Abstract
The therapy of solid tumors with conventional chemotherapeutics, drug delivery preparations and immuno-modulatory agents directed against the tumor cells is corrupted by a major barrier presented by the tumor vasculature. Permeability of the tumor blood vessels for transport of small molecules and macromolecular drug-carrier conjugates is only sufficient in the blood vessels at the tumor-host interface. Downregulation of the expression of adhesion molecules, required for the facilitation of immune cell recruitment, by the tumor vascular endothelium results in an escape of the tumor from host defence. New therapeutic approaches for the treatment of solid tumors are aimed at the tumor vasculature, either at the endothelial cells themselves or at basement membrane or tumor stroma components. Angiogenesis can be directly blocked with angiogenesis inhibitors, while angiogenesis related factors can serve as tumor vasculature specific epitopes for drug delivery strategies. Some glycoproteins expressed by tumor endothelial cells or present in the basement membrane and tumor stroma are also potential tumor selective targets. Therapeutic modalities that are suitable for site specific delivery are agents that increase tumor accumulation of (targeted) chemo/radiotherapeutics through increasing tumor vascular permeability. The observation that for tumor growth the blood supply is a limiting factor, led to the development of strategies to inhibit angiogenesis or block the tumor blood flow. Manipulation of the expression of endothelial cell adhesion molecules by selectively delivering modulatory agents at or in the tumor vascular endothelial cells may induce (bispecific antibody mediated) host defense activity directed against the tumor cells.
Similar content being viewed by others
REFERENCES
G. Molema and D. K. F. Meijer. Targeting of drugs to various blood cell types using (neo-) glycoproteins, antibodies and other protein carriers. Adv Drug Deliv Rev 14:25–50 (1994).
D. K. F. Meijer and G. Molema. Targeting of drugs to the liver. Seminars in liver disease 15:202–256 (1995).
R. Duncan. Drug-polymer conjugates: potential for improved chemotherapy. Anticancer Drugs 3:175–210 (1992).
C. W. Mitchell. Histology, cell and tissue biology. Elsevier Science Publishing Co., Inc. Baltimore, Munchen. 1983; pp. 355–400.
L. M. Li, G. L. Nicolson, and I. J. Fidler. Direct in vitro lysis of metastatic tumor cells by cytokine-activated murine vascular endothelial cells. Cancer Res 51:245–254 (1991).
J. R. Westphal, H. W. Willems, D. J. Ruiter, and R. M. De Waal. Involvement of LFA-1/ICAM and CD2/LFA-3 in human endothelial cell accessory function. Behring Inst Mitt:51–62 (1993).
H. Lum and A. B. Malik. Regulation of vascular endothelial barrier function. Am J Physiol 267:L223–41 (1994).
L. W. Seymour. Passive tumor targeting of soluble macromolecules and drug conjugates. Critical Reviews in Therapeutic Drug Carrier Systems 9:135–187 (1992).
N. Simionescu. Cellular aspects of transcapillary exchange. Physiol Rev 63:1536–1579 (1983).
R. D. Broadwell. Transcytosis of macromolecules through the blood-brain fluid barriers in vivo. In K. L. Audus, T. J. Raub (eds). Biological barriers to protein delivery. Plenum Press, New York. 1993; pp. 269–96.
K. R. Smith and R. T. Borchardt. Permeability and mechanism of albumin, cationized albumin, and glycosylated albumin transcellular transport across monolayers of cultured bovine brain capillary endothelial cells. Pharm Res 6:466–473 (1989).
M. J. Kim, J. Dawes, and W. Jessup. Transendothelial transport of modified low-density lipoproteins. Atherosclerosis 108:5–17 (1994).
N. Simionescu and M. Simionescu. Receptor-mediated transcytosis of albumin: identification of albumin binding proteins in the plasma membrane of capillary endothelium. In M. Tsuchiya (ed). Microcirculation-an update. Elsevier Science Publishers B. V. (Biomedical Division), 1987, pp. 67–82.
