Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis.
Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.
Mandriota
S J
SJ
Department of Morphology, University Medical Centre, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
Jussila
L
L
Jeltsch
M
M
Compagni
A
A
Baetens
D
D
Prevo
R
R
Banerji
S
S
Huarte
J
J
Montesano
R
R
Jackson
D G
DG
Orci
L
L
Alitalo
K
K
Christofori
G
G
Pepper
M S
MS
D000818:Animals; D018076:DNA, Complementary; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000254:growth & development*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000648:ultrastructure; D042582:Vascular Endothelial Growth Factor C
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D042582:Vascular Endothelial Growth Factor C