title: Tumor cells enhance their own CD44 cleavage and motility by generating hyaluronan fragments.
abstract: Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that interacts with cell-surface receptors, including CD44. Although HA usually exists as a high molecular mass polymer, HA of a much lower molecular mass that shows a variety of biological activities can be detected under certain pathological conditions, particularly in tumors. We previously reported that low molecular weight HAs (LMW-HAs) of a certain size range induce the proteolytic cleavage of CD44 from the surface of tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we show that MIA PaCa-2, a human pancreatic carcinoma cell line, secreted hyaluronidases abundantly and generated readily detectable levels of LMW-HAs ranging from approximately 10- to 40-mers. This occurred in the absence of any exogenous stimulation. The tumor-derived HA oligosaccharides were able to enhance CD44 cleavage and tumor cell motility. Inhibition of the CD44-HA interaction resulted in the complete abrogation of these cellular events. These results are consistent with the concept that tumor cells generate HA oligosaccha-rides that bind to tumor cell CD44 through the expression of their own constitutive hyaluronidases. This enhances their own CD44 cleavage and cell motility, which would subsequently promote tumor progression. Such an autocrine/paracrine-like process may represent a novel activation mechanism that would facilitate and promote the malignant potential of tumor cells.
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.forename: Takako
authors.initials: T
authors.lastname: Hirata
authors.forename: Haruko
authors.initials: H
authors.lastname: Hayasaka
authors.forename: Robert
authors.initials: R
authors.lastname: Stern
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Murai
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D008970:Molecular Weight; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D019899:Paracrine Communication
chemical_list: D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase