title: Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma.
abstract: 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.
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Muly
authors.initials: M
authors.lastname: Tham
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.
authors.forename: Karen
authors.initials: K
authors.lastname: Khoo
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Kim Pin
authors.initials: KP
authors.lastname: Yeo
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France.
authors.forename: Amelle
authors.initials: A
authors.lastname: Prevost-Blondel
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Veronique
authors.initials: V
authors.lastname: Angeli
authors.affiliation: Singapore Immunology Network, BMSI, A-STAR, Singapore.|Institut de Recherche Internationales Servier, Suresnes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013514:Surgical Procedures, Operative / Q000379:methods
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: CSF1R inhibition; macrophages; postsurgical relapse; tumor-initiating cell