Loss of smooth muscle calponin results in impaired blood vessel maturation in the tumor-host microenvironment.
The interactions between malignant cells and the microenvironment of the local host tissue play a critical role in tumor growth, metastasis and their response to treatment modalities. We investigated the roles of smooth muscle calponin (Cnn1, also called calponin h1 or basic calponin) in the development of tumor vascul ature in vivo by analyzing mutant mice lacking the Cnn1 gene. Here we show that loss of Cnn1 in host mural cells prevents maturation of tumor vasculature. In vitro studies showed that platelet-derived growth factor B-induced vascular smooth muscle migration was downregulated by the Cnn1-deficiency, and forced expression of Cnn1 restored migration. Moreover, destruction of established tumor mass by treatment with an antivascular endothelial growth factor antibody was markedly enhanced in Cnn1-deficient mice. These data, coupled with the knowledge that structural fragility of normal blood vessels is caused by loss of the Cnn1 gene, suggest that Cnn1 plays an important role in the maturation of blood vessels, and may have implications for therapeutic strategies targeting tumor vasculature for treatment of human cancers.
Yamamura
Hisako
H
Department of Molecular Medicine and Pathophysiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Graduate School of Pharmaceutical Science, Osaka University, Osaka City, Osaka 537-8511, Japan.
Hirano
Noriko
N
Koyama
Hidenori
H
Nishizawa
Yoshiki
Y
Takahashi
Katsuhito
K
D000199:Actins / Q000032:analysis; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D007150:Immunohistochemistry; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D000096985:Calponins
D000199:Actins; D000906:Antibodies; D018952:Antigens, CD34; D000077214:Becaplermin; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000096985:Calponins