Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Dec;85(12):1968–1977. doi: 10.1054/bjoc.2001.2180

Uptake of IgG in osteosarcoma correlates inversely with interstitial fluid pressure, but not with interstitial constituents

C de Lange Davies 1, B Ø Engesæter 1, I Haug 1, I W Ormberg 1, J Halgunset 2, C Brekken 1
PMCID: PMC2363997  PMID: 11747342

Abstract

The uptake of therapeutic macromolecules in solid tumours is assumed to be hindered by the heterogeneous vascular network, the high interstitial fluid pressure, and the extracellular matrix. To study the impact of these factors, we measured the uptake of fluorochrome-labelled IgG using confocal laser scanning microscopy, interstitial fluid pressure by the ‘wick-in-needle’ technique, vascular structure by stereological analysis, and the content of the extracellular matrix constituents collagen, sulfated glycosaminoglycans and hyaluronan by colourimetric assays. The impact of the microenvironment on these factors was studied using osteosarcomas implanted either subcutaneously or orthotopically around the femur in athymic mice. The uptake of IgG was found to correlate inversely with the interstitial fluid pressure and the tumour volume in orthotopic, but not subcutaneous tumours. No correlation was found between IgG uptake and the level of any of the extracellular matrix constituents. The content of both collagen and glycosaminoglycans depended on the site of tumour growth. The orthotopic tumours had a higher vascular density than the subcutaneous tumours, as the vascular surface and length were 2–3-fold higher. The data indicate that the interstitial fluid pressure is a dominant factor in controlling the uptake of macromolecules in solid tumours; and the site of tumour growth is important for the uptake of macromolecules in small tumours, extracellular matrix content and vascularization.© 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: IgG uptake, interstitial fluid pressure, extracellular matrix, vasculature, osteosarcoma

