TY - JOUR
T1 - Targeting receptor tyrosine kinase on lymphatic endothelial cells for the therapy of colon cancer lymph node metastasis
AU - Rebhun, Robert B.
AU - Langley, Robert R.
AU - Yokoi, Kenji
AU - Fan, Dominic
AU - Gershenwaldy, Jeffrey E.
AU - Fidler, Isaiah J.
N1 - Funding Information:
Abbreviations: EOMA, murine hemangioendothelioma; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol-tetrazolium bromide Address all correspondence to: Isaiah J. Fidler, Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected] 1This work was supported, in part, by Cancer Center Support Core grant CA16672 and SPORE in Prostate Cancer grant CA90270 from the National Cancer Institute, National Institutes of Health. Robert Rebhun is the recipient of the American Legion Auxiliary Fellowship in Cancer Research for 2005 to 2006. Received 25 April 2006; Revised 6 July 2006; Accepted 12 July 2006.
PY - 2006
Y1 - 2006
N2 - Oral treatment with the dual-receptor tyrosine kinase inhibitor AEE788 effectively reduces the number of peritumoral lymphatic vessels and the incidence of lymph node metastasis in nude mice with human HT29 colon cancer cells growing in the cecum. Whether inhibition of lymph node metastasis in colon cancer can be achieved by directly targeting lymphatic endothelial cells remains unclear. Using a microsurgical approach, we generated conditionally immortalized lymphatic endothelial cell lines from the H-2Kb-tsA58 mouse mesentery and characterized these cells for the expression of lymphatic endothelial cell markers. Lymphatic endothelial cells were stimulated in culture with an array of tumor cell-produced cytokines, leading to the identification of redundant pathways for proliferation and survival. Treatment with AEE788 decreased the migration, proliferation, and survival of lymphatic endothelial cells, demonstrating that oral treatment with AEE788 effectively decreases the incidence of colon cancer lymphatic metastasis due, in part, to the direct inhibition of lymphatic endothelial cell signaling.
AB - Oral treatment with the dual-receptor tyrosine kinase inhibitor AEE788 effectively reduces the number of peritumoral lymphatic vessels and the incidence of lymph node metastasis in nude mice with human HT29 colon cancer cells growing in the cecum. Whether inhibition of lymph node metastasis in colon cancer can be achieved by directly targeting lymphatic endothelial cells remains unclear. Using a microsurgical approach, we generated conditionally immortalized lymphatic endothelial cell lines from the H-2Kb-tsA58 mouse mesentery and characterized these cells for the expression of lymphatic endothelial cell markers. Lymphatic endothelial cells were stimulated in culture with an array of tumor cell-produced cytokines, leading to the identification of redundant pathways for proliferation and survival. Treatment with AEE788 decreased the migration, proliferation, and survival of lymphatic endothelial cells, demonstrating that oral treatment with AEE788 effectively decreases the incidence of colon cancer lymphatic metastasis due, in part, to the direct inhibition of lymphatic endothelial cell signaling.
KW - Colon cancer
KW - Lymph node metastasis
KW - Lymphangiogenesis
KW - Lymphatic endothelial cells
KW - Tyrosine kinase
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U2 - 10.1593/neo.06322
DO - 10.1593/neo.06322
M3 - Article
C2 - 16984732
AN - SCOPUS:33749069984
SN - 1522-8002
VL - 8
SP - 747
EP - 757
JO - Neoplasia
JF - Neoplasia
IS - 9
ER -