N. Ghinea, M. Thu Vu Hai, M. Groyer-Picard, and E. Milgrom. How protein hormones reach their target cells. Receptor-mediated transcytosis of hCG through endothelium. Journal Cell Biol 125:87–97 (1994).
E. Omoto, J. J. Minguell, and M. Tavassoli. Endothelial transcytosis of iron-transferrin in the liver does not involve endosomal traffic. Pathobiology 60:284–288 (1992).
T. A. Springer. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314 (1994).
S. Ratner. Lymphocyte migration through extracellular matrix. Invasion Metastasis 12:82–100 (1992).
N. Oppenheimer-Marks, L. S. Davis, and P. E. Lipsky. Human T lymphocyte adhesion to endothelial cells and transendothelial migration. Alteration of receptor use relates to the activation status of both the T cell and the endothelial cell. J Immunol 145:140–148 (1990).
J. Folkman. Tumor angiogenesis: a possible control point in tumor growth. Ann Intern Med 82:96–100 (1975).
J. Denekamp. Vasculature as a target for tumour therapy. Prog Appl Microcirc 4:28–38 (1984).
C. T. Baillie, M. C. Winslet, and N. J. Bradley. Tumour vasculature-a potential therapeutic target. Br J Cancer 72:257–267 (1995).
T. P. Fan, R. Jaggar, and R. Bicknell. Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci 16:57–66 (1995).
T. M. Sioussat, H. F. Dvorak, T. A. Brock, and D. R. Senger. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch Biochem Biophys 301:15–20 (1993).
M. W. Dewhirst, C. Y. Tso, R. Oliver, C. S. Gustafson, T. W. Secomb, and J. F. Gross. Morphologic and hemodynamic comparison of tumor and healing normal tissue microvasculature. Int J Radiat Oncol Biol Phys 17:91–99 (1989).
R. K. Jain. Transport of molecules across tumor vasculature. Cancer Metastasis Rev 6:559–593 (1987).
S. Schultz Hector and S. Haghayegh. Beta-fibroblast growth factor expression in human and murine squamous cell carcinomas and its relationship to regional endothelial cell proliferation. Cancer Res 53:1444–1449 (1993).
R. K. Jain. 1995 Whitaker Lecture: delivery of molecules, particles and cells to solid tumors. Annals of Biomedical Engineering 24:457–473 (1996).
F. Yuan, M. Dellian, D. Fukumura, M. Leunig, D. A. Berk, V. P. Torchilin, and R. K. Jain. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756 (1995).
H. F. Dvorak, J. A. Nagy, and A. M. Dvorak. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3:77–85 (1991).
N. Z. Wu. Diminished leukocyte-endothelium interaction in tumor microvessels. Cancer Res 52:4265–4268 (1992).
R. J. Melder, G. C. Koenig, B. P. Witwer, N. Safabakhsh, L. L. Munn, and R. K. Jain. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nature Med 2:992–997 (1996).
A. W. Griffioen, C. A. Damen, G. H. Blijham, and G. Groenewegen. Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88:667–673 (1996).
H. Nelson, P. S. Ramsey, J. H. Donohue, and L. E. Wold. Cell adhesion molecule expression within the microvasculature of human colorectal malignancies. Clinical Immunol Immunopathol 72:129–136 (1994).
A. L. Epstein, L. A. Khawli, J. L. Hornick, and C. R. Taylor. Identification of a monoclonal antibody, TV-1, directed against the basement membrane of tumor vessels, and its use to enhance the delivery of macromolecules to tumors after conjugation with interleukin 2. Cancer Res 55:2673–2680 (1995).
P. J. Swart, L. Beljaars, C. Smit, P. Nieuwenhuis, and D. K. F. Meijer. Lymphatic uptake of negatively charged albumins: implications for anti-HIV efficacy and drug delivery. Submitted.
