Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression
Summary: Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated...
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| Language: | English |
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224027299 |
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| author | Kako Hanada Yuki Saito Takahiro Takagi Mitsuki Go Yota Nakano Toshihiko Inagawa Hideyo Hirai Marcus Fruttiger Susumu Itoh Fumiko Itoh |
| author_facet | Kako Hanada Yuki Saito Takahiro Takagi Mitsuki Go Yota Nakano Toshihiko Inagawa Hideyo Hirai Marcus Fruttiger Susumu Itoh Fumiko Itoh |
| author_sort | Kako Hanada |
| collection | DOAJ |
| description | Summary: Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated tamoxifen-inducible TGF-β type II receptor (TβRII) knockout mice, specifically targeting ECs (TβRIIiΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRIIiΔEC mice exhibited increased tumor angiogenesis with fragile new blood vessels, increased bleeding, and hypoxia compared to control mice. Consequently, the compromised tumor microenvironment precipitated a notable surge in circulating tumor cells. Paradoxically, lung metastasis showed a significant decline. This intriguing discrepancy was explained by a reduction in the engraftment between cancer cells and ECs. Disruption of TGF-β signaling downregulated CD44 on ECs, hindering cancer cell adhesion. These findings highlight TGF-β′s role in promoting metastasis by modulating EC function. |
| format | Article |
| id | doaj-art-57eb9d904df841ccacef2b86e665470a |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-57eb9d904df841ccacef2b86e665470a2025-08-20T02:39:38ZengElsevieriScience2589-00422024-12-01271211150210.1016/j.isci.2024.111502Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expressionKako Hanada0Yuki Saito1Takahiro Takagi2Mitsuki Go3Yota Nakano4Toshihiko Inagawa5Hideyo Hirai6Marcus Fruttiger7Susumu Itoh8Fumiko Itoh9Laboratory of Stem Cell Regulation, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan; Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanLaboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanLaboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanLaboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanLaboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, JapanLaboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanLaboratory of Stem Cell Regulation, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, JapanUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UKLaboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, JapanLaboratory of Stem Cell Regulation, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan; Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan; Corresponding authorSummary: Transforming growth factor β (TGF-β) is abundantly present in the tumor microenvironment, contributing to cancer progression. However, the regulatory mechanism by which TGF-β affects vascular endothelial cells (ECs) in the tumor microenvironment is not well understood. Herein, we generated tamoxifen-inducible TGF-β type II receptor (TβRII) knockout mice, specifically targeting ECs (TβRIIiΔEC), by crossbreeding TβRII-floxed mice with Pdgfb-icreER mice. We established tumor-bearing mice by transplanting Lewis lung carcinoma (LLC) cells. TβRIIiΔEC mice exhibited increased tumor angiogenesis with fragile new blood vessels, increased bleeding, and hypoxia compared to control mice. Consequently, the compromised tumor microenvironment precipitated a notable surge in circulating tumor cells. Paradoxically, lung metastasis showed a significant decline. This intriguing discrepancy was explained by a reduction in the engraftment between cancer cells and ECs. Disruption of TGF-β signaling downregulated CD44 on ECs, hindering cancer cell adhesion. These findings highlight TGF-β′s role in promoting metastasis by modulating EC function.http://www.sciencedirect.com/science/article/pii/S2589004224027299Natural sciencesBiological sciencesSystems biologyCancer systems biologyCancer |
| spellingShingle | Kako Hanada Yuki Saito Takahiro Takagi Mitsuki Go Yota Nakano Toshihiko Inagawa Hideyo Hirai Marcus Fruttiger Susumu Itoh Fumiko Itoh Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression iScience Natural sciences Biological sciences Systems biology Cancer systems biology Cancer |
| title | Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression |
| title_full | Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression |
| title_fullStr | Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression |
| title_full_unstemmed | Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression |
| title_short | Reduced lung metastasis in endothelial cell-specific transforming growth factor β type II receptor-deficient mice with decreased CD44 expression |
| title_sort | reduced lung metastasis in endothelial cell specific transforming growth factor β type ii receptor deficient mice with decreased cd44 expression |
| topic | Natural sciences Biological sciences Systems biology Cancer systems biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224027299 |
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