Keynote Speaker II:
Tissue- and Tumor-specific Molecular Markers in Blood Vessels and Lymphatics
Cancer Research Center, The Burnham Institute,
10901 N. Torrey Pines Rd., La Jolla, CA
We use libraries of phage-displayed peptides to identify specific changes in the
vasculature of normal tissues and tumors. The results show that the blood vessels in
individual tissues are distinct, tumor blood vessels differ from normal blood vessels,
tumor lymphatics differ from normal lymphatics, and the markers of tumor blood
vessels and lymphatics are different. Phage screening also reveals specific features in
the extracellular matrix of tumor vessels and tumor stroma.
A set of new tumor-homing peptides, identified by combining ex vivo screening of the
phage libraries on cell suspensions and in vivo screening for homing to tumor
vasculature, will be discussed in some detail. One of the peptides, F3, was obtained by
ex vivo screening on cell suspensions from the bone marrow, followed by in vivo
screening for tumor homing. F3 recognizes tumor blood vessels (Porkka et al., PNAS, 8,
751, 2002), and a small population of cells in the bone marrow that may represent
endothelial cell precursors. A screening done ex vivo for binding to tumor cell
suspensions treated to remove blood vessel endothelial cells and in vivo for tumor
homing yielded a peptide (Lyp-1) that homes to tumor lymphatics (Laakkonen et al.,
Nature Med. 99, 7444, 2002). Both F3 and Lyp-1 also bind to the tumor cells. A third
peptide, CR, binds to the extracellular matrix of tumor blood vessels and tumor stroma
(Essler et al., submitted).
Fluorescein conjugates of the F3 and Lyp-1 peptides home to tumors after an
intravenous injection, accumulating both in endothelial and tumor cells in the tumors.
The CR peptide homes to tumor stroma. The F3 and LyP-1 peptides have the
remarkable property of being transported, along with the fluorescein marker attached
to them, in the nucleus of the target cells. Thus, these peptides may be particularly
suitable for targeting anti-cancer drugs that act in the nucleus. Ongoing studies aim at
identifying the cell surface molecules that serve as receptors for these peptides and
establishing the utility of the peptides in targeted drug delivery.