Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Mobilization of Macrophage Lineage Cells from Bone Marrow and Stimulates Solid Tumor Growth

Vascular endothelial growth factor and its receptors, including Flt-1 and Flk-1, are involved in angiogenesis under physiologic and pathologic conditions. Recently, Flt-1-expressing cells were reported to contribute to the intracranial growth of glioma cells. However, the role of Flt-1 signaling in...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2010-10, Vol.70 (20), p.8211-8221
Main Authors: MURAMATSU, Masashi, YAMAMOTO, Seiji, OSAWA, Tsuyoshi, SHIBUYA, Masabumi
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Antineoplastic agents
Biological and medical sciences
Bone Marrow Cells - pathology
Bone Marrow Cells - physiology
Carcinoma, Lewis Lung - pathology
Cell Division
Cell Line, Tumor
DNA Primers
Female
Fibroblast Growth Factor 2 - genetics
Lung Neoplasms - pathology
Macrophages - pathology
Macrophages - physiology
Medical sciences
Mice
Mice, Knockout
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Neoplasms - pathology
Neovascularization, Pathologic - pathology
Pharmacology. Drug treatments
Receptor, Fibroblast Growth Factor, Type 1 - deficiency
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumors
Uterine Neoplasms - pathology
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor Receptor-1 - physiology
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Summary:Vascular endothelial growth factor and its receptors, including Flt-1 and Flk-1, are involved in angiogenesis under physiologic and pathologic conditions. Recently, Flt-1-expressing cells were reported to contribute to the intracranial growth of glioma cells. However, the role of Flt-1 signaling in solid tumor growth in s.c. tissue has not been elucidated. To investigate how Flt-1 signaling is involved in the proliferation of solid tumors, we implanted tumor cells into wild-type (Wt) and Flt-1 tyrosine kinase (TK)-deficient (Flt-1 TK(-/-)) mice. Growth of HSML and B16 but not Lewis lung carcinoma cell in s.c. tissue was significantly decreased in Flt-1 TK(-/-) mice. Angiogenesis in HSML and B16 tumors was remarkably reduced in Flt-1 TK(-/-) mice. Moreover, the infiltration of macrophage lineage cells into HSML and B16 tumors was clearly suppressed in Flt-1 TK(-/-) mice. Pericyte marker(+) cells were also reduced in Flt-1 TK(-/-) mice. However, in the border area of tumor, angiogenesis and the infiltration of macrophage lineage cell were basically similar between Wt and Flt-1 TK(-/-) mice. In bone marrow (BM) transplantation experiments, tumor angiogenesis, infiltration of macrophage lineage cells, and tumor growth were significantly suppressed in Wt/Flt-1 TK(-/-) mice implanted with Flt-1 TK(-/-) BM cells compared with those implanted with Wt BM cells. We conclude that Flt-1 signaling is involved in the function of BM-derived cell, such as the migration of macrophages into cancerous tissues, and significantly contributes to angiogenesis and tumor progression.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-10-0202