Trends in Molecular Medicine
Volume 8, Issue 12, 1 December 2002, Pages 563-571
Journal home page for Trends in Molecular Medicine

Review
Probing the structural and molecular diversity of tumor vasculature

https://doi.org/10.1016/S1471-4914(02)02429-2Get rights and content

Abstract

The molecular diversity of the vasculature provides a rational basis for developing targeted diagnostics and therapeutics for cancer. Targeted imaging agents would offer better localization of primary tumors and metastases, and targeted therapies would improve efficacy and reduce side effects. The development of targeted pharmaceuticals requires the identification of specific ligand–receptor pairs, and knowledge of their cellular distribution and accessibility. Using in vivo phage display, a technique by which we can identify organ-specific and disease-specific proteins expressed on the endothelial surface, it is now possible to decipher the molecular signature of blood vessels in normal and diseased tissues. These studies have already led to the identification of peptides that target the normal vasculature of the brain, kidney, pancreas, lung and skin, as well as the abnormal vasculature of tumors, arthritis and atherosclerosis. Membrane dipeptidase in the lungs, interleukin-11 receptor in the prostate, and aminopeptidase N in tumors are examples of molecular targets on blood vessels. Corresponding confocal-microscopic imaging and ultrastructural studies are providing a more complete understanding of the cellular abnormalities of tumor blood vessels, and the distribution and accessibility of potential targets. The combined approach offers a strategy for creating a ligand–receptor map of the human vasculature, and forms a foundation for the development and application of targeted therapies in cancer and other diseases.

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

References (82)

  • H. Hashizume

    Openings between defective endothelial cells explain tumor vessel leakiness

    Am. J. Pathol.

    (2000)
  • S. Morikawa

    Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors

    Am. J. Pathol.

    (2002)
  • G.P. Smith et al.

    Libraries of peptides and proteins displayed on filamentous phage

    Methods Enzymol.

    (1993)
  • D. Rajotte et al.

    Membrane dipeptidase is the receptor for a lung-targeting peptide identified by in vivo phage display

    J. Biol. Chem.

    (1999)
  • F. Bussolino

    Molecular mechanisms of blood vessel formation

    Trends Biochem. Sci.

    (1997)
  • W. Arap

    Steps toward mapping the human vasculature by phage display

    Nat. Med.

    (2002)
  • R. Pasqualini et al.

    Translation of vascular proteomics into individualized therapeutics

  • C. Crone et al.

    Capillary permeability to small solutes

  • A.E. Taylor et al.

    Exchange of macromolecules across the microcirculation

  • H.S. Bennett

    Morphological classifications of vertebrate blood capillaries

    Am. J. Physiol.

    (1959)
  • G. Majno

    Ultrastructure of the vascular membrane

  • G. Majno et al.

    Endothelium 1977: a review

    Adv. Exp. Med. Biol.

    (1978)
  • M. Simionescu et al.

    Ultrastructure of the microvascular wall: functional correlations

  • J.A.G. Rhodin

    Histology: A Text and Atlas

    (1974)
  • G. Majno et al.

    Cells, Tissue, and Disease: Principles of General Pathology

    (1996)
  • H.G. Burkitt

    Wheater's Functional Histology. A Text and Colour Atlas

    (1993)
  • T.S. Reese et al.

    Fine structural localization of a blood–brain barrier to exogenous peroxidase

    J. Cell Biol.

    (1967)
  • M.W. Brightman et al.

    Junctions between intimately apposed cell membranes in the vertebrate brain

    J. Cell Biol.

    (1969)
  • D.W. Fawcett

    Electron microscopic observations on the structural components of the blood–testis barrier

    J. Reprod. Fertil.

    (1970)
  • M. Dym et al.

    The blood–testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium

    Biol. Reprod.

    (1970)
  • E.E. Schneeberger

    Glomerular permeability to protein molecules – its possible structural basis

    Nephron

    (1974)
  • E.M. Renkin et al.

    Glomerular filtration

    N. Engl. J. Med.

    (1974)
  • N.D. Anderson

    Specialized structure and metabolic activities of high endothelial venules in rat lymphatic tissues

    Immunology

    (1976)
  • E.C. Butcher

    Organ specificity of lymphocyte migration: mediation by highly selective lymphocyte interaction with organ-specific determinants on high endothelial venules

    Eur. J. Immunol.

    (1980)
  • M. Muto

    A scanning and transmission electron microscopic study on rat bone marrow sinuses and transmural migration of blood cells

    Arch. Histol. Jpn.

    (1976)
  • C.A. Goresky et al.

    Microcirculatory events in the liver and spleen

  • J.D. Fenstermacher et al.

    Blood–brain barrier

  • A.S. Verkman

    Aquaporin water channels and lung physiology

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2000)
  • L.S. King

    Decreased pulmonary vascular permeability in aquaporin-1-null humans

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • S.M. Danilov

    Lung is the target organ for a monoclonal antibody to angiotensin-converting enzyme

    Lab. Invest.

    (1991)
  • J.M. Strum et al.

    Radioautographic demonstration of 5-hydroxytryptamine-3H uptake by pulmonary endothelial cells

    J. Cell Biol.

    (1972)
  • Cited by (0)

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