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Lymphatic Zip Codes in Premalignant Lesions and Tumors

¹ Cancer Research Center and ² Program in Molecular Pathology, Burnham Institute for Medical Research; ³ Department of Pathology, University of California San Diego, School of Medicine, La Jolla, California; and ⁴ Department of Biochemistry and Biophysics, and the Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, San Francisco, California

Requests for reprints: Erkki Ruoslahti, Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-646-3100; Fax: 858-646-3198; E-mail: ruoslahti{at}ljcrf.edu or Douglas Hanahan, Department of Biochemistry and Biophysics, University of California San Diego, School of Medicine, La Jolla, CA 92093. E-mail: dh{at}biochem.ucsf.edu.

Blood vessels in tumors are morphologically and functionally distinct from normal resting blood vessels. We probed lymphatic vessels in premalignant lesions and tumors by in vivo screening of phage-displayed peptide libraries, asking whether they too have distinctive signatures. The resulting peptides begin to define such signatures. One peptide identified the lymphatics in a human melanoma xenograft. Another recognized the lymphatics in prostate cancers but not in premalignant prostate lesions; this peptide similarly identifies human prostate cancer lymphatics. A third was selective for the lymphatics in the premalignant prostate lesions. A fourth identified the lymphatics in dysplasias and squamous carcinomas of the cervix and skin. None recognize lymphatics in normal tissues. Thus, tumor development is associated with organ- and stage-specific changes in lymphatics. Systemic treatment of mice with fusions of a lymphatic homing peptide and a proapoptotic motif reduced the number of tumor lymphatics in prostate tumor and melanoma, forecasting future lymphatic targeting agents for detection and therapeutic intervention. (Cancer Res 2006; 66(11): 5696-706)

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