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Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors

Abstract

Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase-transgenic mice, which constitutively overexpress heparanase, and heparanase-knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients.

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Acknowledgements

We thank members of the Joyce Lab; Drs Jacqueline Bromberg and Andrew Koff for discussion on this topic; and Robert Bowman, Daniela Quail, Alberto Schuhmacher and Hao-Wei Wang for reading the manuscript. We gratefully acknowledge Xiaoping Chen and Lin Song for excellent technical assistance; Marsha Quick and Karoline Dubin for project assistance; Elyn Reidel, MSKCC Epidemiology and Biostatistics Department for statistical analysis of RT2 tumor grades; Sho Fujisawa and the Molecular Cytology Core Facility for assistance with the MetaMorph lymphangiogenesis analysis; the MSKCC Flow Cytometry Core for technical assistance and advice; and Aisha Khan of the cGMP Cell Processing Facility, Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine for providing normal islets. This research was funded by the National Cancer Institute R01 CA125162 and Cycle for Survival (JAJ). KEH was supported in part by a Grayer Fellowship.

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Correspondence to J A Joyce.

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Hunter, K., Palermo, C., Kester, J. et al. Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors. Oncogene 33, 1799–1808 (2014). https://doi.org/10.1038/onc.2013.142

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