Download PDF
Semin Thromb Hemost 2003; 29(5): 489-498
DOI: 10.1055/s-2003-44557
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Tumor Microenvironment and Hemorheological Abnormalities

Gianfranco Baronzio1 , Isabel Freitas2 , Hau C. Kwaan3
  • 1Physician, Family Medicine Area, ASl 1 Legnano, Milano, Italy
  • 2Professor of Cell Biology, Department of Animal Biology and CNR Institute of Molecular Genetics, University of Pavia, Pavia, Italy
  • 3Professor, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Further Information

Publication History

Publication Date:
21 November 2003 (online)

    Permissions and Reprints

ABSTRACT

This article reviews the various mechanisms in a malignant tumor that lead to hypoxia, production of tumor interstitial fluid, and rheological changes in its microenvironment. In addition, the associated procoagulant effects are described. The latter phenomenon is the result of complex and dynamic interplay among tumor cells, endothelial cells, circulating blood cells, and angiogenic, clotting, and hemorheological factors. The implications of these abnormalities on therapeutic approach are discussed.

KEYWORDS

Hypoxia - tumor interstitial fluid - VEGF - thrombosis - hemorheology

REFERENCES

  • 1 Guppy M. The hypoxic core: a possible answer to the cancer paradox.  Biochem Biophys Res Commun . 2002;  299 676-680
    CrossrefPubMedSearch in Google Scholar
  • 2 Freitas I, Baronzio G F. Tumor hypoxia, reoxygenation and oxygenation strategies: possible role in photodynamic therapy.  J Photochem Photobiol B . 1991;  11 3-30
    CrossrefPubMedSearch in Google Scholar
  • 3 Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply and metabolic microenvironment of human tumors, a review.  Cancer Res . 1989;  49 6449-6465
    PubMedSearch in Google Scholar
  • 4 Risau W. Mechanisms of angiogenesis.  Nature . 1997;  386 671-674
    CrossrefPubMedSearch in Google Scholar
  • 5 Denko N C, Giaccia A J. Tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and metastasis.  Cancer Res . 2001;  61 795-798
    PubMedSearch in Google Scholar
  • 6 Hlatky L, Hahnfeldt P, Tsionou C. et al . Vascular endothelial growth factor: environmental controls and effects in angiogenesis.  Br J Cancer . 1996 (suppl XII);  s151-s156
    PubMedSearch in Google Scholar
  • 7 Grunstein J, Roberts W G, Mathieu-Costello O. et al . Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function.  Cancer Res . 1999;  59 1592-1598
    PubMedSearch in Google Scholar
  • 8 Shweiki D, Itin A, Soffer D. et al . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.  Nature . 1992;  59 843-845
    PubMedSearch in Google Scholar
  • 9 Pepper M S. Lymphangiogenesis and tumor metastasis: myth or reality?.  Clin Cancer Res . 2001;  7 462-468
    PubMedSearch in Google Scholar
  • 10 Nagy J A, Vasile E, Feng D. et al . Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis.  J Exp Med . 2002;  196 1497-1506
    CrossrefPubMedSearch in Google Scholar
  • 11 Shurin M R, Lu L, Kalinsky P. et al . TH1/TH2 in cancer, transplantation and pregnancy.  Semin Immunopathol . 1999;  21 339-359
    PubMedSearch in Google Scholar
  • 12 Vaupel P. Tumor blood flow. In: Molls M, Vaupel P, eds. Blood Perfusion and Microenvironment of Human Tumors Berlin: Springer-Verlag; 2000: 41-46
    Search in Google Scholar
  • 13 Vaupel P. The influence of tumor blood flow and microenvironmental factors on the efficacy of radiation, drugs and localized hyperthermia.  Klin Pädiatr . 1997;  209 243-249
    PubMedSearch in Google Scholar
  • 14 Griffiths J R, McIntyre D J, Howe F A, Stubbs M. Why are cancers acidic? A carrier mediated diffusion model for H+ transport in the interstitial fluid. In: Goodie JA, Chadwick DJ, eds. The Tumor Microenvironment: Causes and Consequences of Hypoxia and Acidity. Novartis Foundation Symposium 2001. New York: John Wiley; 2001: 46-67
    Search in Google Scholar
  • 15 Asby B S, Cantab M B. pH studies in human malignant tumors.  Lancet . 1996;  2 312-315
    PubMedSearch in Google Scholar
  • 16 Neufeld G, Kessler O, Vadasz Z, Gluzman-Poltora K Z. The contribution of proangiogenic factors to the progression of malignant disease.  Surg Oncol Clin N Am . 2001;  10 339-356