P.N. Lanken, J. H. Hansen-Flaschen, P. M. Sampson, G. G. Pietra, F. R. Haselton, and A. P. Fishman. Passage of unchanged dextrans from blood to lymph in awake sheep. J Appl Physiol 59:580–591 (1985).
R. H. J. Begent, M. J. Verhaar, K. A. Chester, J. L. Casey, A. J. Green, M. P. Napier, L. D. Hope-Stone, N. Cushen, P. A. Keep, C. J. Johnson, et al. Clinical evidence of efficient tumor targeting based on a single-chain Fv antibody selected from a combinatorial library. Nature Med 2:979–984 (1996).
J. Folkman. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416 (1972).
M. S. O'Reilly, L. Holmgren, Y. Shing, C. Chen, R. A. Rosenthal, Y. Cao, M. Moses, W. S. Lane, E. H. Sage, and J. Folkman. Angiostatin: a circulating endothelial cell inhibitor that suppresses angiogenesis and tumor growth. Cold Spring Harb Symp Quant Biol 59:471–482 (1994).
M. S. O'Reilly, L. Holmgren, Y. Shing, C. Chen, R. A. Rosenthal, M. Moses, W. S. Lane, Y. Cao, E. H. Sage, and J. Folkman. Angiostatin: a novel angiogenesis-inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315–328 (1994).
M. S. O'Reilly, H. Brem, and J. Folkman. Treatment of murine hemangioendotheliomas with the angiogenesis inhibitor AGM-1470. J Pediatr Surg 30:325–329 (1995).
M. Asano, A. Yukita, T. Matsumoto, S. Kondo, and H. Suzuki. Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121. Cancer Res 55:5296–5301 (1995).
J. Lu, B. Li, N. Singh, et al. The inhibition of the growth of various solid human tumors with monoclonal antibodies (mAb) to vascular endothelial growth factor (VEGF). Proc American Association for Cancer Research 35:528 (1994).
P. E. Thorpe and F. J. Burrows. Antibody-directed targeting of the vasculature of solid tumors. Breast Cancer Res Treat 36:237–251 (1995).
H. H. Hagemeier, E. Vollmer, S. Goerdt, K. Schulze Osthoff, and C. Sorg. A monoclonal antibody reacting with endothelial cells of budding vessels in tumors and inflammatory tissues, and nonreactive with normal adult tissues. Int J Cancer 38:481–488 (1986).
R. O. Schlingemann, F. J. Rietveld, R. M. De Waal, N. J. Bradley, A. I. Skene, A. J. Davies, M. F. Greaves, J. Denekamp, and D.J. Ruiter. Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal micro-processes in the tumor stroma. Lab Invest 62:690–696 (1990).
W. J. Rettig, P. Garin Chesa, J. H. Healey, S. L. Su, E. A. Jaffe, and L. J. Old. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci USA 89:10832–10836 (1992).
K. Lin, J. A. Nagy, E. M. Masse, et al. Selective accumulation of antibodies to vascular permeability factor in mouse tumors. Proc American Association for Cancer Research 35:510 (1994).
R. M. Reilly, J. Sandhu, T. M. Alvarez Diez, S. Gallinger, J. Kirsh, and H. Stern. Problems of delivery of monoclonal antibodies. Pharmaceutical and pharmacokinetic solutions. Clin Pharmacokinet 28:126–142 (1995).
L. F. Brown, B. Berse, R. W. Jackman, K. Tognazzi, E. J. Manseau, H. F. Dvorak, and D. R. Senger. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 143:1255–1262 (1993).
H. F. Dvorak, L. F. Brown, M. Detmar, and A. M. Dvorak. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039 (1995).
Qu Hong, J. A. Nagy, D. R. Senger, H. F. Dvorak, and A. M. Dvorak. Ultrastructural localization of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) to the abluminal plasma membrane and vesiculovacuolar-organelles of tumor microvascular endothelium. J Histochem Cytochem 43:381–389 (1995).
