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Neoplastic Modulation of Extracellular Matrix: Proteoglycan Changes in the Rabbit Mesentery Induced by V2 Carcinoma Cells¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [R. V. I.], and the Division of Cancer Research, Institute of Pathology, University of Zurich, Birchstrasse 95, CH-8050, Zurich, Switzerland [W. M-G.]

Previous studies have shown that the invasion of V2 carcinoma cells in the rebbit mesentery is associated with marked extracellular matrix synthesis leading eventually to an overall increase in mesenteric mass. The purpose of the present study was to investigate the structural and biochemical composition of the extracellular matrix in tumor-free parts of rabbit mesenteries at various stages after intraperitoneal implantation of V2 carcinoma cells. The overall thickness of the tumor-implanted mesenteries increased progressively and peaked at about Day 14, when it was about 8 times greater than the untreated or liver-implanted controls. This was mainly the result of an accumulation of extracellular matrix components. In particular, there was a marked increase in both collagen fibers and proteoglycan granules, as well as filaments, probably hyaluronic acid, as visualized by ruthenium hexammine trichloride. Stereological analysis showed a 6-fold increase in collagen fibers and a significant increase in the density and average diameter of proteoglycan granules. Biochemical analysis revealed a marked elevation in uronic acid content in the tumor-implanted mesenteries. Specifically, they contained 2.6 and 8.6 times the amount of hyaluronic acid and chondroitin sulfate, respectively, than did controls. Furthermore, the relative percentage of chondroitin sulfate was elevated markedly (26 versus 6% in controls). However, the content of heparan or dermatan sulfate did not vary significantly. Stereological analysis of the fibroblasts showed that their absolute number had doubled and that the cell volume of the individual fibroblast had increased markedly. This suggests that the fibroblasts were responsible for the excessive production of the extracellular matrix. These results support the concept that carcinoma cells can modulate their surrounding extracellular environment by stimulating the synthesis of connective tissue in the host mesenchymal cells.

¹ This study was supported in part by NIH Grant CA-39481, by a Junior Faculty Research Award (JFRA-95) from the American Cancer Society and by The Lydia Hochstrasser Foundation of the University of Zurich.

² To whom requests for reprints should be addressed, at Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical School, 3400 Spruce Street/G1, Philadelphia, PA 19104.

Received 12/21/84. Revised 7/ 8/85. Accepted 7/10/85.