The c-myc proto-oncogene is de-regulated in many human cancers, and increased Myc expression is often associated with poor prognosis. We identified rapid growth of functional lymphatic and blood vessels during early stages of lymphomagenesis in E/mu-c-myc mice, where Myc is overexpressed in B cells. Myc induces vascular endothelial growth factor (VEGF-A) mRNA translation in B cells, which could mediate at least in part the growth of lymphatic and blood vessels, which both express VEGF receptor-2. We propose that the lymphangiogenesis and increased lymph flow through lymph nodes promotes the rapid formation of metastatic lymphomas in E/mu-c-myc mice. GFP-tagged E?-c-myc tumor cells will be transplanted into E/mu-c-myc or wild type mice, to test whether Myc-induced lymph node alterations promote lymphoma dissemination. We identified lymph node lymphangiogenesis in mouse models of metastatic solid tumors, suggesting that lymph node lymphatic vessel growth also supports solid tumor dissemination. Metastatic and non-metastatic B16 melanoma cell lines will be transplanted into E/mu-c-myc or wild type mice, to test whether lymph node lymphangiogenesis promotes solid tumor metastasis via the lymphatics. Myc will be overexpressed in non-metastatic melanomas using retroviral vectors to determine whether this oncogene promotes metastasis by inducing tumor and/or lymph node lymphangiogenesis. Several VEGF family members are expressed in E/mu-c-myc B cells, which could mediate lymphatic vessel growth and increased lymph flow within the lymph nodes. VEGF, VEGF-C, or VEGF-D activity will be inhibited in E/mu-c-myc or B16 tumors using a variety of approaches, to determine which factors mediate lymph node alterations. Treatments inhibiting lymph node lymphangiogenesis will test whether increased lymph flow is required for effective metastasis. Identification of the factors directing lymph node alterations and tumor dissemination will be useful in the development of diagnostic assays and therapies for metastasis via the lymph nodes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068328-10
Application #
7050532
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
1996-05-15
Project End
2009-04-30
Budget Start
2006-06-01
Budget End
2007-04-30
Support Year
10
Fiscal Year
2006
Total Cost
$329,265
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Habenicht, Lauren M; Albershardt, Tina C; Iritani, Brian M et al. (2016) Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy. Oncoimmunology 5:e1204505
Jordan-Williams, Kimberly L; Ramanujam, Neela; Farr, Andrew G et al. (2016) The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses. PLoS One 11:e0156079
Ganti, Sheila N; Albershardt, Tina C; Iritani, Brian M et al. (2015) Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth. Sci Rep 5:12255
Partridge, S C; Kurland, B F; Liu, C-L et al. (2015) Tumor-induced lymph node alterations detected by MRI lymphography using gadolinium nanoparticles. Sci Rep 5:15641
Ruddell, Alanna; Kirschbaum, Sara B; Ganti, Sheila N et al. (2015) Tumor-induced alterations in lymph node lymph drainage identified by contrast-enhanced MRI. J Magn Reson Imaging 42:145-52
Ruddell, Alanna; Croft, Alexandra; Kelly-Spratt, Karen et al. (2014) Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads. BMC Cancer 14:354
Jordan-Williams, Kimberly L; Ruddell, Alanna (2014) Culturing purifies murine lymph node lymphatic endothelium. Lymphat Res Biol 12:144-9
Albershardt, Tina C; Iritani, Brian M; Ruddell, Alanna (2012) Evaluation of reference genes for quantitative PCR analysis of mouse lymphocytes. J Immunol Methods 384:196-9
Ruddell, Alanna; Harrell, Maria I; Furuya, Momoko et al. (2011) B lymphocytes promote lymphogenous metastasis of lymphoma and melanoma. Neoplasia 13:748-57
Furuya, Momoko; Kirschbaum, Sara B; Paulovich, Amanda et al. (2010) Lymphatic endothelial murine chloride channel calcium-activated 1 is a ligand for leukocyte LFA-1 and Mac-1. J Immunol 185:5769-77

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