Cripto, also named Teratocarcinoma derived growth factor 1 (Tdgf1), is the founding member of the EGF-CFC family of structurally related proteins that have been identified in several vertebrate species. Cripto plays an important role during early embryo development and also during cancer progression. CRIPTO is expressed with high frequency in different human epithelial cancers, mainly breast and colon cancers. Moreover, in the plasma of healthy volunteers low levels of CRIPTO were detected, whereas a statistically significant increase was found in patients with colon and breast carcinoma. Functional data indicate that downregulation of Cripto expression in coloncarcinoma cell lines affects transformed phenotype. On the other hand, Cripto overexpression induces apoptosis both in vitro, in HC-11 mouse mammary epithelial cells and in vivo in mouse mammary gland. In the latter case, however, mice develop breast adenocarcinoma after a long latency period. These results suggest that Cripto is involved in the control of cell proliferation and/or apoptosis during tumor progression, but the mechanism involved is still unclear. Our main goal is to explore in vivo the role of Cripto in colon tumor progression and study the mechanism involved. At this purpose, we have chosen an experimental mouse model to analyse the development of colon cancer, based on the mutagenic agent azoxymethane (AOM) that exerts colonotropic carcinogenicity. We analysed both wt and Cripto heterozygous mice generated in our laboratory, while the Cripto-/- mice die during early embryonic life. Wt and Cripto heterozygotes respond differentially to AOM treatment, meaning that Cripto haploinsufficiency affects colon cancer development. Surprisingly, Cripto+/- mice show reduced apoptosis and develop tumors at a higher frequency, with increased multiplicity and tumor area than wt mice. These results suggest that Cripto heterozygotes have a higher susceptibility to AOM for the development of colon tumors and provide the first in vivo functional evidence of a role of Cripto in colon cancer.
Analysis of the role of Cripto in colon carcinoma development using Cripto heterozygous mice as model system
Giorgio E;Liguoro A;Liguori GL
2012
Abstract
Cripto, also named Teratocarcinoma derived growth factor 1 (Tdgf1), is the founding member of the EGF-CFC family of structurally related proteins that have been identified in several vertebrate species. Cripto plays an important role during early embryo development and also during cancer progression. CRIPTO is expressed with high frequency in different human epithelial cancers, mainly breast and colon cancers. Moreover, in the plasma of healthy volunteers low levels of CRIPTO were detected, whereas a statistically significant increase was found in patients with colon and breast carcinoma. Functional data indicate that downregulation of Cripto expression in coloncarcinoma cell lines affects transformed phenotype. On the other hand, Cripto overexpression induces apoptosis both in vitro, in HC-11 mouse mammary epithelial cells and in vivo in mouse mammary gland. In the latter case, however, mice develop breast adenocarcinoma after a long latency period. These results suggest that Cripto is involved in the control of cell proliferation and/or apoptosis during tumor progression, but the mechanism involved is still unclear. Our main goal is to explore in vivo the role of Cripto in colon tumor progression and study the mechanism involved. At this purpose, we have chosen an experimental mouse model to analyse the development of colon cancer, based on the mutagenic agent azoxymethane (AOM) that exerts colonotropic carcinogenicity. We analysed both wt and Cripto heterozygous mice generated in our laboratory, while the Cripto-/- mice die during early embryonic life. Wt and Cripto heterozygotes respond differentially to AOM treatment, meaning that Cripto haploinsufficiency affects colon cancer development. Surprisingly, Cripto+/- mice show reduced apoptosis and develop tumors at a higher frequency, with increased multiplicity and tumor area than wt mice. These results suggest that Cripto heterozygotes have a higher susceptibility to AOM for the development of colon tumors and provide the first in vivo functional evidence of a role of Cripto in colon cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