    PubMedSearch in Google Scholar
  • 17 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med . 1971;  285 1182l-1186
    PubMedSearch in Google Scholar
  • 18 Zhong H, De Marzo M A, Laughner E. et al . Overexpression of hypoxia-inducible factor 1α in common human cancer and their metastases.  Cancer Res . 1999;  59 5830-5835
    PubMedSearch in Google Scholar
  • 19 Minet E, Mottet D, Roland I. et al . Hypoxia-induced activation of HIF-1: role of HIF-1 alpha-Hsp 90 interaction.  FEBS Lett . 1999;  460 251-256
    CrossrefPubMedSearch in Google Scholar
  • 20 Shweiki D, Itin A, Soffer D. et al . Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.  Nature . 1992;  359 843-845
    CrossrefPubMedSearch in Google Scholar
  • 21 Semenza G L. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology.  Trends Mol Med . 2001;  7 345-350
    CrossrefPubMedSearch in Google Scholar
  • 22 Dachs G U, Tozer G M. Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation.  Eur J Cancer . 2000;  36 1649-1660
    CrossrefPubMedSearch in Google Scholar
  • 23 Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications.  Semin Oncol . 2002;  29 (suppl 16) 10-14
    PubMedSearch in Google Scholar
  • 24 Dvorak H F, Nagy J A, Feng D, Brown L F, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis.  Curr Top Microbiol Immunol . 1999;  237 97-132
    PubMedSearch in Google Scholar
  • 25 Konerding M A, Malkusch W, Klaptor B. et al . Evidence for characteristic vascular patterns in solid tumors: quantitative studies using corrosion casts.  Br J Cancer . 1999;  80 724-732
    CrossrefPubMedSearch in Google Scholar
  • 26 Konerding M A, Steiberg F, van Ackern C. et al . Vascular patterns of tumors: Scanning and transmission electron microscopic studies on human xenografts.  Strahlenther Onkol . 1992;  168 444-452
    PubMedSearch in Google Scholar
  • 27 Gullino P M. The internal milieu of tumors.  Prog Exp Tumor Res . 1966;  8 1-25
    PubMedSearch in Google Scholar
  • 28 Gullino P M. Extracellular compartments of solid tumors. In: Beckert FB, ed. Cancer, a Comprehensive Treatise Vol. 3, Biology of Tumors: Cellular Biology and Growth. New York: Plenum 1975: 327-354
    Search in Google Scholar
  • 29 Dvorak H F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy.  J Clin Oncol . 2002;  20 4368-4380
    CrossrefPubMedSearch in Google Scholar
  • 30 Feng D, Nagy J A, Pyne K. et al . Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators.  Microcirculation . 1999;  6 23-44
    CrossrefPubMedSearch in Google Scholar
  • 31 Nagy J A, Brown L F, Senger D R. et al . Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition.  Biochim Biophys Acta . 1989;  948 305-326
    PubMedSearch in Google Scholar
  • 32 Freitas I, Baronzio G F, Bono B. et al . Tumor interstitial fluid: misconsidered component of the internal milieu of a solid tumor.  Anticancer Res . 1997;  17 165-172
    PubMedSearch in Google Scholar
  • 33 Jain R K. Determinants of tumor blood flow: A review.  Cancer Res . 1988;  48 2641-2658
    PubMedSearch in Google Scholar
  • 34 Baronzio G F, Galante F, Gramaglia A. et al . Tumor microcirculation and its significance in therapy: possible role of omega-3 fatty acids as rheological modifiers.  Med Hypotheses . 1998;  50 175-182
    PubMedSearch in Google Scholar
  • 35 Tamsmaa J T, Keizer H J, Meinders A E. Pathogenesis of malignant ascites: Starlings law of capillary hemodynamics revisited.  Ann Oncol . 2001;  12 1353-1357
    CrossrefPubMedSearch in Google Scholar
  • 36 Renkin E. Some consequences of capillary permeability to macromolecules: Starling's hypothesis reconsidered.  Am J Physiol . 1986;  250 H706-H710
    PubMedSearch in Google Scholar
  • 37 Bates D O, Hillman N J, Williams B. et al . Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure.  Cancer Res . 1989;  49 3506-3512
    PubMedSearch in Google Scholar
  • 38 Sevick E M, Jain R. Viscous resistance to blood flow in solid tumors: effect of hematocrit and intratumor viscosity.  Cancer Res . 1989;  49 3513-3519
