The pathways and molecules regulating metastasis are of great interest, as tumor spread is the major cause of death in cancer patients. Sentinel- or tumor-draining lymph node (TDLN) pathology analysis currently provide the major diagnostic to assess metastatic potential and the need for adjuvant therapy in many human cancers, including melanoma, colon, breast, and head and neck cancers, suggesting that the lymph nodes are somehow involved in metastasis. We discovered extensive TDLN lymphatic sinus growth and increased lymph flow which precede and predict metastasis in murine models of melanoma, squamous cell carcinoma, and lymphoma. These TDLN alterations could actively promote tumor dissemination via the lymphatics. B cells are required for these TDLN alterations, suggesting the hypothesis that B cells or B cell-derived products drive LN lymphangiogenesis and metastasis. The mechanism of abnormal B cell accumulation in TDLNs will be investigated to determine if it involves abnormal entry, egress, or localization. Potential abnormalities of B cell development or activation will be tested that could promote TDLN lymphatic sinus growth and also result in the incomplete anti-tumor immune response. The contribution of B cell-derived immunoglobulins or other secreted components to TDLN lymphangiogenesis and metastasis will be tested by injection of serum from tumor-na?ve or tumor-bearing mice into B cell-deficient mice developing melanomas, to determine whether they reconstitute TDLN lymphatic sinus growth and melanoma spread to the TDLN. B cells from different genetic backgrounds will also be transplanted to test the effects of tumor-specific versus no-specific B cells on TDLN alterations and metastasis. Macrophage/myeloid B cell involvement in B cell accumulation and TDLN alterations will be tested, as the innate immune response could promote B cell TDLN accumulation. Molecules induced by tumor-associated innate immune cells could drive B cell accumulation in TDLNs, and these will be screened for by cDNA microarray or immunoassay comparison of tumors, TDLNs, and normal LNs. B cell-derived factors that could drive TDLN lymphangiogenesis will be identified by comparison of TDLN and control LN B cell mRNA and proteins. The contribution of candidate B cell-derived factors to LN lymphangiogenesis and metastasis will then be tested in transplantation assays using B cells that are deficient for lymphatic growth factor expression. These studies will provide insight to the requirements for TDLN B cell accumulation, antitumor antibody response, and lymphangiogenic growth factors in the promotion of TDLN lymphangiogenesis and metastasis. These insights will inform strategies for the development of diagnostic tools and targeted therapies to identify and prevent metastasis in human cancer patients.

Public Health Relevance

An understanding of the pathways of cancer spread could lead to improved diagnosis and to therapeutic approaches to block metastasis. Lymph node alterations were identified that could be involved in metastasis and in the immune system response to cancer. Our experiments will investigate the contribution of this lymph node response to tumor spread to draining lymph nodes and other locations in the body.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068328-18
Application #
8617087
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
1996-05-15
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
18
Fiscal Year
2014
Total Cost
$289,380
Indirect Cost
$102,079
Name
University of Washington
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Jordan-Williams, Kimberly L; Ruddell, Alanna (2014) Culturing purifies murine lymph node lymphatic endothelium. Lymphat Res Biol 12:144-9
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
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
Maggio-Price, Lillian; Treuting, Piper; Bielefeldt-Ohmann, Helle et al. (2009) Bacterial infection of Smad3/Rag2 double-null mice with transforming growth factor-beta dysregulation as a model for studying inflammation-associated colon cancer. Am J Pathol 174:317-29
Harrell, Maria I; Iritani, Brian M; Ruddell, Alanna (2008) Lymph node mapping in the mouse. J Immunol Methods 332:170-4
Ruddell, Alanna; Harrell, Maria I; Minoshima, Satoshi et al. (2008) Dynamic contrast-enhanced magnetic resonance imaging of tumor-induced lymph flow. Neoplasia 10:706-13, 1 p following 713
Ruddell, A; Kelly-Spratt, K S; Furuya, M et al. (2008) p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis. Oncogene 27:3145-55
Harrell, Maria I; Iritani, Brian M; Ruddell, Alanna (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774-86
Maggio-Price, Lillian; Treuting, Piper; Zeng, Weiping et al. (2006) Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res 66:828-38

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