Cripto haploinsufficiency affects in vivo colon tumor development

Giorgio,Emilia; Liguoro,Annamaria; D'Orsi,Luca; Mancinelli,Sara; Barbieri,Antonio; Palma,Giuseppe; Arra,Claudio; Liguori,Giovanna L.

doi:10.3892/ijo.2014.2412

Cripto haploinsufficiency affects in vivo colon tumor development

Authors:
- Emilia Giorgio
- Annamaria Liguoro
- Luca D'Orsi
- Sara Mancinelli
- Antonio Barbieri
- Giuseppe Palma
- Claudio Arra
- Giovanna L. Liguori
View Affiliations

Affiliations: Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ (IGB), Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy, Istituto Nazionale per lo studio e la cura dei Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
Published online on: April 30, 2014 https://doi.org/10.3892/ijo.2014.2412
Pages: 31-40
Copyright: © Giorgio et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colorectal cancer is one of the most common and aggressive cancers arising from alterations in various signaling pathways, such as the WNT, RAS-MAPK, PI3K and transforming growth factor-β (TGF-β) pathways. Cripto (also called Teratocarcinoma-derived growth factor), the original member of the vertebrate EGF-CFC family, plays a key role in all of these pathways and is deeply involved in early embryo development and cancer progression. The role of Cripto in colon and breast cancer, in particular, has been investigated, as it is still not clearly understood. In this article, we provide the first in vivo functional evidence of a role of Cripto in colon cancer development. We analyzed the effect of Cripto haploinsufficiency on colon tumor formation by treating Cripto heterozygous mice with the colonotropic carcinogen azoxymethane (AOM). Of note, in our model system, Cripto haploinsufficiency increased tumorigenesis. Moreover, we revealed a correlation between the differential AOM response found in wt and Cripto+/- mice and the expression levels of glucose regulated protein-78 (Grp78), a heat shock protein required for Cripto signaling pathways. We hypothesize that the balance between Cripto and Grp78 expression levels might be crucial in cancer development and may account for the increased tumorigenesis in Cripto heterozygous mice. In summary, our results highlight the heterogeneous effect of Cripto on tumorigenesis and the consequent high level of complexity in the Cripto regulatory pathway, whose imbalance causes tumors.

