title: Uptake of IgG in osteosarcoma correlates inversely with interstitial fluid pressure, but not with interstitial constituents.
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.
authors.affiliation: Department of Physics, The Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: C
authors.initials: C
authors.lastname: de Lange Davies
authors.forename: B Ø
authors.initials: BØ
authors.lastname: Engesaeter
authors.forename: I
authors.initials: I
authors.lastname: Haug
authors.forename: I W
authors.initials: IW
authors.lastname: Ormberg
authors.forename: J
authors.initials: J
authors.lastname: Halgunset
authors.forename: C
authors.initials: C
authors.lastname: Brekken
mesh_terms: D000818:Animals; D001692:Biological Transport; D001859:Bone Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000032:analysis; D005109:Extracellular Matrix / Q000737:chemistry / Q000502:physiology; D005260:Female; D005266:Femoral Neoplasms / Q000378:metabolism / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000032:analysis; D007074:Immunoglobulin G / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000032:analysis; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D011312:Pressure; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
chemical_list: D005456:Fluorescent Dyes; D006025:Glycosaminoglycans; D007074:Immunoglobulin G; D009363:Neoplasm Proteins; D006820:Hyaluronic Acid; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate