Hyaluronan production increases the malignant properties of mesothelioma cells

Abstract

Malignant pleural mesotheliomas is in most cases associated with elevated amounts of hyaluronan. To investigate the importance of hyaluronan for the malignant properties of mesotheliomas, we have expressed murine hyaluronan synthase 2 (HAS2) in the non-hyaluronan producing mesothelioma cell line, Mero-25. We found that upon hyaluronan overproduction the mesothelioma cells changed their epitheloid character to a fibroblastic phenotype and were surrounded by pericellular matrices, the size of which correlated to the amount of synthesized hyaluronan. HAS2-transfected cells with the ability to synthesize about 520 ng hyaluronan/5 × 104cells/24 h exhibited about a 2-fold increase in the expression of the cell surface hyaluronan receptor CD44 and their locomotion increased compared to that of mock-transfected Mero-25 cells. Furthermore, the malignant properties of mesothelioma cell clones as determined by the ability to grow in a soft agar assay correlated to their hyaluronan production. These results provide evidence for an important role of hyaluronan in the aggressive spread of mesotheliomas in adjacent non-cancerous stromal tissues. © 2001 Cancer Research Campaign http://www.bjcancer.com

Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells

“…In MPM, local invasiveness is characteristic, whereas distant metastasis is infrequently observed. Such invasive growth requires ECM for MPM cells as previously reported (Li and Heldin, 2001). Moreover, the acquisition of chemoresistance by HA-CD44 interaction could be advantage for MPM cells to protect themselves by anti-cancer agents.…”

“…Recent studies have revealed that HA strongly promotes anchorage-independent growth and that the resistance of cancer cells to growth arrest and apoptosis under anchorage-independent conditions is dependent on the constitutive interactions between HA and CD44 (Li and Heldin, 2001;Zoltan-Jones et al, 2003). The treatment of tumor cells with hyaluronidase was observed to increase the activities of various chemotherapeutic agents.…”

Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors

“…This is consistent with earlier observations that an abnormally high expression of hyaluronan in colorectal carcinoma is an unfavorable prognostic factor for the patients. 10 Furthermore, previous studies in other cell systems, i.e., fibrosarcoma 19 or mesothelioma cells, 20 revealed that Has2 overexpression by the tumor cells enhanced tumor growth rate and anchorage-independent growth. Evidence has been presented that hyaluronan-CD44 interactions are important in malignant growth.…”

“…Evidence has been presented that hyaluronan-CD44 interactions are important in malignant growth. 20,44 Because vascularization is important for tumor growth, the observation of a significant decrease in blood vessel density in tumors derived from Has2-d-transfectants is interesting. In con- .…”

“…1). The 2 hyaluronan producing clones synthesized hyaluronan chains of an average molecular weight of about 2 ϫ 10 6 , as determined by gel chromatography 20 …”