Podoplanin+ tumor lymphatics are rate limiting for breast cancer metastasis.

Autor: Chen Y; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America., Keskin D; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America., Sugimoto H; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America., Kanasaki K; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America., Phillips PE; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America., Bizarro L; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America., Sharpe A; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America., LeBleu VS; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America., Kalluri R; Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2018 Dec 28; Vol. 16 (12), pp. e2005907. Date of Electronic Publication: 2018 Dec 28 (Print Publication: 2018).
DOI: 10.1371/journal.pbio.2005907
Abstrakt: Metastatic dissemination employs both the blood and lymphatic vascular systems. Solid tumors dynamically remodel and generate both vessel types during cancer progression. Lymphatic vessel invasion and cancer cells in the tumor-draining lymph nodes (LNs) are prognostic markers for breast cancer metastasis and patient outcome, and tumor-induced lymphangiogenesis likely influences metastasis. Deregulated tumor tissue fluid homeostasis and immune trafficking associated with tumor lymphangiogenesis may contribute to metastatic spreading; however, the precise functional characterization of lymphatic endothelial cells (LECs) in tumors is challenged by the lack of specific reagents to decipher their rate-limiting role in metastasis. Therefore, we generated novel transgenic mice (PDPN promoter-driven Cre recombinase transgene [PDPN-Cre] and PDPN promoter-driven thymidine kinase transgene [PDPN-tk]) that allow for the identification and genetically controlled depletion of proliferating podoplanin (Pdpn)-expressing LECs. We demonstrate that suppression of lymphangiogenesis is successfully achieved in lymphangioma lesions induced in the PDPN-tk mice. In multiple metastatic breast cancer mouse models, we identified distinct roles for LECs in primary and metastatic tumors. Our findings support the functional contribution of primary tumor lymphangiogenesis in controlling metastasis to axillary LNs and lung parenchyma. Reduced lymphatic vessel density enhanced primary tumor lymphedema and increased the frequency of intratumoral macrophages but was not associated with a significant impact on primary tumor growth despite a marked reduction in metastatic dissemination. Our findings identify the rate-limiting contribution of the breast tumor lymphatic vessels for lung metastasis.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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