Abstract
Tumor-associated macrophages have recently emerged as a key regulatory cell type during cancer progression, and have been found to promote tumor malignancy in the majority of studies performed to date. We show in this study that CD68+ macrophages positively correlate with tumor grade and liver metastasis in human pancreatic neuroendocrine tumors (PNETs). To investigate the potential mechanisms whereby macrophages can promote PNET progression, we crossed the RIP1-Tag2 (RT2) mouse model of pancreatic islet cancer to colony-stimulating factor-1 (CSF-1)-deficient Csf1op/op mice, which have reduced numbers of tissue macrophages. Csf1op/op RT2 mice had a substantial reduction in cumulative tumor burden, which interestingly resulted from a significant decrease in angiogenic switching and tumor number, rather than an evident effect on tumor growth. In the tumors that did develop in CSF-1-deficient animals, however, there were no significant differences in tumor cell proliferation, apoptosis, angiogenesis or invasion. CSF-1 deficiency decreased macrophage infiltration by approximately 50% during all stages of RT2 tumor progression. Interestingly, several cytokines were upregulated in CSF-1-deficient RT2 tumors, and neutrophil infiltration was increased. These results show that macrophages are important for promoting PNET development and suggest that additional factors contribute to the recruitment and survival of myeloid cells in RT2 tumors in the absence of CSF-1.
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Acknowledgements
We thank Xiaoping Chen and Kenishana Simpson for excellent technical assistance; Dr Jeffrey Pollard, Albert Einstein College of Medicine for the Csf1op pyrosequencing protocol; Drs Jan Hendrikx and Jennifer Wilshire, MSKCC Flow Cytometry Core Facility for assistance with flow cytometric sorting; Drs Agnes Viale, Juan Li, Magali Cavatore, Liliana Villafania, MSKCC Genomics Core Facility for assistance with RT–PCR and pyrosequencing; Drs Guangli Li and Ouathek Ouerfelli, MSKCC Organic Synthesis Core Facility for synthesis of the Cy3B-Cathepsin-ABP; and Elyn Reidel, MSKCC Epidemiology and Biostatistics Department, for statistical analysis of tumor size distribution. This research was supported by the following: National Cancer Institute TMEN Grant (NIH U54-CA126518), NCI R01 (CA125162), and the Geoffrey Beene Foundation (JAJ); NIH T32 Training Fellowship (SMP); American Cancer Society Postdoctoral Fellowship (BBG); Frank L. Horsfall Fellowship (HWW, VG); and Geoffrey Beene Fellowship (VG).
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Pyonteck, S., Gadea, B., Wang, HW. et al. Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene 31, 1459–1467 (2012). https://doi.org/10.1038/onc.2011.337
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DOI: https://doi.org/10.1038/onc.2011.337
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