Research Papers:

Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation

Muly Tham _, Kar Wai Tan, Jo Keeble, Xiaojie Wang, Sandra Hubert, Luke Barron, Nguan Soon Tan, Masashi Kato, Armelle Prevost-Blondel, Veronique Angeli and Jean-Pierre Abastado

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Oncotarget. 2014; 5:12027-12042. https://doi.org/10.18632/oncotarget.2482

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Muly Tham1, Kar Wai Tan1,7, Jo Keeble1, Xiaojie Wang1, Sandra Hubert1, Luke Barron2, Nguan Soon Tan3, Masashi Kato4, Armelle Prevost-Blondel5, Veronique Angeli6 and Jean-Pierre Abastado1,8

1 Singapore Immunology Network, BMSI, A-STAR, Singapore

2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

3 School of Biological Sciences, Nanyang Technological University, Singapore

4 Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan

5 Institut Cochin, Université Paris Descartes, CNRS UMR, Paris, France

6 Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

7 Department of Clinical Research, Singapore General Hospital, Singapore

8 Institut de Recherche Internationales Servier, 50 rue Carnot, Suresnes cedex, France


Muly Tham, email:

Keywords: Arginase, Macrophages, TGFβ, Tumor-initiating cell

Received: July 13, 2014 Accepted: September 15, 2014 Published: September 16, 2014


M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34- but not CD34+ tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34- TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34- TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth.

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