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Cancer Res. 2016 May 1;76(9):2507-12. doi: 10.1158/0008-5472.CAN-15-3114. Epub 2016 Apr 20.

Carcinoma Cell Hyaluronan as a "Portable" Cancerized Prometastatic Microenvironment.

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Cancer Research Laboratories, London Regional Cancer Center, Victoria Hospital, London, Ontario, Canada. Departments of Oncology, Biochemistry and Surgery, Schulich School of Medicine, Western University, London, Ontario, Canada.
Department of Biomedical Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, Minneapolis, Minnesota.
Masonic Cancer Center, Minneapolis, Minnesota. Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota.


Hyaluronan (HA) is a structurally simple polysaccharide, but its ability to act as a template for organizing pericellular matrices and its regulated synthesis and degradation are key to initiating repair responses. Importantly, these HA functions are usurped by tumor cells to facilitate progression and metastasis. Recent advances have identified the functional complexities associated with the synthesis and degradation of HA-rich matrices. Three enzymes synthesize large HA polymers while multiple hyaluronidases or tissue free radicals degrade these into smaller bioactive fragments. A family of extracellular and cell-associated HA-binding proteins/receptors translates the bioinformation encrypted in this complex polymer mixture to activate signaling networks required for cell survival, proliferation, and migration in an actively remodeling microenvironment. Changes in HA metabolism within both the peritumor stroma and parenchyma are linked to tumor initiation, progression, and poor clinical outcome. We review evidence that metastatic tumor cells must acquire the capability to autonomously synthesize, assemble, and process their own "portable" HA-rich microenvironments to survive in the circulation, metastasize to ectopic sites, and escape therapeutic intervention. Strategies to disrupt the HA machinery of primary tumor and circulating tumor cells may enhance the effectiveness of current conventional and targeted therapies. Cancer Res; 76(9); 2507-12.

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