Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

Author:

Kultti Anne1ORCID,Zhao Chunmei1,Singha Netai C.1,Zimmerman Susan1ORCID,Osgood Ryan J.1,Symons Rebecca1,Jiang Ping1,Li Xiaoming1,Thompson Curtis B.1,Infante Jeffrey R.2,Jacobetz Michael A.3,Tuveson David A.4,Frost Gregory I.5,Shepard H. Michael1,Huang Zhongdong1

Affiliation:

1. Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, CA 92121, USA

2. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 250 25th Avenue North, Nashville, TN 37203, USA

3. Labfinity, 8110 Cordova Road, Suite 119, Cordova, TN 38016, USA

4. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA

5. Intrexon Corporation, 6620 Mesa Ridge Road, San Diego, CA 92121, USA

Abstract

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmicβ-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin andβ-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

Publisher

Hindawi Limited

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine

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