p19 Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis

• Published in: Oncogene Vol. 27; no. 22; pp. 3145 - 3155
• Main Authors: RUDDELL, A, KELLY-SPRATT, K. S, FURUYA, M, PARGHI, S. S, KEMP, C. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 15.05.2008; Nature Publishing Group
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Acetic acid; Animals; Anthracene; B-Lymphocytes - pathology; Biological and medical sciences; Cancer; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Care and treatment; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Chemotaxis, Leukocyte - genetics; Complications and side effects; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - physiology; Diagnosis; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetics; Health aspects; Lymph nodes; Lymph Nodes - physiology; Lymphangiogenesis - genetics; Lymphatic Metastasis; Lymphatic system; Lymphocytes B; Macrophages - pathology; Metastases; Metastasis; Mice; Mice, Transgenic; Molecular and cellular biology; Neovascularization, Pathologic - genetics; Oncology; p53 Protein; Papilloma; Phenotypes; Risk factors; Rodents; Skin Neoplasms - blood supply; Skin Neoplasms - chemically induced; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Squamous cell carcinoma; Tetradecanoylphorbol Acetate; Tumor cells; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Tumors; Vascular Endothelial Growth Factor A - metabolism; United States; Carcinoma; TP53 Gene; Lymph node; lymphangiogenesis; Malignant tumor; Metastasis; Carcinogenesis; pl9/Arf; Cancer; Tumor suppressor gene; p53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210973

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.