Lymph nodes are the initial sites of metastasis for most solid tumors, including breast carcinoma and melanoma. Progression from lymph node metastases to distant metastases is suggested by the clinical record as excision of tumor-bearing, draining lymph nodes can improve clinical outcome for many tumor types. Surprisingly, little is known about the factors in the lymph node microenvironment that may contribute to tumor metastasis. Our preliminary data show that primary tumors precondition draining as well as distal lymph nodes for tumor metastasis by inducing integrin ?4?1 and VEGF-R3-mediated lymphangiogenesis but not hemangiogenesis in lymph nodes. Lymph node lymphangiogenesis is then required for tumor metastasis to lymph nodes. Selective inhibition of integrin ?4?1 or VEGF-R3 in lymph nodes blocks lymph node lymphangiogenesis and prevents tumor metastasis to lymph nodes. In contrast, stimulation of lymph node lymphangiogenesis by injections of VEGF-C accelerates metastasis to stimulated lymph nodes. Stimulation of lymph node lymphangiogenesis in normal mice also promoted tumor cell homing to and extravasation into stimulated lymph nodes even in the absence of a primary tumor when tumor cells were injected directly into the lymphatic system. This homing could be blocked by suppressing lymphangiogenesis with antagonists of integrin ?4?1 or VEGF-R3. These studies suggest that lymph node lymphangiogenesis directly promotes lymph node metastasis by enhancing tumor cell adhesion and extravasation into the node. To further our understanding of the role of the lymph node microenvironment in tumor metastasis, we will test the hypotheses that integrin ?4?1 mediated signaling via paxillin promotes lymphatic endothelial cell migration and that integrin ?4?1 mediated signaling via Protein Kinase A, Raf and caspase 8 promote lymphatic endothelial cell survival during lymphangiogenesis and subsequent tumor metastasis;that lymph node lymphatic endothelium promotes the homing, adhesion and extravasation of tumor cells by expressing key tumor cell chemoattractants such as CCL21 as well as tumor cell adhesion ligands/receptors, such as integrin ?4?1, VCAM and E-Selectin;and that inflammatory mediators and bone marrow derived cells within the lymph node play roles in promoting tumor metastasis.
The aims of this proposal are: 1) To determine the role of integrin ?4?1-paxillin interaction during lymphatic endothelial cell migration;2) To determine the roles of protein kinase A, Raf and caspase 8 in integrin ?4?1 mediated lymphatic endothelial cell survival during lymphangiogenesis;3) To evaluate the roles of specific chemokine and adhesion receptors in promoting tumor cell attraction and adhesion to lymphatic endothelium during tumor metastases;4) To determine the contributions of inflammatory mediators and cells in lymph node lymphangiogenesis and metastasis. Importantly, our preliminary findings on the role of lymph node lymphangiogenesis in tumor metastasis indicate that detection of lymph node lymphangiogenesis may facilitate cancer diagnosis by helping to predict the sites of metastatic lesions yet to form. These results also suggest that inhibitors of lymph node lymphangiogenesis may play important roles in cancer therapeutics. The studies proposed in this application are likely to lead to the development and testing of new agents to diagnose and prevent or treat metastatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA126820-05
Application #
8205031
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2008-01-07
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$391,453
Indirect Cost
$138,085
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kaneda, Megan M; Messer, Karen S; Ralainirina, Natacha et al. (2016) PI3K? is a molecular switch that controls immune suppression. Nature 539:437-442
Kaneda, Megan M; Cappello, Paola; Nguyen, Abraham V et al. (2016) Macrophage PI3K? Drives Pancreatic Ductal Adenocarcinoma Progression. Cancer Discov 6:870-85
Gunderson, Andrew J; Kaneda, Megan M; Tsujikawa, Takahiro et al. (2016) Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov 6:270-85
Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin ?4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10:e0120815
Garmy-Susini, Barbara; Avraamides, Christie J; Desgrosellier, Jay S et al. (2013) PI3K? activates integrin ?4?1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci U S A 110:9042-7
Schmid, Michael C; Franco, Irene; Kang, Sang Won et al. (2013) PI3-kinase ? promotes Rap1a-mediated activation of myeloid cell integrin ?4?1, leading to tumor inflammation and growth. PLoS One 8:e60226
Foubert, Philippe; Varner, Judith A (2012) Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol Biol 757:471-86
Kato, Hisashi; Liao, Zhongji; Mitsios, John V et al. (2012) The primacy of ?1 integrin activation in the metastatic cascade. PLoS One 7:e46576
Schmid, Michael C; Avraamides, Christie J; Foubert, Philippe et al. (2011) Combined blockade of integrin-?4?1 plus cytokines SDF-1? or IL-1? potently inhibits tumor inflammation and growth. Cancer Res 71:6965-75
Schmid, Michael C; Avraamides, Christie J; Dippold, Holly C et al. (2011) Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3k?, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19:715-27

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