Suppression of lymphangiogenesis induced by Flt-4 antibody in gastric low-grade mucosa-associated lymphoid tissue lymphoma by Helicobacter heilmannii infection.
OBJECTIVE
Our recent study revealed that per oral infection with Helicobacter heilmannii induced low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the gastric fundus of C57BL/6 mice after a period of 6 months, although the pathophysiological mechanism of lymphoma expansion remains to be clarified. The present study was undertaken to elucidate the interaction of this tumor with angiogenesis and lymphangiogenesis. In addition, the effect of Flt-4 antibodies on lymphoma expansion was investigated.


METHODS
C57BL/6 female mice infected with H. heilmannii for 3 months were used in the experiments. Localization of vascular endothelial growth factor C (VEGF-C) and Flt-4 immunoreactivity were detected by indirect immunohistochemical methods. Localization of lymphatic and vascular endothelial cells was investigated by localization of prox-1. In addition, Flt-4 antibody with and without Flt-1 or Flk-1 antibodies was administered i.p. to clarify their effects on tumor size.


RESULTS
MALT lymphoma has a rich microvascular network consisting of immature capillaries, lymphatics and venules. By immunohistochemical analysis, prox-1 immunoreactivity was observed mostly in the marginal area of the lymphoma, where VEGF-C and Flt-4 immunoreactivities were also seen. Stereomicroscopic study revealed that administration of Flt-4 and Flt-1 antibodies significantly reduced the surface area of the lymphoma in the mouse stomach.


CONCLUSIONS
A VEGF-C-mediated mechanism plays an important role in the expansion of MALT lymphoma and the administration of VEGF receptor antibodies had a suppressive effect on tumor growth.
Nakamura
Masahiko
M
Division of Pathophysiolgy, Research and Education Center for Clinical Pharmacy, School of Pharmaceutical Sciences, Mitaka, Tokyo, Japan. nakamuram@pharm.kitasato-u.ac.jp
Matsui
Hidenori
H
Takahashi
Tetsufumi
T
Ogawa
Satoshi
S
Tamura
Ryo
R
Murayama
Somay Y
SY
Takahashi
Shinichi
S
Tsuchimoto
Kanji
K
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016481:Helicobacter Infections / Q000382:microbiology*; D018247:Helicobacter heilmannii / Q000472:pathogenicity*; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D042583:Lymphangiogenesis / Q000187:drug effects*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000382:microbiology / Q000503:physiopathology / Q000517:prevention & control; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D000906:Antibodies; D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D000098551:Prospero-Related Homeobox 1 Protein; C467483:vascular endothelial growth factor C, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3