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. 2000 Jun 15;83(2):225–231. doi: 10.1054/bjoc.2000.1229

Disparate responses of tumour vessels to angiotensin II: tumour volume-dependent effects on perfusion and oxygenation

O Thews 1, D K Kelleher 1, P Vaupel 1
PMCID: PMC2363484  PMID: 10901375

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 (p O 2) was measured polarographically using O 2-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 p O 2 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 O 2 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

Keywords: angiotensin II, tumour vasculature, tumour blood flow, tumour perfusion, tumour oxygenation

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Selected References

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  1. Andrade S. P., Beraldo W. T. Pharmacological reactivity of neoplastic and non-neoplastic associated neovasculature to vasoconstrictors. Int J Exp Pathol. 1998 Dec;79(6):425–432. doi: 10.1046/j.1365-2613.1998.00081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Braun R. D., Lanzen J. L., Dewhirst M. W. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol. 1999 Aug;277(2 Pt 2):H551–H568. doi: 10.1152/ajpheart.1999.277.2.H551. [DOI] [PubMed] [Google Scholar]
  3. Brizel D. M., Scully S. P., Harrelson J. M., Layfield L. J., Bean J. M., Prosnitz L. R., Dewhirst M. W. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996 Mar 1;56(5):941–943. [PubMed] [Google Scholar]
  4. Bush R. S., Jenkin R. D., Allt W. E., Beale F. A., Bean H., Dembo A. J., Pringle J. F. Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer Suppl. 1978 Jun;3:302–306. [PMC free article] [PubMed] [Google Scholar]
  5. CATER D. B., GRIGSON C. M., WATKINSON D. A. Changes of oxygen tension in tumours induced by vasoconstrictor and vasodilator drugs. Acta radiol. 1962 Dec;58:401–434. doi: 10.3109/00016926209169582. [DOI] [PubMed] [Google Scholar]
  6. Chaplin D. J., Hill S. A. Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumours. Br J Cancer. 1995 Jun;71(6):1210–1213. doi: 10.1038/bjc.1995.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DAY E. D. VASCULAR RELATIONSHIPS OF TUMOR AND HOST. Prog Exp Tumor Res. 1964;4:57–97. doi: 10.1159/000385974. [DOI] [PubMed] [Google Scholar]
  8. Dewhirst M. W., Braun R. D., Lanzen J. L. Temporal changes in PO2 of R3230AC tumors in Fischer-344 rats. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):723–726. doi: 10.1016/s0360-3016(98)00304-6. [DOI] [PubMed] [Google Scholar]
  9. Dworkin M. J., Carnochan P., Allen-Mersh T. G. Effect of continuous regional vasoactive agent infusion on liver metastasis blood flow. Br J Cancer. 1997;76(9):1205–1210. doi: 10.1038/bjc.1997.534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dworkin M. J., Carnochan P., Allen-Mersh T. G. Nitric oxide inhibition sustains vasopressin-induced vasoconstriction. Br J Cancer. 1995 May;71(5):942–944. doi: 10.1038/bjc.1995.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Freitas I., Baronzio G. F. Tumor hypoxia, reoxygenation and oxygenation strategies: possible role in photodynamic therapy. J Photochem Photobiol B. 1991 Oct;11(1):3–30. doi: 10.1016/1011-1344(91)80264-i. [DOI] [PubMed] [Google Scholar]
  12. GULLINO P. M., GRANTHAM F. H. 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. 1961 Dec;27:1465–1491. [PubMed] [Google Scholar]
  13. Giaccia AJ. Hypoxic Stress Proteins: Survival of the Fittest. Semin Radiat Oncol. 1996 Jan;6(1):46–58. doi: 10.1053/SRAO0060046. [DOI] [PubMed] [Google Scholar]
  14. Graeber T. G., Osmanian C., Jacks T., Housman D. E., Koch C. J., Lowe S. W., Giaccia A. J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996 Jan 4;379(6560):88–91. doi: 10.1038/379088a0. [DOI] [PubMed] [Google Scholar]
  15. Gulledge C. J., Dewhirst M. W. Tumor oxygenation: a matter of supply and demand. Anticancer Res. 1996 Mar-Apr;16(2):741–749. [PubMed] [Google Scholar]
