Abstract
Perfusion and oxygenation of experimental tumours were studied during angiotensin II (AT II) administration whereby the rate of the continuous AT II infusion was chosen to increase the mean arterial blood pressure (MABP) by 50–70 mmHg. In subcutaneous DS- sarcomas the red blood cell (RBC) flux was assessed using the laser Doppler technique and the mean tumour oxygen partial pressure (pO2) was measured polarographically using O2-sensitive catheter and needle electrodes. Changes in RBC flux with increasing MABP depended mainly on tumour size. In small tumours, RBC flux decreased with rising MABP whereas in larger tumours RBC flux increased parallel to the MABP. As a result of these volume-dependent effects on tumour blood flow, the impact of AT II on tumour pO2 was also mainly tumour volume-related. In small tumours oxygenation decreased with increasing MABP during AT II infusion, whereas in large tumours a positive relationship between blood pressure and O2 status was found. This disparate behaviour might be the result of the co-existence of two functionally distinct populations of tumour vessels. In small tumours, perfusion decreases presumably due to vasoconstriction of pre-existing host vessels feeding the tumour. In larger malignancies, newly formed tumour vessels predominate and seem not to have this vasoresponsive capability (lack of smooth muscle cells and/or AT receptors), resulting in an improvement of perfusion which is not tumour-related per se, but is due to the increased perfusion pressure. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Andrade SP and Beraldo WT (1998) Pharmacological reactivity of neoplastic and non-neoplastic associated neovasculature to vasoconstrictors. Int J Exp Pathol 79: 425–432
Braun RD, Lanzen JL and Dewhirst MW (2000) Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol 277: H551–H568
Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR and Dewhirst MW (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56: 941–943
Bush RS, Jenkin RDT, Allt WEC, Beale FA, Dembo AJ and Pringle JF (1978) Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer 37: 302–306
Cater DB, Grigson CMB and Watkinson DA (1962) Changes of oxygen tension in tumours induced by vasoconstrictor and vasodilator drugs. Acta Radiol 58: 401–436
Chaplin DJ and Hill SA (1995) Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumours. Br J Cancer 71: 1210–1213
Day ED (1964) Vascular relationships of tumor and host. Prog Exp Tumor Res 4: 57–97
Dewhirst MW, Braun RD and Lanzen JL (1998) Temporal changes in PO2of R3230AC tumors in Fischer-344 rats. Int J Radiat Oncol Biol Phys 42: 723–726
Dworkin MJ, Carnochan P and Allen-Mersh TG (1995) Nitric oxide inhibition sustains vasopressin-induced vasoconstriction. Br J Cancer 71: 942–944
Dworkin MJ, Carnochan P and Allen-Mersh TG (1997) Effect of continuous regional vasoactive agent infusion on liver metastasis blood flow. Br J Cancer 76: 1205–1210
Freitas I and Baronzio GF (1991) Tumor hypoxia, reoxygenation and oxygenation strategies: Possible role in photodynamic therapy. J Photochem Photobiol 11: 3–30
Giaccia AJ (1996) Hypoxic stress proteins: survival of the fittest. Seminars in Radiation Oncology 6: 46–58
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379: 88–91
Gulledge CJ and Dewhirst MW (1996) Tumor oxygenation: A matter of supply and demand. Anticancer Res 16: 741–750
Gullino PM and Grantham FH (1961) Studies on the exchange of fluids between host and tumor. II. The blood flow of hepatomas and other tumors in rats and mice. J Natl Cancer Inst 27: 1465–1491
Hall EJ (1994). Radiobiology for the Radiologist, Lippincott: Philadelphia
Hemingway DM, Angerson WJ, Anderson JH, Goldberg JA, McArdle CS and Cooke TG (1992) Monitoring blood flow to colorectal liver metastases using laser Doppler flowmetry: the effect of angiotensin II. Br J Cancer 66: 958–960
Hirst DG (1989) Tumor blood flow modification therapeutic benefit: is this approach ready for clinical application? Review. Gray Laboratory 1989 Annual Report, Michael B, Hance M (eds) pp 14–17, Cancer Research Campaign: London
