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The abnormal accumulation of hyaluronan in the solid tumor microenvironment is associated with poor prognosis in several human cancers. Hyaluronan often accumulates in the tumor stroma. To understand the role of hyaluronan-accumulating stroma in tumor progression, we engineered a hyaluronan-producing fibroblast cell line 3T3HAS3 by lentiviral transduction of the human hyaluronan synthase 3 gene into Balb/c 3T3 cells. The 3T3HAS3 cells produced significant amounts of hyaluronan in vitro, which bind to the cell surface of the human breast cancer cell line MDA-MB-468. When co-grafted with MDA-MB-468 cells in nude mice, 3T3HAS3 significantly enhanced tumor growth. Immunohistochemical analysis of tumor xenografts showed that MDA-MB-468 cells were surrounded by hyaluronan-accumulating stroma, closely resembling the morphology observed in human breast cancer specimens. Tumor growth of this co-graft model required hyaluronan production from 3T3HAS3 cells, as demonstrated by the delayed tumor growth upon hyaluronan removal by expression of the human PH20 gene in 3T3HAS3 cells, or by systemic administration of PEGylated recombinant human PH20 (PEGPH20). In contrast, neither the expression of CD44, a well-characterized hyaluronan receptor, in tumor and stromal fibroblasts, nor the binding of hyaluronan to CD44 in MDA-MB-468 tumor cells was essential for tumor growth. Small scale screening of signaling changes in xenograft tumors suggested that the AMPK/mTOR pathway may respond to hyaluronan removal by PEGPH20. Collectively, these data demonstrate that the growth of an engineered breast cancer xenograft model with hyaluronan-accumulating stroma is dependent on hyaluronan, and that hyaluronan-CD44 interaction may not be the main mechanism through which hyaluronan promotes tumor progression in certain tumors. Citation Format: Chunmei Zhao, Benjamin J. Thompson, Kelly Chen, Mathieu Marella, Susan Zimmerman, Trevor Kimbler, Barbara Blouw, Sheryl Garrovillo, Lei Huang, Adrian Radi, Zhongdong Huang, H. Michael Shepard, Sanna Rosengren, Christopher D. Thanos, Daniel C. Maneval. The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2101.

cancer research

Abstract 2101: The growth of a xenograft breast cancer tumor model with engineered hyaluronan-accumulating stroma is dependent on hyaluronan and independent of CD44