    PubMedSearch in Google Scholar
  • 39 Freitas I, Baronzio G F, Bertone V. et al . Stroma formation in Ehrlich carcinoma. I. Oedema phase. A mitosis burst as an index of physiological reoxygenation?.  Anticancer Res . 1991;  11 569-578
    PubMedSearch in Google Scholar
  • 40 Freitas I, Bono B, Bertone V. et al . Characterization of the metabolism of perinecrotic cells in solid tumors by enzyme histochemistry.  Anticancer Res . 1996;  16 1491-1502
    PubMedSearch in Google Scholar
  • 41 Cicala C, Cirino G. Linkage between inflammation and coagulation: an update on the molecular basis of the crosstalk.  Life Sci . 1998;  62 1817-1824
    CrossrefPubMedSearch in Google Scholar
  • 42 Sylven B, Bois I. Protein content and enzymatic assays of interstitial fluid from some normal tissues and transplanted mouse tumors.  Cancer Res . 1960;  20 831-834
    PubMedSearch in Google Scholar
  • 43 Vaupel P, Hockel M. Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance.  Int J Oncol . 2000;  17 869-879
    CrossrefPubMedSearch in Google Scholar
  • 44 Boucher Y, Kirkwood J M, Opacic D, Desantis M, Jain R K. Interstitial hypertension in superficial metastatic melanomas in humans.  Cancer Res . 1991;  51 6691-6694
    PubMedSearch in Google Scholar
  • 45 Boucher Y, Jain R K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse.  Cancer Res . 1992;  52 5110-5114
    PubMedSearch in Google Scholar
  • 46 Jain R K. Vascular and interstitial barriers to delivery of therapeutic agents in tumors.  Cancer Metastasis Rev . 1990;  9 253-266
    CrossrefPubMedSearch in Google Scholar
  • 47 Jain R K. Therapeutic implications of tumor physiology.  Curr Opin Oncol . 1991;  3 1105-1108
    PubMedSearch in Google Scholar
  • 48 Stoher E A, Boucher Y, Stangasinger M, Jain R. Oncotic pressure in solid tumors is elevated.  Cancer Res . 2000;  60 4251-4255
    PubMedSearch in Google Scholar
  • 49 Wiig H, Aukland K, Tenstad O. Isolation of interstitial fluid from rat mammary tumors by a centrifugation method.  Am J Physiol Heart Circ Physiol . 2003;  284 H416-H424
    PubMedSearch in Google Scholar
  • 50 Baronzio G, Freitas I, Griffini P. et al . Omega-3 fatty acids can improve radioresponse modifying tumor interstitial pressure, blood rheology and membrane peroxidability.  Anticancer Res . 1994;  14 1145-1154
    PubMedSearch in Google Scholar
  • 51 Stoltz J F, Singh M, Riha P. Microrheological parameters. In: Stoltz JF, Singh M, Riha P, eds. Hemorheology in Practice Amsterdam: IOS Press 1999: 27-53
    Search in Google Scholar
  • 52 Yan S-F, Mackman N, Kisiel W. et al . Hypoxia/hypoemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis.  Artherioscler Thromb Vasc Biol . 1999;  1 2029-2035
    PubMedSearch in Google Scholar
  • 53 Browder T, Folkman J, Pirie-Sheperd S. The hemostatic system as regulator of angiogenesis.  J Biochem . 2000;  275 1521-1524
    CrossrefPubMedSearch in Google Scholar
  • 54 Fernandez P M, Rickles F. Tissue factor and angiogenesis in cancer.  Curr Opin Hematol . 2002;  9 401-406
    CrossrefPubMedSearch in Google Scholar
  • 55 Ruf W, Mueller B. Tissue factor in cancer angiogenesis and metastasis.  Curr Opin Hematol . 1996;  3 379-384
    CrossrefPubMedSearch in Google Scholar
  • 56 Verheul H M, Hoekman K, Lupu F, van der Valk P, Brotterman H J. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.  Clin Cancer Res . 2000;  6 166-170
    PubMedSearch in Google Scholar
  • 57 Verheul H M, Jorna A S, Hoekman K. et al . Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets.  Blood . 2000;  96 4216-4221
    PubMedSearch in Google Scholar
  • 58 Sahni A, Francis C W. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation.  Blood . 2000;  96 3772-3778
    PubMedSearch in Google Scholar
  • 59 Lee T-H, Avraham H, Lee S H. et al . Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells.  J Biol Chem . 2002;  277 10445-10451
    CrossrefPubMedSearch in Google Scholar
  • 60 Kadambi A, Moutacarreira C, Cook Y. et al . Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A.  Cancer Res . 2001;  61 2404-2408
    PubMedSearch in Google Scholar
