journal: Gastroenterology Date: 2002-03 Impact factor: 22.682
Authors: Sunghoon Kim; Claire Domon-Dell; Qingding Wang; Dai H Chung; Antonio Di Cristofano; Pier Paolo Pandolfi; Jean-Noel Freund; B Mark Evers Journal: Gastroenterology Date: 2002-10 Impact factor: 22.682
Authors: Laurianne Van Landeghem; M Agostina Santoro; Adrienne E Krebs; Amanda T Mah; Jeffrey J Dehmer; Adam D Gracz; Brooks P Scull; Kirk McNaughton; Scott T Magness; P Kay Lund Journal: Am J Physiol Gastrointest Liver Physiol Date: 2012-02-23 Impact factor: 4.052
Authors: Thinh T Nguyen; Joanne G A Savory; Travis Brooke-Bisschop; Randy Ringuette; Tanya Foley; Bradley L Hess; Kirk J Mulatz; Laura Trinkle-Mulcahy; David Lohnes Journal: J Biol Chem Date: 2017-01-12 Impact factor: 5.157