Full Text

The Full Text of this article is available as a PDF (159.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BITTER T., MUIR H. M. A modified uronic acid carbazole reaction. Anal Biochem. 1962 Oct;4:330–334. doi: 10.1016/0003-2697(62)90095-7. [DOI] [PubMed] [Google Scholar]
  2. Bernsen H. J., Rijken P. F., Hagemeier N. E., van der Kogel A. J. A quantitative analysis of vascularization and perfusion of human glioma xenografts at different implantation sites. Microvasc Res. 1999 May;57(3):244–257. doi: 10.1006/mvre.1999.2143. [DOI] [PubMed] [Google Scholar]
  3. Boucher Y., Baxter L. T., Jain R. K. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 1990 Aug 1;50(15):4478–4484. [PubMed] [Google Scholar]
  4. 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 Sep 15;52(18):5110–5114. [PubMed] [Google Scholar]
  5. Brekken C., Bruland Ø S., de Lange Davies C. Interstitial fluid pressure in human osteosarcoma xenografts: significance of implantation site and the response to intratumoral injection of hyaluronidase. 2000 Sep- OctAnticancer Res. 20(5B):3503–3512. [PubMed] [Google Scholar]
  6. Brekken C., Hjelstuen M. H., Bruland Ø S., de Lange Davies C. Hyaluronidase-induced periodic modulation of the interstitial fluid pressure increases selective antibody uptake in human osteosarcoma xenografts. 2000 Sep- OctAnticancer Res. 20(5B):3513–3519. [PubMed] [Google Scholar]
  7. Fabra A., Nakajima M., Bucana C. D., Fidler I. J. Modulation of the invasive phenotype of human colon carcinoma cells by organ specific fibroblasts of nude mice. Differentiation. 1992 Dec;52(1):101–110. doi: 10.1111/j.1432-0436.1992.tb00504.x. [DOI] [PubMed] [Google Scholar]
  8. Fadnes H. O., Reed R. K., Aukland K. Interstitial fluid pressure in rats measured with a modified wick technique. Microvasc Res. 1977 Jul;14(1):27–36. doi: 10.1016/0026-2862(77)90138-8. [DOI] [PubMed] [Google Scholar]
  9. Farndale R. W., Buttle D. J., Barrett A. J. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. 1986 Sep 4;883(2):173–177. doi: 10.1016/0304-4165(86)90306-5. [DOI] [PubMed] [Google Scholar]
  10. Fidler I. J. Modulation of the organ microenvironment for treatment of cancer metastasis. J Natl Cancer Inst. 1995 Nov 1;87(21):1588–1592. doi: 10.1093/jnci/87.21.1588. [DOI] [PubMed] [Google Scholar]
  11. Fodstad O., Brøgger A., Bruland O., Solheim O. P., Nesland J. M., Pihl A. Characteristics of a cell line established from a patient with multiple osteosarcoma, appearing 13 years after treatment for bilateral retinoblastoma. Int J Cancer. 1986 Jul 15;38(1):33–40. doi: 10.1002/ijc.2910380107. [DOI] [PubMed] [Google Scholar]
  12. Fukumura D., Xavier R., Sugiura T., Chen Y., Park E. C., Lu N., Selig M., Nielsen G., Taksir T., Jain R. K. Tumor induction of VEGF promoter activity in stromal cells. Cell. 1998 Sep 18;94(6):715–725. doi: 10.1016/s0092-8674(00)81731-6. [DOI] [PubMed] [Google Scholar]
  13. Fukumura D., Yuan F., Monsky W. L., Chen Y., Jain R. K. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol. 1997 Sep;151(3):679–688. [PMC free article] [PubMed] [Google Scholar]
  14. Gohongi T., Fukumura D., Boucher Y., Yun C. O., Soff G. A., Compton C., Todoroki T., Jain R. K. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1. Nat Med. 1999 Oct;5(10):1203–1208. doi: 10.1038/13524. [DOI] [PubMed] [Google Scholar]
  15. Hilmas D. E., Gillette E. L. Morphometric analyses of the microvasculature of tumors during growth and after x-irradiation. Cancer. 1974 Jan;33(1):103–110. doi: 10.1002/1097-0142(197401)33:1<103::aid-cncr2820330116>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  16. Hobbs S. K., Monsky W. L., Yuan F., Roberts W. G., Griffith L., Torchilin V. P., Jain R. K. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4607–4612. doi: 10.1073/pnas.95.8.4607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Iozzo R. V. Proteoglycans: structure, function, and role in neoplasia. Lab Invest. 1985 Oct;53(4):373–396. [PubMed] [Google Scholar]
  18. Jackson R. L., Busch S. J., Cardin A. D. Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes. Physiol Rev. 1991 Apr;71(2):481–539. doi: 10.1152/physrev.1991.71.2.481. [DOI] [PubMed] [Google Scholar]
  19. Jain R. K., Baxter L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 1988 Dec 15;48(24 Pt 1):7022–7032. [PubMed] [Google Scholar]
  20. Jain R. K. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):149–168. doi: 10.1016/s0169-409x(00)00131-9. [DOI] [PubMed] [Google Scholar]
  21. Jain R. K. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987 Jun 15;47(12):3039–3051. [PubMed] [Google Scholar]
  22. Jørgen H., Gundersen G. Estimation of tubule or cylinder LV, SV and VV on thick sections. J Microsc. 1979 Dec;117(3):333–345. doi: 10.1111/j.1365-2818.1979.tb04690.x. [DOI] [PubMed] [Google Scholar]
  23. KEDEM O., KATCHALSKY A. Thermodynamic analysis of the permeability of biological membranes to non-electrolytes. Biochim Biophys Acta. 1958 Feb;27(2):229–246. doi: 10.1016/0006-3002(58)90330-5. [DOI] [PubMed] [Google Scholar]
  24. Knudson W., Biswas C., Toole B. P. Interactions between human tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6767–6771. doi: 10.1073/pnas.81.21.6767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lee C. G., Heijn M., di Tomaso E., Griffon-Etienne G., Ancukiewicz M., Koike C., Park K. R., Ferrara N., Jain R. K., Suit H. D. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000 Oct 1;60(19):5565–5570. [PubMed] [Google Scholar]
  26. Netti P. A., Berk D. A., Swartz M. A., Grodzinsky A. J., Jain R. K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000 May 1;60(9):2497–2503. [PubMed] [Google Scholar]
  27. 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]
  28. Pluen A., Boucher Y., Ramanujan S., McKee T. D., Gohongi T., di Tomaso E., Brown E. B., Izumi Y., Campbell R. B., Berk D. A. Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc Natl Acad Sci U S A. 2001 Mar 27;98(8):4628–4633. doi: 10.1073/pnas.081626898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Qiu X. L., Brown L. V., Parameswaran S., Marek V. W., Ibbott G. S., Lai-Fook S. J. Effect of hyaluronidase on albumin diffusion in lung interstitium. Lung. 1999;177(5):273–288. doi: 10.1007/pl00007647. [DOI] [PubMed] [Google Scholar]
  30. Rubin K., Sjöquist M., Gustafsson A. M., Isaksson B., Salvessen G., Reed R. K. Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA. Int J Cancer. 2000 Jun 1;86(5):636–643. doi: 10.1002/(sici)1097-0215(20000601)86:5<636::aid-ijc6>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  31. Saltzman W. M., Radomsky M. L., Whaley K. J., Cone R. A. Antibody diffusion in human cervical mucus. Biophys J. 1994 Feb;66(2 Pt 1):508–515. doi: 10.1016/s0006-3495(94)80802-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Solesvik O. V., Rofstad E. K., Brustad T. Vascular structure of five human malignant melanomas grown in athymic nude mice. Br J Cancer. 1982 Oct;46(4):557–567. doi: 10.1038/bjc.1982.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sunderkötter C., Steinbrink K., Goebeler M., Bhardwaj R., Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994 Mar;55(3):410–422. doi: 10.1002/jlb.55.3.410. [DOI] [PubMed] [Google Scholar]
  34. Swabb E. A., Wei J., Gullino P. M. Diffusion and convection in normal and neoplastic tissues. Cancer Res. 1974 Oct;34(10):2814–2822. [PubMed] [Google Scholar]
  35. WOESSNER J. F., Jr The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys. 1961 May;93:440–447. doi: 10.1016/0003-9861(61)90291-0. [DOI] [PubMed] [Google Scholar]
  36. Yuan F. Transvascular drug delivery in solid tumors. Semin Radiat Oncol. 1998 Jul;8(3):164–175. doi: 10.1016/s1053-4296(98)80042-8. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES