Vascular endothelial growth factor-C secreted by pancreatic cancer cell line promotes lymphatic endothelial cell migration in an in vitro model of tumor lymphangiogenesis.
OBJECTIVE
To investigate mechanisms underlying lymphatic node metastasis in pancreatic cancer, we examined roles of vascular endothelial growth factor-C (VEGF-C) in tumor lymphangiogenesis.


METHODS
We measured VEGF-C secretion by pancreatic cancer cell lines using enzyme-linked immunosorbent assay and examined effects of different cell lines on lymphatic endothelial cells (LECs) in vitro.


RESULTS
We identified VEGF-C high-secretion (MIA PaCa-2) and low-secretion cell lines (BxPC-3). The trend of enhancement of LEC proliferation by recombinant human VEGF-C (rVEGF-C) was not statistically significant. Numbers of migrating cells were increased by rVEGF-C treatment in a dose-dependent manner. The MIA PaCa-2 cell culture supernatant caused greater LEC migration than the BxPC-3 supernatant. The VEGF-C effects were significantly inhibited by rVEGF receptor 3 (rVEGF R3)/Fc chimera. In LEC/fibroblast coculture on collagen gel, LEC capillary formation was significantly enhanced by coculture with MIA PaCa-2 cells compared with BxPC-3 cells. Enhanced capillary formation with MIA PaCa-2 cells was inhibited by rVEGF R3/Fc chimera, implying VEGF-C involvement in progression of LEC sprouting in a tumor microenvironment.


CONCLUSIONS
Because VEGF-C secreted by pancreatic cancer cells plays an important role in LEC migration in pancreatic cancer lymphangiogenesis, it is possible that rVEGF R3/Fc chimera might have a role in controlling lymph node metastasis.
Ochi
Nobuo
N
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan. nochi@med.nagoya-cu.ac.jp
Matsuo
Yoichi
Y
Sawai
Hirozumi
H
Yasuda
Akira
A
Takahashi
Hiroki
H
Sato
Mikinori
M
Funahashi
Hitoshi
H
Okada
Yuji
Y
Manabe
Tadao
T
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3