Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma.
OBJECTIVE
In primary uveal and cutaneous melanoma lesions, extracellular matrix (ECM) is often deposited in arcs, loops, and network patterns. Based on prognostic relevance, these patterns appear to play a significant role in facilitating metastasis. It has been demonstrated that these patterns were capable of transmitting fluid. The current study was undertaken to elucidate further the functional role of these patterns in tumor perfusion and to examine the composition of the patterns by immunohistochemistry.


METHODS
To study the role of these patterns in perfusion, fluorochrome-labeled bovine serum albumin, bovine insulin, and dextrans of different molecular sizes were injected intravenously into nude mice bearing subcutaneous human cutaneous melanoma xenografts. Distribution of the human melanoma cells and murine host cells was analyzed by DNA in situ hybridization. To elucidate the composition of these patterns, human uveal melanoma tissues were analyzed for expression of ECM components by immunohistochemistry.


RESULTS
Small molecules (Stokes' radius <4.4 nm) crossed the vessel wall and spread along the ECM patterns within 2 to 10 minutes, whereas larger molecules (Stokes' radius approximately 5.8 nm) required 30 to 45 minutes to enter. Murine host cells were found exclusively in the ECM pattern compartment. In primary uveal melanoma, different types of collagen, ECM-associated heparan sulfate proteoglycans, and different types of cells were present in the patterns.


CONCLUSIONS
The data suggest that the ECM deposited as arcs, loops, and network patterns, accommodate the transport of plasma-derived molecules, (e.g., nutrients), to the tumor lesion, thus enhancing tumor growth and progression, and facilitating infiltration of tumor tissue by host-derived cells.
Clarijs
Ruud
R
Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. r.clarijs@pathol.umcn.nl
van Dijk
Marcory
M
Ruiter
Dirk J
DJ
de Waal
Robert M W
RM
D000818:Animals; D001692:Biological Transport; D003094:Collagen / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012710:Serum Albumin, Bovine / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000473:pathology
D003911:Dextrans; D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D007328:Insulin; D012710:Serum Albumin, Bovine; D003094:Collagen