  • 61 Heil M, Clauss M, Suzuki K. et al . Vascular endothelial growth factor-VEGF stimulates monocytes migration through endothelial monolayers via increased integrin expression.  Eur J Cell Biol . 2000;  79 850-857
    PubMedSearch in Google Scholar
  • 62 Griffioen A W, Tromp S C, Hillen H FP. Angiogenesis modulates the tumor immune response.  Int J Exp Pathol . 1998;  79 363-368
    CrossrefPubMedSearch in Google Scholar
  • 63 Koehne P, Strauss W, Schindler S E. et al . Lack of hypoxic stimulation of VEGF secretion from neutrophils and platelets.  Am J Physiol Heart Circ Physiol . 2000;  279 H817-824
    PubMedSearch in Google Scholar
  • 64 Michiels C, Arnould T, Remacle J. Endothelial cell response to hypoxia: initiation of a cascade of cellular interactions.  Biochim Biophys Acta . 2000;  1497 1-10
    PubMedSearch in Google Scholar
  • 65 Salven P, Orfana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor.  Clin Cancer Res . 1999;  5 487-491
    PubMedSearch in Google Scholar
  • 66 Tietjen G W, Chien S, Scholz P. et al . Changes in blood viscosity and plasma proteins in carcinoma.  J Surg Oncol . 1977;  9 53-59
    PubMedSearch in Google Scholar
  • 67 von Tempelhoff F G, Heilman L, Hommel G. et al . Hyperviscosity syndrome in patients with ovarian carcinoma.  Cancer . 1998;  82 1104-1111
    CrossrefPubMedSearch in Google Scholar
  • 68 Kwaan H, Gordon L. Thrombotic microangiopathy in the cancer patient.  Acta Haematol . 2001;  106 52-56
    CrossrefPubMedSearch in Google Scholar
  • 69 Takakura N, Watanabe T, Suenobu S. et al . A role for hematopoietic stem cells in promoting angiogenesis.  Cell . 2000;  102 199-209
    CrossrefPubMedSearch in Google Scholar
  • 70 Lyden D, Hattori K, Dias S. et al . Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.  Nature Med . 2001;  7 1194-1201
    CrossrefPubMedSearch in Google Scholar
  • 71 Cines D B, Pollack E S, Buck C A. et al . Endothelial cells in physiology and in pathophysiology of vascular disorders.  Blood . 1998;  91 3527-3561
    PubMedSearch in Google Scholar
  • 72 Santos M T, Valles J, Aznar J. Cell-cell interaction in thrombosis: modulation of platelet function and possibilities of pharmacological control with aspirin.  Turk J Haematol . 2002;  19 103-111
    PubMedSearch in Google Scholar
  • 73 Karmali R A. Eicosanoids in neoplasia.  Prev Med . 1987;  16 493-502
    CrossrefPubMedSearch in Google Scholar
  • 74 Bockman R S. Prostaglandins in cancer: a review.  Cancer Invest . 1983;  1 485-493
    PubMedSearch in Google Scholar
  • 75 Ten V S, Pinsky D. Endothelial response to hypoxia: physiological adaptation and pathologic dysfunction.  Curr Opin Crit Care . 2002;  8 242-250
    CrossrefPubMedSearch in Google Scholar
  • 76 Gorski D H, Beckett M A, Jaskowiak N T. et al . Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation.  Cancer Res . 1999;  59 3374-3378
    PubMedSearch in Google Scholar
  • 77 Geng L, Donnelly E, McMahon G. et al . Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy.  Cancer Res . 2001;  61 2413-2418
    PubMedSearch in Google Scholar
  • 78 Pietras K, Ostman A, Sjoquist M. et al . Inhibition of platelet-derived growth factor reduces interstitial hypertension and increases transcapillary transport in tumors.  Cancer Res . 2001;  61 2929-2934
    PubMedSearch in Google Scholar
  • 79 Teicher B A, Holden S A, Ara G. et al . Influence of antiangiogenic treatment on 9L gliosarcoma: oxygenation and response to cytotoxic therapy.  Int J Cancer . 1995;  61 732-737
    PubMedSearch in Google Scholar
  • 80 Roca C, Primo L. Hyperthermia and angiogenesis: results and perspectives. In: Barongio GF, ed. Hyperthermia in Cancer Treatment: Locoregional Radiofrequency Hyperthermia, Interstitial and Perfusional Hyperthermia Georgetown, TX: Landes Bioscience Publisher; 2004; (in press)
  • 81 Schmitt O, Schubert C, Feyerabend T. et al . Preferential topography of proteins regulating vascularization and apoptosis in a MX1 xenotrasplant after treatment with hypoxia, hyperthermia, isofosfamide, and irradiation.  Am J Clin Oncol . 2002;  25 325-336
    CrossrefPubMedSearch in Google Scholar