Netrin-4 overexpression suppresses primary and metastatic colorectal tumor progression

Eveno,Clarisse; Contreres,Jean-Olivier; Hainaud,Patricia; Nemeth,Judith; Dupuy,Evelyne; Pocard,Marc

doi:10.3892/or.2012.2104

Netrin-4 overexpression suppresses primary and metastatic colorectal tumor progression

Authors:
- Clarisse Eveno
- Jean-Olivier Contreres
- Patricia Hainaud
- Judith Nemeth
- Evelyne Dupuy
- Marc Pocard
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Affiliations: INSERM U965 Angiogenesis and Translational Research, Lariboisière Hospital, AP-HP, 75010 Paris, France, Department of Pathology, Paris Diderot, Paris 7 University, Lariboisière Hospital, AP-HP, 75010 Paris, France
Published online on: October 23, 2012 https://doi.org/10.3892/or.2012.2104
Pages: 73-78

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Abstract

Tumor angiogenesis is closely associated with clinical staging and has been proposed to correlate with clinical response in terms of subsequent metastases following primary resection. Netrin-4 (NT-4) regulates angiogenic responses. Therefore, we sought to examine the effects of NT-4 on the primary tumor growth of colon cancer cells, liver and lung metastases of colon cancer cells, and responses following primary tumor resection. We used 3 different mouse models of orthotopic primary tumor and liver and lung metastases, comparing 2 human colon cancer cells lines: wild-type (low expression of NT-4) and NT-4 (overexpression of NT-4) LS174 cells. NT-4 overexpression inhibited the primary tumor growth of colorectal LS174 xenografts in nude mice (144.3±12.9 vs. 62.4±4.5 mm3; p<0.0001) as well as its related local and systemic recurrence (38 vs. 0%; p<0.01). NT-4 overexpression also markedly decreased colorectal cancer progression in terms of tumor number and volume of liver metastases in the NT-4 group of the orthotopic liver metastasis model (25 vs. 90% and 4±1 vs. 709±190 mm3, p<0.001 and p<0.05). Collectively, our findings indicate that NT-4 overexpression decreases colorectal lung metastasis and its associated lymph node involvement. NT-4 overexpression decreases tumor recurrence and metastasis after surgical resection, likely via an anti-angiogenic effect. These observations suggest that NT-4 may hold therapeutic potential in the treatment of colorectal cancer growth and major metastatic sites.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
2	Lieberman D: Progress and challenges in colorectal cancer screening and surveillance. Gastroenterology. 138:2115–2126. 2010. View Article : Google Scholar : PubMed/NCBI
3	Leonard GD, Brenner B and Kemeny NE: Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 23:2038–2048. 2005. View Article : Google Scholar : PubMed/NCBI
4	Mahmoud N and Bullard Dunn K: Metastasectomy for stage IV colorectal cancer. Dis Colon Rectum. 53:1080–1092. 2010. View Article : Google Scholar : PubMed/NCBI
5	Stangl R, Altendorf-Hofmann A, Charnley RM and Scheele J: Factors influencing the natural history of colorectal liver metastases. Lancet. 343:1405–1410. 1994. View Article : Google Scholar : PubMed/NCBI
6	Fortner JG, Silva JS, Golbey RB, Cox EB and Maclean BJ: Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I Treatment by hepatic resection. Ann Surg. 199:306–316. 1984. View Article : Google Scholar : PubMed/NCBI
7	Scheele J, Stang R, Altendorf-Hofmann A and Paul M: Resection of colorectal liver metastases. World J Surg. 19:59–71. 1995. View Article : Google Scholar : PubMed/NCBI
8	Tomlinson JS, Jarnagin WR, DeMatteo RP, et al: Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 25:4575–4580. 2007.PubMed/NCBI
9	Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
10	Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 21:60–65. 2003. View Article : Google Scholar : PubMed/NCBI
11	Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E and Sarkar S: Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 23:3706–3712. 2005. View Article : Google Scholar : PubMed/NCBI
12	Allegra CJ, Yothers G, O’Connell MJ, et al: Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 29:11–16. 2011. View Article : Google Scholar : PubMed/NCBI
13	Van de Veire S, Stalmans I, Heindryckx F, et al: Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell. 141:178–190. 2010.PubMed/NCBI
14	Cirulli V and Yebra M: Netrins: beyond the brain. Nat Rev Mol Cell Biol. 8:296–306. 2007. View Article : Google Scholar
15	Dumartin L, Quemener C, Laklai H, et al: Netrin-1 mediates early events in pancreatic adenocarcinoma progression, acting on tumor and endothelial cells. Gastroenterology. 138:1595–1606. 2010. View Article : Google Scholar : PubMed/NCBI
16	Lejmi E, Leconte L, Pedron-Mazoyer S, et al: Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proc Natl Acad Sci USA. 105:12491–12496. 2008. View Article : Google Scholar : PubMed/NCBI
17	Nacht M, St Martin TB, Byrne A, Klinger KW, Teicher BA, Madden SL and Jiang Y: Netrin-4 regulates angiogenic responses and tumor cell growth. Exp Cell Res. 315:784–794. 2009. View Article : Google Scholar : PubMed/NCBI
18	Eveno C, Broqueres-You D, Feron JG, et al: Netrin-4 delays colorectal cancer carcinomatosis by inhibiting tumor angiogenesis. Am J Pathol. 178:1861–1869. 2011. View Article : Google Scholar : PubMed/NCBI
19	Hoffman RM: Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs. 17:343–359. 1999. View Article : Google Scholar : PubMed/NCBI
20	Miles D, Harbeck N, Escudier B, et al: Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol. 29:83–88. 2011. View Article : Google Scholar : PubMed/NCBI
21	Chen HX and Cleck JN: Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 6:465–477. 2009. View Article : Google Scholar : PubMed/NCBI
22	Gressett SM and Shah SR: Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother. 43:490–501. 2009. View Article : Google Scholar : PubMed/NCBI
23	Higa GM and Abraham J: Biological mechanisms of bevacizumab-associated adverse events. Expert Rev Anticancer Ther. 9:999–1007. 2009. View Article : Google Scholar : PubMed/NCBI
24	Ranpura V, Hapani S and Wu S: Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA. 305:487–494. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zangari M, Fink LM, Elice F, Zhan F, Adcock DM and Tricot GJ: Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol. 27:4865–4873. 2009. View Article : Google Scholar : PubMed/NCBI
26	Eikesdal HP and Kalluri R: Drug resistance associated with antiangiogenesis therapy. Semin Cancer Biol. 19:310–317. 2009. View Article : Google Scholar : PubMed/NCBI
27	Eichmann A, Makinen T and Alitalo K: Neural guidance molecules regulate vascular remodeling and vessel navigation. Genes Dev. 19:1013–1021. 2005. View Article : Google Scholar : PubMed/NCBI
28	Larrivee B, Freitas C, Trombe M, et al: Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev. 21:2433–2447. 2007. View Article : Google Scholar : PubMed/NCBI
29	Lu X, Le Noble F, Yuan L, et al: The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature. 432:179–186. 2004. View Article : Google Scholar : PubMed/NCBI
30	Wilson BD, Ii M, Park KW, et al: Netrins promote developmental and therapeutic angiogenesis. Science. 313:640–644. 2006. View Article : Google Scholar : PubMed/NCBI