Abstract
The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics.
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Acknowledgements
We thank Maria Harrell and Kay Gurley for advice, and NIH NCI R01-CA68328 (A Ruddell) and R01-CA99517 (CJ Kemp) grants for support.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Ruddell, A., Kelly-Spratt, K., Furuya, M. et al. p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis. Oncogene 27, 3145–3155 (2008). https://doi.org/10.1038/sj.onc.1210973
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DOI: https://doi.org/10.1038/sj.onc.1210973
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