Hirst DG, Hirst VK, Shaffi KM, Prise VE and Joiner B (1991) The influence of vasoactive agents on the perfusion of tumours growing in three sites in the mouse. Int J Radiat Biol 60: 211–218
Höckel M, Knoop C, Schlenger K, Vomdran B, Baussmann E, Mitze M, Knapstein PG and Vaupel P (1993) Intratumoral pO2predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50
Höckel M, Schlenger K, Aral B, Mitze M, Schäffer U and Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515
Hori K, Suzuki M, Abe I, Saito S and Sato H (1985) Increase in tumor vascular area due to increased blood flow by angiotensin II in rats. J Natl Cancer Inst 74: 453–459
Hori K, Zhang QH, Saito S, Tanda S, Li HC and Suzuki M (1993) Microvascular mechanisms of change in tumor blood flow due to angiotensin II, epinephrine, and methoxamine: a functional morphometric study. Cancer Res 53: 5528–5534
Horsman MR (1993) Hypoxia in tumours: its relevance, identification, and modification. Medical Radiology. Current topics in clinical radiobiology, Beck-Bomholdt HP99–112, Springer: Berlin
Jain RK Ward-Hartley (1984) Tumor blood flow – characterization, modifications, and role of hyperthermia. IEEE Trans Son Ultrason SU-31: 504–526
Jirtle RL (1988) Chemical modification of tumour blood flow. Int J Hyperthermia 4: 355–371
Jirtle R, Clifton KH and Rankin JH (1978) Effects of several vasoactive drugs on the vascular resistance of MT-W9B tumors in W/Fu rats. Cancer Res 38: 2385–2390
Kelleher DK, Engel T and Vaupel PW (1995) Changes in microregional perfusion, oxygenation, ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A hyperthermia. Int J Hyperthermia 11: 241–255
Kelleher DK, Thews O and Vaupel P (1998) Regional perfusion and oxygenation of tumors upon methylxanthine derivative administration. Int J Radiat Oncol Biol Phys 42: 861–864
Kennovin GD, Flitney FW and Hirst DG (1994) ‘Upstream’ modification of vasoconstrictor responses in rat epigastric artery supplying an implanted tumour. Adv Exp Med Biol 345: 411–416
Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D and Hong K Dewhirst-MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56: 5522–5528
Kohzuki M, Tanda S, Hori K, Yoshida K, Kamimoto M, Wu XM and Sato T (1998) Endothelin receptors and angiotensin II receptors in tumor tissue. J Cardiovasc Pharmacol 31: S531–S533
Konerding MA, Steinberg F and Budach V 1989 a) The vascular system of xenotransplanted tumors – scanning electron and light microscopic studies. Scanning Microsc 3: 327–335
Konerding MA, Steinberg F and Streffer C 1989 b) The vasculature of xenotransplanted human melanomas and sarcomas on nude mice. I. Vascular corrosion casting studies. Acta Anat (Basel) 136: 21–26
Konerding MA, Steinberg F and Streffer C 1989 c) The vasculature of xenotransplanted human melanomas and sarcomas on nude mice. II. Scanning and transmission electron microscopic studies. Acta Anat (Basel) 136: 27–33
Konerding MA, Miodonski AJ and Lametschwandtner A (1995) Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc 9: 1233–1243
Mattsson J, Alpsten M, Appelgren L and Peterson HI (1980) Influence of noradrenaline on local tumor blood flow. Eur J Cancer 16: 99–102
Mattsson J, Appelgren L, Hamberger B and Peterson HI (1979) Tumor vessel innervation and influence of vasoactive drugs on tumor blood flow. Tumor Blood Circulation, Peterson HI (ed) pp 129–135, CRC Press: Boca Raton
Netti PA, Hamberg LM, Babich JW, Kierstead D, Graham W, Hunter GJ, Wolf GL, Fischman A, Boucher Y and Jain RK (2000) Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci USA 96: 3137–3142
Nordsmark M, Overgaard M and Overgaard J (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41: 31–39
Peterson HI (1983) Innervation von Tumorgefässen, Einfluss vasoaktiver Substanzen und Regulation der Tumordurchblutung. Mikrozirk Forsch Klin 2: 69–77
Peterson HI (1991) Modification of tumour blood flow – a review. Int J Radiat Biol 60: 201–210
Powell ME, Hill SA, Saunders MI, Hoskin PJ and Chaplin DJ (1997) Human tumor blood flow is enhanced by nicotinamide and carbogen breathing. Cancer Res 57: 5261–5264
Reinhold HS (1979) in vivo observations of tumor blood flow. Tumor Blood Circulation, Peterson HI (ed) pp 115–128, CRC Press: Boca Raton
Shan SQ, Rosner GL, Braun RD, Hahn J, Pearce C and Dewhirst MW (1997) Effects of diethylamine/nitric oxide on blood perfusion and oxygenation in the R3230Ac mammary carcinoma. Br J Cancer 76: 429–437
Shankar A, Loizidou M, Bumstock G and Taylor I (2000) Noradrenaline improves the tumour to normal blood flow ratio and drug delivery in a model of liver metastases. Br J Surg 86: 453–457
Suzuki M, Hori K, Abe I, Saito S and Sato H (1981) A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J Natl Cancer Inst 67: 663–669
Suzuki M, Hori K, Abe I, Saito S and Sato H (1982) Selective increase in tumor oxygen tension with angiotensin II. Invasion Metastasis 2: 33–39
Suzuki M, Hori K, Abe I, Saito S and Sato H (1984) Functional characterization of the microcirculation in tumors. Cancer Metastasis Rev 3: 115–126
Tokuda K, Abe H, Aida T, Sugimoto S and Kaneko S (1990) Modification of tumor blood flow and enhancement of therapeutic effect of ACNU on experimental rat gliomas with angiotensin II. J Neurooncol 8: 205–212
Tozer GM and Shaffi KM (1993) Modification of tumour blood flow using the hypertensive agent angiotensin II. Br J Cancer 67: 981–988
Tozer GM and Shaffi KM (1995) The response of tumour vasculature to angiotensin II revealed by its systemic and local administration to “tissue-isolated” tumours. Br J Cancer 72: 595–600
Tozer GM, Shaffi KM, Prise VE and Bell KM (1996) Spatial heterogeneity of tumour blood flow modification induced by angiotensin II: Relationship to receptor distribution. Int J Cancer 65: 658–663
Trotter MJ, Chaplin DJ and Olive PL (1991) Effect of angiotensin II on intermittent tumour blood flow and acute hypoxia in the murine SCCVII carcinoma. Eur J Cancer 27: 887–893
UKCCCR (1998) United Kingdom Co-ordinating Committee on Cancer Research guidelines for the welfare of animals in experimental neoplasia (2nd edn). Br J Cancer 77: 1–10
Vaupel PW (1993) Oxygenation of solid tumors. Drug Resistance in Oncology, Teicher BA (ed) pp 53–85, Marcel Dekker: New York
Vaupel P, Kelleher DK, Thews O and Hummel M (2000) Tumour blood flow: critical issues and modification. In: Moriarty M, Mothersill C, Seymour C, Edington M, Ward JF, Fry RJM (eds)Radiation Research, Vol. 2 (Proceedings, 11th International Congress on Radiation Research), Allen Press: Lawrence
Vaupel P and Gabbert H (1986) Evidence for and against a tumor type-specific vascularity. Strahlenther Onkol 162: 633–638
Vaupel P and Mueller-Klieser W (1986) Cell line and growth site as relevant parameters governing tumor tissue oxygenation. Adv Exp Med Biol 200: 633–643
Vaupel P, Kallinowski F and Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465
Vaupel P, Kelleher DK and Thews O (1998) Modulation of tumor oxygenation. Int J Radiat Oncol Biol Phys 42: 843–848
Vaupel P, Schlenger K, Knoop C and Höckel M (1991) Oxygenation of human tumors: Evaluation of tissue oxygen distribution in breast cancers by computerized O2tension measurements. Cancer Res 51: 3316–3322
Warren BA (1979) The vascular morphology of tumors. In Tumor Blood Circulation, Peterson HI (ed) pp 1–47, CRC Press: Boca Raton
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Thews, O., Kelleher, D. & Vaupel, P. Disparate responses of tumour vessels to angiotensin II: tumour volume-dependent effects on perfusion and oxygenation. Br J Cancer 83, 225–231 (2000). https://doi.org/10.1054/bjoc.2000.1229
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.2000.1229
Keywords
This article is cited by
-
Activation of P-glycoprotein (Pgp)-mediated drug efflux by extracellular acidosis: in vivo imaging with 68Ga-labelled PET tracer
European Journal of Nuclear Medicine and Molecular Imaging (2010)