View Figures

View References

1.	Masseria C: Colorectal cancer in Italy: a review of current national and regional practice on screening and treatment. Eur J Health Econ. 10(Suppl 1): S41–S49. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Muzny DM, et al: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar
3.	Demant P: Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nat Rev Genet. 4:721–734. 2003. View Article : Google Scholar : PubMed/NCBI
4.	Sjoblom T, Jones S, Wood LD, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 314:268–274. 2006. View Article : Google Scholar : PubMed/NCBI
5.	Bass AJ, Lawrence MS, Brace LE, et al: Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet. 43:964–968. 2011. View Article : Google Scholar : PubMed/NCBI
6.	Persico MG, Liguori GL, Parisi S, D’Andrea D, Salomon DS and Minchiotti G: Cripto in tumors and embryo development. Biochim Biophys Acta. 1552:87–93. 2001.PubMed/NCBI
7.	Minchiotti G, Parisi S, Liguori GL, D’Andrea D and Persico MG: Role of the EGF-CFC gene cripto in cell differentiation and embryo development. Gene. 287:33–37. 2002. View Article : Google Scholar : PubMed/NCBI
8.	de Castro NP, Rangel MC, Nagaoka T, Salomon DS and Bianco C: Cripto-1: an embryonic gene that promotes tumorigenesis. Future Oncol. 6:1127–1142. 2010.
9.	Gray PC and Vale W: Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis. FEBS Lett. 586:1836–1845. 2012.PubMed/NCBI
10.	Colas JF and Schoenwolf GC: Subtractive hybridization identifies chick-cripto, a novel EGF-CFC ortholog expressed during gastrulation, neurulation and early cardiogenesis. Gene. 255:205–217. 2000. View Article : Google Scholar
11.	Salomon DS, Bianco C, Ebert AD, et al: The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer. Endocr Relat Cancer. 7:199–226. 2000. View Article : Google Scholar : PubMed/NCBI
12.	Shen MM and Schier AF: The EGF-CFC gene family in vertebrate development. Trends Genet. 16:303–309. 2000. View Article : Google Scholar : PubMed/NCBI
13.	Ding J, Yang L, Yan YT, Chen A, Desai N, Wynshaw-Boris A and Shen MM: Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature. 395:702–707. 1998. View Article : Google Scholar : PubMed/NCBI
14.	Liguori GL, Echevarria D, Improta R, et al: Anterior neural plate regionalization in cripto null mutant mouse embryos in the absence of node and primitive streak. Dev Biol. 264:537–549. 2003. View Article : Google Scholar : PubMed/NCBI
15.	Minchiotti G, Parisi S, Liguori G, et al: Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its distribution during early mouse development. Mech Dev. 90:133–142. 2000. View Article : Google Scholar : PubMed/NCBI
16.	Chu J, Ding J, Jeays-Ward K, Price SM, Placzek M and Shen MM: Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis. Development. 132:5539–5551. 2005. View Article : Google Scholar : PubMed/NCBI
17.	Bianco C, Rangel MC, Castro NP, et al: Role of Cripto-1 in stem cell maintenance and malignant progression. Am J Pathol. 177:532–540. 2010. View Article : Google Scholar : PubMed/NCBI
18.	Massague J, Blain SW and Lo RS: TGF beta signaling in growth control, cancer, and heritable disorders. Cell. 103:295–309. 2000. View Article : Google Scholar : PubMed/NCBI
19.	Adkins HB, Bianco C, Schiffer SG, et al: Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. J Clin Invest. 112:575–587. 2003. View Article : Google Scholar : PubMed/NCBI
20.	Gray PC, Shani G, Aung K, Kelber J and Vale W: Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signaling. Mol Cell Biol. 26:9268–9278. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Nagaoka T, Karasawa H, Turbyville T, et al: Cripto-1 enhances the canonical Wnt/beta-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors. Cell Signal. 25:178–189. 2013. View Article : Google Scholar : PubMed/NCBI
22.	Shani G, Fischer WH, Justice NJ, Kelber JA, Vale W and Gray PC: GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth. Mol Cell Biol. 28:666–677. 2008. View Article : Google Scholar : PubMed/NCBI
23.	Kelber JA, Panopoulos AD, Shani G, et al: Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene. 28:2324–2336. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Ciardiello F, Kim N, Saeki T, et al: Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci USA. 88:7792–7796. 1991. View Article : Google Scholar : PubMed/NCBI
25.	Saeki T, Stromberg K, Qi CF, et al: Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors. Cancer Res. 52:3467–3473. 1992.
26.	Ciardiello F, Tortora G, Bianco C, et al: Inhibition of CRIPTO expression and tumorigenicity in human colon cancer cells by antisense RNA and oligodeoxynucleotides. Oncogene. 9:291–298. 1994.PubMed/NCBI
27.	De Luca A, Casamassimi A, Selvam MP, et al: EGF-related peptides are involved in the proliferation and survival of MDA-MB-468 human breast carcinoma cells. Int J Cancer. 80:589–594. 1999.PubMed/NCBI
28.	Normanno N, De Luca A, Bianco C, et al: Cripto-1 over-expression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells. J Cell Physiol. 198:31–39. 2004. View Article : Google Scholar : PubMed/NCBI
