Abstract
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.
Highlights
The endothelial lining of blood vessels is highly diversified
We chose the C8161 human melanoma as the first topic because xenografts of tumors generated with this cell line in nude mice contain lymphatic vessels that are not recognized by the homing peptide LyP-1, which binds to lymphatic endothelial cells in breast carcinomas [13]
We incubated a phage display library with a cell suspension of whole C8161 tumor tissue, allowing phage to bind, and used immunomagnetic beads to isolate lymphatic endothelial cells that carried along any phage bound to these cells
Summary
The endothelial lining of blood vessels is highly diversified. Tumor blood vessels have tumor type–specific and, in some stages, stage-specific characteristics; in vivo screening of phage libraries has yielded distinct sets of homing peptides selectively recognizing angiogenic signatures in two transgenic mouse models of organ-specific tumorigenesis. Homing peptides can distinguish the angiogenic blood vessels of premalignant lesions from those of fully malignant lesions in the same tumor. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Giraudo: Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment and Department of Oncological Sciences, University of Turin, 10060 Candiolo, Turin, Italy. Current address for J.A. Hoffman: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92021. D. Hanahan is an American Cancer Society Research Professor
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