Loss of neural cell adhesion molecule induces tumor metastasis by up-regulating lymphangiogenesis

Ivana Crnic, Karin Strittmatter, Ugo Cavallaro, Lucie Kopfstein, Lotta Jussila, Kari Alitalo, Gerhard Christofori

Research output: Contribution to journalArticle

Abstract

Reduced expression of neural cell adhesion molecule (NCAM) has been implicated in the progression to tumor malignancy in cancer patients. Previously, we have shown that the loss of NCAM function causes the formation of lymph node metastasis in a transgenic mouse model of pancreatic β cell carcinogenesis (Rip1Tag2). Here we show that tumors of NCAM-deficient Rip1Tag2 transgenic mice exhibit up-regulated expression of the lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and -D (17% in wild-type versus 60% in NCAM-deficient Rip1Tag2 mice) and, with it, increased lymphangiogenesis (0% in wild-type versus 19% in NCAM-deficient Rip1Tag2 mice). Repression of VEGF-C and -D function by adenoviral expression of a soluble form of their cognate receptor, VEGF receptor-3, results in reduced tumor lymphangiogenesis (56% versus 28% in control versus treated mice) and lymph node metastasis (36% versus 8% in control versus treated mice). The results indicate that the loss of NCAM function causes lymph node metastasis via VEGF-C- and VEGF-D-mediated lymphangiogenesis. These results also establish Rip1Tag2;NCAM-deficient mice as a unique model for stochastic, endogenous tumor lymphangiogenesis and lymph node metastasis in immunocompetent mice.

Original languageEnglish
Pages (from-to)8630-8638
Number of pages9
JournalCancer Research
Volume64
Issue number23
DOIs
Publication statusPublished - Dec 1 2004

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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