29.	Wu Z, Li G, Wu L, Weng D, Li X and Yao K: Cripto-1 over-expression is involved in the tumorigenesis of nasopharyngeal carcinoma. BMC Cancer. 9:3152009. View Article : Google Scholar : PubMed/NCBI
30.	Bianco C, Strizzi L, Mancino M, et al: Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clin Cancer Res. 12:5158–5164. 2006. View Article : Google Scholar : PubMed/NCBI
31.	Bianco C, Strizzi L, Normanno N, Khan N and Salomon DS: Cripto-1: an oncofetal gene with many faces. Curr Top Dev Biol. 67:85–133. 2005. View Article : Google Scholar : PubMed/NCBI
32.	Strizzi L, Bianco C, Normanno N, et al: Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J Cell Physiol. 201:266–276. 2004. View Article : Google Scholar : PubMed/NCBI
33.	Strizzi L, Bianco C, Hirota M, et al: Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice. J Pathol. 211:36–44. 2007. View Article : Google Scholar : PubMed/NCBI
34.	Sun Y, Strizzi L, Raafat A, et al: Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis. Am J Pathol. 167:585–597. 2005. View Article : Google Scholar : PubMed/NCBI
35.	Wechselberger C, Strizzi L, Kenney N, et al: Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma. Oncogene. 24:4094–4105. 2005. View Article : Google Scholar : PubMed/NCBI
36.	Xu C, Liguori G, Persico MG and Adamson ED: Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes. Development. 126:483–494. 1999.PubMed/NCBI
37.	Bissahoyo A, Pearsall RS, Hanlon K, et al: Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: effects of dose, route, and diet. Toxicol Sci. 88:340–345. 2005. View Article : Google Scholar : PubMed/NCBI
38.	Guda K, Giardina C, Nambiar P, Cui H and Rosenberg DW: Aberrant transforming growth factor-beta signaling in azoxymethane-induced mouse colon tumors. Mol Carcinog. 31:204–213. 2001. View Article : Google Scholar : PubMed/NCBI
39.	Nambiar PR, Girnun G, Lillo NA, Guda K, Whiteley HE and Rosenberg DW: Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly used as transgenic/ knockout progenitors. Int J Oncol. 22:145–150. 2003.PubMed/NCBI
40.	Liguori GL, Borges AC, D’Andrea D, et al: Cripto-independent Nodal signaling promotes positioning of the A-P axis in the early mouse embryo. Dev Biol. 315:280–289. 2008. View Article : Google Scholar : PubMed/NCBI
41.	Liguori GL, Echevarria D, Bonilla S, et al: Characterization of the functional properties of the neuroectoderm in mouse Cripto(−/−) embryos showing severe gastrulation defects. Int J Dev Biol. 53:549–557. 2009.PubMed/NCBI
42.	Amundson SA, Myers TG and Fornace AJ Jr: Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene. 17:3287–3299. 1998. View Article : Google Scholar : PubMed/NCBI
43.	Aizu W, Guda K, Nambiar P, et al: p53 and its co-activator p300 are inversely regulated in the mouse colon in response to carcinogen. Toxicol Lett. 144:213–224. 2003. View Article : Google Scholar : PubMed/NCBI
44.	Saad RS, Kordunsky L, Liu YL, Denning KL, Kandil HA and Silverman JF: Lymphatic microvessel density as prognostic marker in colorectal cancer. Mod Pathol. 19:1317–1323. 2006. View Article : Google Scholar : PubMed/NCBI
45.	Rangel MC, Karasawa H, Castro NP, Nagaoka T, Salomon DS and Bianco C: Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. Am J Pathol. 180:2188–2200. 2012. View Article : Google Scholar : PubMed/NCBI
46.	Takahashi M, Fukuda K, Sugimura T and Wakabayashi K: Beta-catenin is frequently mutated and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. Cancer Res. 58:42–46. 1998.PubMed/NCBI
47.	Lee AS: GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 67:3496–3499. 2007. View Article : Google Scholar : PubMed/NCBI
48.	Huang S, Chen Y, Podsypanina K and Li Y: Comparison of expression profiles of metastatic versus primary mammary tumors in MMTV-Wnt-1 and MMTV-Neu transgenic mice. Neoplasia. 10:118–124. 2008. View Article : Google Scholar : PubMed/NCBI
49.	Saccone S, Rapisarda A, Motta S, Dono R, Persico GM and Della Valle G: Regional localization of the human EGF-like growth factor CRIPTO gene (TDGF-1) to chromosome 3p21. Hum Genet. 95:229–230. 1995. View Article : Google Scholar : PubMed/NCBI
50.	Lerman MI and Minna JD: The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 60:6116–6133. 2000.
51.	Maitra A, Wistuba II, Washington C, et al: High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss. Am J Pathol. 159:119–130. 2001. View Article : Google Scholar
52.	Cheng Y, Poulos NE, Lung ML, et al: Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3. Proc Natl Acad Sci USA. 95:3042–3047. 1998. View Article : Google Scholar : PubMed/NCBI
53.	Alimov A, Kost-Alimova M, Liu J, et al: Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma. Oncogene. 19:1392–1399. 2000. View Article : Google Scholar : PubMed/NCBI
54.	Pardali K and Moustakas A: Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta. 1775:21–62. 2007.PubMed/NCBI
55.	Dong D, Ni M, Li J, et al: Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angio-genesis in transgene-induced mammary tumor development. Cancer Res. 68:498–505. 2008. View Article : Google Scholar : PubMed/NCBI