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

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 beta 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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Crnic I,Strittmatter K,Cavallaro U,Kopfstein L,Jussila L,Alitalo K,Christofori G

doi

10.1158/0008-5472.CAN-04-2523

subject

Has Abstract

pub_date

2004-12-01 00:00:00

pages

8630-8

issue

23

eissn

0008-5472

issn

1538-7445

pii

64/23/8630

journal_volume

64

pub_type

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