Stimulatory effects of pleural fluids from mesothelioma patients on CD44 expression, hyaluronan production and cell proliferation in primary cultures of normal mesothelial and transformed cells

Abstract

Cell lines established from human malignant mesotheliomas, but not from normal mesothelial cells, have been shown possess hyaluronan receptors, and to secrete factors that stimulate hyaluronan production by fibroblasts and normal mesothelial cells. In the present study we investigated the generality of this observation, namely the presence of hyaluro nan receptors and factors which induce stimulation of hyaluronan synthesis in primary mesothelioma and mesothelial cell cultures. Functionally active hyaluronan‐binding sites on the surface of malignant mesothelioma cells in primary cultures, established from pleural effusions of 3 different patients, were demonstrated using 3H‐hyaluronan. Primary cultures of normal mesothelial cells from non‐mesothelioma effusions did not exhibit any binding ability. Pleural fluids from mesothelioma patients both stimulated hyaluronan synthesis and promoted proliferation of normal mesothelial cells to a larger extent than non‐mesothelioma fluids. The hyaluronan‐stimulatory activity was only slightly neutralized by antibodies against PDGF‐BB TGF‐8; antibodies against bFGF had no effect. Although the concentration of hyaluronan was much higher in pleural fluids from mesothelioma than from non‐mesothelioma patients, molecular weight was almost the same. The hyaluronan‐binding capacity of early‐passage mesothelioma cells derived from pleural effusions can be an additional marker, in combination with other diagnostic tools, to distinguish between mesothelioma and mesothelial cells.

Hyaluronan production increases the malignant properties of mesothelioma cells

“…The increase in the expression of CD44 molecules (Figure 7) and the increased migratory ability of HAS2 transfectants (Figure 6), suggests that hyaluronan production by mesothelioma correlates with local invasive behaviour. It is of importance to point out here that cell lines and earlypassage mesothelioma cells, but not normal mesothelial cells, express functionally active CD44 hyaluronan receptors (Asplund and Heldin, 1994;Teder et al, 1996). The functional CD44 molecules on mesothelioma could result in an enhanced motility of tumour cells along areas reach in hyaluronan.…”

Hyaluronan content in pleural fluid as a prognostic factor in patients with malignant pleural mesothelioma

“…It has been discussed previously whether the elevated concentrations of Hya found in the pleural effusion are due to synthesis of this polysaccharide by the mesothelioma cells or to a paracrine stimulation of surrounding mesothelial and fibroblastic cells 34, 35. Such paracrine stimulation also would imply an autocrine stimulus of both proliferation and motility by the mesothelioma cell.…”

CD44 and its ligand hyaluronan as potential biomarkers in malignant pleural mesothelioma: evidence and perspectives

“…Another aspect of importance is that the pleural fluids from MPM patients exhibited profound HA-stimulatory activity as compared with the nonmesothelioma fluids, thus, demonstrating that HA-binding capacity may serve as an additional marker in combination with other diagnostic tools to delineate between MPM and normal mesothelial cells [99]. Table 2 shows an overview of the diagnostic value of HA in MPM.…”

“…1940 [85]HA proposed as a diagnostic toolElectrophoresis/Pleural fluidsBoersma et al 1975 [91]HA as a major GAG confirms MPM diagnosisElectrophoresis/MPM and other tumor tissuesWaxler et al 1979 [94]High HA is a clinical finding in MPMGAG-degrading enzyme assay/pleural tissuesArai et al 1979 [36]Increased total GAG aids in differential diagnosis between diffuse MPM and ADCIHC/MPM tissuesKawai et al 1985 [95]HA indicates diffuse MPMColorimetric assay/pleural fluidsMatzel and Schubert. 1979 [93]HA aids in differential diagnosis between MPM and primary ADCElectrophoresis/MPM and other tumor tissuesChiu et al 1984 [87]Increased HA level is associated with tumor damageIHC/pleural effusionsThylen et al 1999 [88]Dahl et al 1989 [35]HA is an indicator for MPMHPLC/pleural and peritoneal effusionsRoboz et al 1985 [86]Increased serum HA indicates progressive MPMRadiometric assay/patient serumFrebourg et al 1987 [34]Dahl et al 1984Thylen et al 1994HA and chondroitin sulfate are basic features of MPMIHC/tumor tissues and pleural fluidsNakano et al 1986 [96]Positive HA staining highly predictive of MPMHA-binding probe/MPM and ADC tissuesAzumi et al 1992 [90]Presence of HA distinguishes MPM from ADCIHC, HPLC/pleural effusion and tumor tissuesKlominek et al 1989 [89]Attanoos et al 1997 [80]High HA with CEA aid in differential diagnosis of MPMRadiometric assay/Pleural fluids and patient serumAtagi et al 1997 [92]Pettersson et al 1988 [33]Increased HA-binding in pleural effusion cells serves as additional diagnostic marker[3H] hyaluronate binding assay/primary cell culturesTeder et al 1996 [99]High intracellular HA delineates MPM from ADCIHC/serous fluidsAfify et al 2005 [81]Increased HA level is not specific for MPM diagnosisELISA assay/Pleural effusions and serumHillerdal et al 1991 [98]Combination of HA and cytology may improve diagnosis of MPMImmunoassay and IHC/pleural effusionsWelker et al 2007 […”