Tumor cells enhance their own CD44 cleavage and motility by generating hyaluronan fragments

doi:10.1074/jbc.M506740200

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Papers In Press, published online ahead of print December 29, 2005
J. Biol. Chem, 10.1074/jbc.M506740200
Submitted on June 21, 2005
Revised on November 17, 2005
Accepted on December 29, 2005

Tumor cells enhance their own CD44 cleavage and motility by generating hyaluronan fragments

Kazuki N Sugahara, Takako Hirata, Haruko Hayasaka, Robert Stern, Toshiyuki Murai, and Masayuki Miyasaka

Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871

Corresponding Author: mmiyasak{at}orgctl.med.osaka-u.ac.jp

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 oligosaccharides 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.

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