  16. Hirst D. G., Hirst V. K., Shaffi K. M., Prise V. E., Joiner B. The influence of vasoactive agents on the perfusion of tumours growing in three sites in the mouse. Int J Radiat Biol. 1991 Jul-Aug;60(1-2):211–218. doi: 10.1080/09553009114551861. [DOI] [PubMed] [Google Scholar]
  17. Hockel M., Schlenger K., Aral B., Mitze M., Schaffer U., Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996 Oct 1;56(19):4509–4515. [PubMed] [Google Scholar]
  18. Hori K., Suzuki M., Abe I., Saito S., Sato H. Increase in tumor vascular area due to increased blood flow by angiotensin II in rats. J Natl Cancer Inst. 1985 Feb;74(2):453–459. [PubMed] [Google Scholar]
  19. Hori K., Zhang Q. H., Saito S., Tanda S., Li H. C., Suzuki M. Microvascular mechanisms of change in tumor blood flow due to angiotensin II, epinephrine, and methoxamine: a functional morphometric study. Cancer Res. 1993 Nov 15;53(22):5528–5534. [PubMed] [Google Scholar]
  20. Höckel M., Knoop C., Schlenger K., Vorndran B., Baussmann E., Mitze M., Knapstein P. G., Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993 Jan;26(1):45–50. doi: 10.1016/0167-8140(93)90025-4. [DOI] [PubMed] [Google Scholar]
  21. Jirtle R. L. Chemical modification of tumour blood flow. Int J Hyperthermia. 1988 Jul-Aug;4(4):355–371. doi: 10.3109/02656738809016490. [DOI] [PubMed] [Google Scholar]
  22. Jirtle R., Clifton K. H., Rankin J. H. Effects of several vasoactive drugs on the vascular resistance of MT-W9B tumors in W/Fu rats. Cancer Res. 1978 Aug;38(8):2385–2390. [PubMed] [Google Scholar]
  23. Kelleher D. K., Engel T., Vaupel P. W. Changes in microregional perfusion, oxygenation, ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A hyperthermia. Int J Hyperthermia. 1995 Mar-Apr;11(2):241–255. doi: 10.3109/02656739509022460. [DOI] [PubMed] [Google Scholar]
  24. Kelleher D. K., Thews O., Vaupel P. Regional perfusion and oxygenation of tumors upon methylxanthine derivative administration. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):861–864. doi: 10.1016/s0360-3016(98)00318-6. [DOI] [PubMed] [Google Scholar]
  25. Kennovin G. D., Flitney F. W., Hirst D. G. "Upstream" modification of vasoconstrictor responses in rat epigastric artery supplying an implanted tumour. Adv Exp Med Biol. 1994;345:411–416. doi: 10.1007/978-1-4615-2468-7_54. [DOI] [PubMed] [Google Scholar]
  26. Kimura H., Braun R. D., Ong E. T., Hsu R., Secomb T. W., Papahadjopoulos D., Hong K., Dewhirst M. W. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 1996 Dec 1;56(23):5522–5528. [PubMed] [Google Scholar]
  27. Kohzuki M., Tanda S., Hori K., Yoshida K., Kamimoto M., Wu X. M., Sato T. Endothelin receptors and angiotensin II receptors in tumor tissue. J Cardiovasc Pharmacol. 1998;31 (Suppl 1):S531–S533. doi: 10.1097/00005344-199800001-00153. [DOI] [PubMed] [Google Scholar]
  28. Konerding M. A., Miodonski A. J., Lametschwandtner A. Microvascular corrosion casting in the study of tumor vascularity: a review. Scanning Microsc. 1995;9(4):1233–1244. [PubMed] [Google Scholar]
  29. Konerding M. A., Steinberg F., Budach V. The vascular system of xenotransplanted tumors--scanning electron and light microscopic studies. Scanning Microsc. 1989 Mar;3(1):327–336. [PubMed] [Google Scholar]
  30. Konerding M. A., Steinberg F., Streffer C. The vasculature of xenotransplanted human melanomas and sarcomas on nude mice. I. Vascular corrosion casting studies. Acta Anat (Basel) 1989;136(1):21–26. doi: 10.1159/000146792. [DOI] [PubMed] [Google Scholar]
  31. Konerding M. A., Steinberg F., Streffer C. The vasculature of xenotransplanted human melanomas and sarcomas on nude mice. II. Scanning and transmission electron microscopic studies. Acta Anat (Basel) 1989;136(1):27–33. doi: 10.1159/000146793. [DOI] [PubMed] [Google Scholar]
  32. Mattsson J., Alpsten M., Appelgren L., Peterson H. I. Influence of noradrenaline on local tumour blood flow. Eur J Cancer. 1980 Jan;16(1):99–102. doi: 10.1016/0014-2964(80)90114-0. [DOI] [PubMed] [Google Scholar]
  33. Netti P. A., Hamberg L. M., Babich J. W., Kierstead D., Graham W., Hunter G. J., Wolf G. L., Fischman A., Boucher Y., Jain R. K. Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3137–3142. doi: 10.1073/pnas.96.6.3137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nordsmark M., Overgaard M., Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996 Oct;41(1):31–39. doi: 10.1016/s0167-8140(96)91811-3. [DOI] [PubMed] [Google Scholar]
  35. Peterson H. I. Modification of tumour blood flow--a review. Int J Radiat Biol. 1991 Jul-Aug;60(1-2):201–210. doi: 10.1080/09553009114551851. [DOI] [PubMed] [Google Scholar]
  36. Powell M. E., Hill S. A., Saunders M. I., Hoskin P. J., Chaplin D. J. Human tumor blood flow is enhanced by nicotinamide and carbogen breathing. Cancer Res. 1997 Dec 1;57(23):5261–5264. [PubMed] [Google Scholar]
  37. Shan S. Q., Rosner G. L., Braun R. D., Hahn J., Pearce C., Dewhirst M. W. Effects of diethylamine/nitric oxide on blood perfusion and oxygenation in the R3230Ac mammary carcinoma. Br J Cancer. 1997;76(4):429–437. doi: 10.1038/bjc.1997.406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shankar A., Loizidou M., Burnstock G., Taylor I. Noradrenaline improves the tumour to normal blood flow ratio and drug delivery in a model of liver metastases. Br J Surg. 1999 Apr;86(4):453–457. doi: 10.1046/j.1365-2168.1999.01045.x. [DOI] [PubMed] [Google Scholar]
  39. Suzuki M., Hori K., Abe I., Saito S., Sato H. A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J Natl Cancer Inst. 1981 Sep;67(3):663–669. [PubMed] [Google Scholar]
  40. Suzuki M., Hori K., Abe I., Saito S., Sato H. Functional characterization of the microcirculation in tumors. Cancer Metastasis Rev. 1984;3(2):115–126. doi: 10.1007/BF00047659. [DOI] [PubMed] [Google Scholar]
  41. Suzuki M., Hori K., Abe I., Saito S., Sato H. Selective increase in tumor oxygen tension with angiotensin II. Invasion Metastasis. 1982;2(1):33–39. [PubMed] [Google Scholar]
  42. Tokuda K., Abe H., Aida T., Sugimoto S., Kaneko S. Modification of tumor blood flow and enhancement of therapeutic effect of ACNU on experimental rat gliomas with angiotensin II. J Neurooncol. 1990 Jun;8(3):205–212. doi: 10.1007/BF00177353. [DOI] [PubMed] [Google Scholar]
  43. Tozer G. M., Shaffi K. M. Modification of tumour blood flow using the hypertensive agent, angiotensin II. Br J Cancer. 1993 May;67(5):981–988. doi: 10.1038/bjc.1993.180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tozer G. M., Shaffi K. M., Prise V. E., Bell K. M. Spatial heterogeneity of tumour blood flow modification induced by angiotensin II: relationship to receptor distribution. Int J Cancer. 1996 Mar 1;65(5):658–663. doi: 10.1002/(SICI)1097-0215(19960301)65:5<658::AID-IJC16>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  45. Tozer G. M., Shaffi K. M. The response of tumour vasculature to angiotensin II revealed by its systemic and local administration to 'tissue-isolated' tumours. Br J Cancer. 1995 Sep;72(3):595–600. doi: 10.1038/bjc.1995.379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Trotter M. J., Chaplin D. J., Olive P. L. Effect of angiotensin II on intermittent tumour blood flow and acute hypoxia in the murine SCCVII carcinoma. Eur J Cancer. 1991;27(7):887–893. doi: 10.1016/0277-5379(91)90140-9. [DOI] [PubMed] [Google Scholar]
  47. Vaupel P., Gabbert H. Evidence for and against a tumor type-specific vascularity. Strahlenther Onkol. 1986 Oct;162(10):633–638. [PubMed] [Google Scholar]
  48. Vaupel P., Kallinowski F., Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989 Dec 1;49(23):6449–6465. [PubMed] [Google Scholar]
  49. Vaupel P., Kelleher D. K., Thews O. Modulation of tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998 Nov 1;42(4):843–848. doi: 10.1016/s0360-3016(98)00324-1. [DOI] [PubMed] [Google Scholar]
  50. Vaupel P., Mueller-Klieser W. Cell line and growth site as relevant parameters governing tumor tissue oxygenation. Adv Exp Med Biol. 1986;200:633–643. doi: 10.1007/978-1-4684-5188-7_76. [DOI] [PubMed] [Google Scholar]
  51. Vaupel P., Schlenger K., Knoop C., Höckel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991 Jun 15;51(12):3316–3322. [PubMed] [Google Scholar]

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