F. J. Burrows, P. Tazzari, P. Amlot, A. F. Gazdar, E. J. Derbyshire, S. W. King, E. S. Vitetta, and P. E. Thorpe. Endoglin is an endothelial cell proliferation marker that is selectively expressed in tumor vasculature. Clinical Cancer Res 1:1623–1634 (1995).
A. W. Griffioen, C. A. Damen, G. H. Blijham, and G. Groenewegen. Endoglin/CD105 may nor be an optimal tumor endothelial treatment target. Breast Cancer Res Treat 39:239–240 (1996).
P. Garin-Chesa, L. J. Old, and W. J. Rettig. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87:7235–7239 (1990).
K. Kairemo, K. Ljunggren, S. E. Strand, J. Hiltunen, P. Penttila, T. Nikula, A. Laine, and T. Wahlstrom. Radioimmunotherapy with 90Y-labeled monoclonal antibodies in a nude mouse ovarian cancer model. Acta Oncol 32:801–805 (1993).
D. Fukumura, H. A. Salehi, B. Witwer, R. F. Tuma, R. J. Melder, and R. K. Jain. Tumor necrosis factor-a induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site and host strain. Cancer Res 55:4824–4829 (1995).
N. Renard, D. Lienard, L. Lespagnard, A. Eggermont, R. Heimann, and F. Lejeune. Early endothelium activation and polymorphonuclear cell invasion precede specific necrosis of human melanoma and sarcoma treated by intravascular high-dose tumour necrosis factor alpha (rTNFa). Int J Cancer 57:656–663 (1994).
U. D. Staerz, O. Kanagawa, and M. J. Bevan. Hybrid antibodies can target sites for attack by T cells. Nature 314:628–631 (1985).
B. J. Kroesen, W. Helfrich, A. Bakker, A. S. Wubbena, H. Bakker, H. B. Kal, T. H. The, and L. de Leij. Reduction of EGP-2 positive pulmonary metastases by bispecific-antibody-redirected T cells in an immunocompetent rat model. Int J Cancer 61:812–818 (1995).
B. J. Kroesen, J. Buter, D. T. Sleijfer, R. A. J. Janssen, W. T. A. van der Graaf, T. H. The, L. de Leij, and N. H. Mulder. Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2. Br J Cancer 70:652–661 (1994).
F. J. Burrows and P. E. Thorpe. Eradication of large solid tumors in mice with an immunotoxin directed against tumor vasculature. Proc Natl Acad Sci USA 90:8996–9000 (1993).
P. Thorpe, X. Huang, E. Derbyshire, S. King, G. Molema, and T. Edgington. Tumor Infarction: immunoconjugates that coagulate the vasculature of solid tumors. Proc American Association for Cancer Research 36:488 (1995).
X. Huang, G. Molema, S. King, L. Watkins, T. S. Edgington, and P. E. Thorpe. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Accepted for publication in Science.
P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier, and D. A. Cheresh. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164 (1994).
R. R. Evans, T. P. Calmels, B. R. Pitt, M. A. Brookens, C. S. Johnson, R. A. Modzelewski, and J. S. Lazo. Gene therapy and endothelial cell targeting for cancer. Ann N Y Acad Sci 716:257–264 (1994).
R. W. Jansen, G. Molema, R. Pauwels, D. Schols, E. De Clercq, and D. K. F. Meijer. Potent in vitro anti-HIV-1 activity of modified human serum albumins. Mol Pharmacol 39:818–823 (1991).
D. K. F. Meijer, G. Molema, F. Moolenaar, D. De Zeeuw, and P. J. Swart. (Glyco)-protein drug carriers with an intrinsic therapeutic activity: the concept of dual targeting. J Cont Rel 39:163–172 (1996).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Molema, G., de Leij, L.F.M.H. & Meijer, D.K.F. Tumor Vascular Endothelium: Barrier or Target in Tumor Directed Drug Delivery and Immunotherapy. Pharm Res 14, 2–10 (1997). https://doi.org/10.1023/A:1012038930172
Issue Date:
DOI: https://doi.org/10.1023/A:1012038930172