Trends in Molecular Medicine
ReviewProbing the structural and molecular diversity of tumor vasculature
Section snippets
Diversity of normal blood vessels
The concept of structural heterogeneity within the vasculature developed in tandem with advances in the understanding of the functions of different organs. An early indication that capillaries are not all alike came from the observation of organ-related differences in vascular permeability 5., 6.. Another key indicator emerged from the examination of blood vessels in different organs by transmission electron microscopy in the 1950s. These studies identified three general types of capillaries:
Probing the molecular heterogeneity of the vasculature
Molecules that could be used as receptors for targeted therapies can be identified by probing the molecular diversity of cell surfaces. This approach has several advantages over the identification of proteins by gene profiling or biochemical purification of isolated cells. First, proteins naturally positioned in cell membranes are more likely to maintain their functional conformation, as compared with isolated receptors that can be lost upon purification and immobilization outside the context
Vascular addresses of blood vessels
Vascular targeting exploits molecular differences that exist in blood vessels of different organs and tissues, as well as differences between normal blood vessels and angiogenic or remodeled blood vessels. Differences in plasma-membrane proteins (‘vascular zip codes’) can be used to target therapeutic or imaging agents directly to a particular organ or tumor. For the treatment of cancer, this approach might reduce or eliminate some of the problems associated with conventional therapy, such as
Conclusions
With increasing understanding of the structural abnormalities of tumor blood vessels, and development of the in vivo phage-display technique to probe the molecular diversity of the vasculature, the identification of ligand–receptor pairs for vascular targeting can be translated into real clinical applications. By guiding anticancer agents selectively to tumor vessels, new and improved forms of targeted anticancer therapy can be developed. In addition to the promise of peptide-guided therapy,
Acknowledgements
We thank the members of our respective laboratories and their collaborators for valuable insights and for generating much of the data featured in this review. Our work was supported by grants from the National Institutes of Health (CA-90270 and CA-8297601 to R.P., CA-90270 and CA-9081001 to W.A., and HL-24136 and HL-59157 to D.M.M.), grants from University of California Biotechnology Strategic Targets for Alliances in Research (BioSTAR Project 00–10106) and MBT Munich Biotechnology AG (to
Glossary
- Bacteriophage:
- A virus that infects and propagates in bacteria. Often shortened to ‘phage’.
- Biopanning:
- Screening of a phage-display peptide library against one or more targets.
- Cationic liposomes:
- Positively charged lipid vesicles used as drug delivery vehicles.
- Continuous capillaries:
- Capillaries with endothelial cells that lack holes or discontinuities and have comparatively low solute flux.
- Discontinuous capillaries:
- Capillaries with endothelial cells that have transcellular openings not covered by
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