RT Journal Article
SR Electronic
T1 Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5407
OP 5421
DO 10.1158/1078-0432.CCR-18-0125
VO 24
IS 21
A1 Cho, Haaglim
A1 Seo, Youngha
A1 Loke, Kin Man
A1 Kim, Seon-Wook
A1 Oh, Seong-Min
A1 Kim, Jun-Hyeong
A1 Soh, Jihee
A1 Kim, Hyoen Sik
A1 Lee, Hyunju
A1 Kim, Jin
A1 Min, Jung-Joon
A1 Jung, Da-Woon
A1 Williams, Darren Reece
YR 2018
UL http://clincancerres.aacrjournals.org/content/24/21/5407.abstract
AB Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell–activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the “henchmen” for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407–21. ©2018 AACR.