Cripto, also named Teratocarcinoma derived growth factor 1 (Tdgf 1), is the founding member of the EGF-CFC genes family, coding for membrane-anchored extracellular factors essential for vertebrate embryo development (Liguori et al., 2003; Persico et al., 2001). Cripto plays also an important role in tumor progression, in fact CRIPTO is expressed with high frequency in different human epithelial cancers, including breast, colon, stomach, pancreas, ovary and testis cancers (Strizzi et al., 2005). Moreover, very low levels of CRIPTO were detected in the plasma of healthy volunteers, whereas a statistically significant increase was found in patients with colon and breast carcinoma (Bianco et al., 2006). Functional data indicate that downregulation of Cripto expression in coloncarcinoma cell lines affects transformed phenotype. Human Colon carcinoma cells in which Cripto is downregulated form tumors in nude mice that were significantly smaller and had a longer latency period (Normanno et al., 2004). Cripto overexpression also induces apoptosis both in vitro, in HC-11 mouse mammary epithelial cells (De Santis et al., 2000) and in vivo in mouse mammary gland. In the latter case, however, mice develop breast adenocarcinoma after a long latency period (Sun et al., 2005). All together 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 whether Cripto might be a good candidate as biomarker in colon tumor progression and as a target gene in colon carcinoma therapy. At this purpose, we have chosen an experimental mouse model to study the development of colon cancers, based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. We analysed both wt and Cripto heterozygous mice generated in our laboratory. Wt and Cripto heterozygous mice respond differentially to AOM treatment, meaning that half reduction of Cripto gene dosage may be sufficient to affect colon cancer development. In particular, Cripto+/- show reduced apoptosis, following single AOM injection. Moreover, the percentage of mice developing tumors, the tumor multiplicity and tumor volume is higher in Cripto+/- than in wt mice. These preliminary results suggest that Cripto heterozygotes have a higher susceptibility to AOM in the development of colon tumors and provide the first in vivo 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
Liguoro A;Liguori GL
2008
Abstract
Cripto, also named Teratocarcinoma derived growth factor 1 (Tdgf 1), is the founding member of the EGF-CFC genes family, coding for membrane-anchored extracellular factors essential for vertebrate embryo development (Liguori et al., 2003; Persico et al., 2001). Cripto plays also an important role in tumor progression, in fact CRIPTO is expressed with high frequency in different human epithelial cancers, including breast, colon, stomach, pancreas, ovary and testis cancers (Strizzi et al., 2005). Moreover, very low levels of CRIPTO were detected in the plasma of healthy volunteers, whereas a statistically significant increase was found in patients with colon and breast carcinoma (Bianco et al., 2006). Functional data indicate that downregulation of Cripto expression in coloncarcinoma cell lines affects transformed phenotype. Human Colon carcinoma cells in which Cripto is downregulated form tumors in nude mice that were significantly smaller and had a longer latency period (Normanno et al., 2004). Cripto overexpression also induces apoptosis both in vitro, in HC-11 mouse mammary epithelial cells (De Santis et al., 2000) and in vivo in mouse mammary gland. In the latter case, however, mice develop breast adenocarcinoma after a long latency period (Sun et al., 2005). All together 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 whether Cripto might be a good candidate as biomarker in colon tumor progression and as a target gene in colon carcinoma therapy. At this purpose, we have chosen an experimental mouse model to study the development of colon cancers, based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. We analysed both wt and Cripto heterozygous mice generated in our laboratory. Wt and Cripto heterozygous mice respond differentially to AOM treatment, meaning that half reduction of Cripto gene dosage may be sufficient to affect colon cancer development. In particular, Cripto+/- show reduced apoptosis, following single AOM injection. Moreover, the percentage of mice developing tumors, the tumor multiplicity and tumor volume is higher in Cripto+/- than in wt mice. These preliminary results suggest that Cripto heterozygotes have a higher susceptibility to AOM in the development of colon tumors and provide the first in vivo 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.
