Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma
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Muly Tham1, Karen Khoo1, Kim Pin Yeo2, Masashi Kato3, Amelle Prevost-Blondel4, Veronique Angeli2, Jean-Pierre Abastado1,5
1Singapore Immunology Network, BMSI, A-STAR, Singapore
2Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan
4Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France
5Institut de Recherche Internationales Servier, Suresnes, France
Keywords: CSF1R inhibition, Macrophages, Postsurgical relapse, Tumor-initiating cell
Received: December 09, 2014 Accepted: January 09, 2015 Published: February 13, 2015
Surgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection.
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