Abstract P4-04-25: Naked mole rat hyaluronan synthase 2 displays similar effects as human hyaluronan synthase 2 and promotes tumor growth in a mouse xenograft model (2015)

Abstract Accumulation of hyaluronan (HA) is correlated with poor prognosis in many human cancer including breast cancer and pancreatic cancer. Hyaluronan synthase 2 (HAS2) is one of the three HA synthase genes (HAS1-3) found in mammals. Up-regulation of the HAS2 gene has been observed in breast cancer patients; and HAS2 expression correlates with the incidence of metastasis and lower rate of overall patient survival (Okuda et al 2012). Interestingly, a recent study suggested that the naked mole rat (nmr) HAS2 enzyme may function differently than the HAS2 proteins from mice and humans, and its expression had a tumor suppressor effect (Tian et al 2013). The nmrHAS2 protein sequence was distinct from other mammals in the cytoplasmic loop where the active site resides, which led to the hypothesis that nmrHAS2 may contribute to the production of extremely high molecular weight HA species. Furthermore, nmrHAS2 is required for the resistance of nmr skin fibroblasts to malignant transformation. In this study, we examined whether the nmrHAS2 gene can also render human cells resistant to tumor progression. We have previously observed that HA level in the pancreatic cancer model AsPC1 can be modulated by the over-expression of the human HAS3 protein (Osgood et al 2014). To compare and contrast the effect of nmrHAS2 and huHAS2 on HA production and tumor growth, nmrHAS2 and huHAS2 AsPC1 models were engineered using a recombinant lentivirus encoding the nmrHAS2 and huHAS2 genes respectively. Over-expression of nmrHAS2 and huHAS2 both significantly increased the HA level in AsPC1 cells. Both nmrHAS2 and huHAS2 promoted the growth of AsPC1 in an intramuscular xenograft tumor model. Ex vivo analysis of tumor xenografts showed that nmrHAS2 and huHAS2 AsPC1 tumors contain elevated levels of HA, and the size range of the HA in the nmrHAS2 tumors is similar to that in the huHAS2 AsPC1 tumors. Therefore, nmrHAS2 functions similarly as huHAS2 gene and promotes tumor growth in the human pancreatic tumor model AsPC1. References: Okuda H, Kobayashi A, Xia B, Watabe M, Pai SK et al. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal Cells. Cancer Research 72:537-47, 2012. Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499:346-349, 2013. Osgood RJ, Skipper JF, Cowell JA, Chen Y, Zhu L et al. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances Nab-Paclitaxel plus gemcitabine efficacy in human pancreatic cancer xenografts. AACR Special Conference Pancreatic Cancer 2014. Citation Format: Chunmei Zhao, Susan Zimmerman, Calvin T Vu, Michael Shepard, Zhongdong Huang. Naked mole rat hyaluronan synthase 2 displays similar effects as human hyaluronan synthase 2 and promotes tumor growth in a mouse xenograft model [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-25.