title: CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome.
abstract: Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan-CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA-binding defective mutant R41A in osteoblastic SaOS-2 cells resulted in HA-independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS-2 cells resulted in an HA-dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44-associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.
authors.forename: Ana
authors.initials: A
authors.lastname: Gvozdenovic
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.forename: Patrick
authors.initials: P
authors.lastname: Brennecke
authors.forename: Knut
authors.initials: K
authors.lastname: Husmann
authors.forename: Yufei
authors.initials: Y
authors.lastname: Li
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary*; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid