CCL9 INDUCED BY TGF-β SIGNALING IN MYELOID CELLS ENHANCES TUMOR CELL SURVIVAL IN THE PREMETASTATIC LUNG

metastasis;TGF-β;cytokines;myeloid cells;tumor microenvironment;breast cancer;Biology

Yan, HangyiZheng, Yixian ;

Johns Hopkins University

关键词: metastasis;    TGF-β;    cytokines;    myeloid cells;    tumor microenvironment;    breast cancer;    Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/44609/YAN-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

The majority of cancer patients die from metastasis. To achieve metastasis, tumor cells must first survive and then proliferate to form colonies. Compelling data have shown the indispensable participation of host microenvironment for metastasis. Bone marrow derived myeloid cells sculpt a tumor-promoting microenvironment in the premetastatic organs prior to tumor cell arrival. However, the molecular mechanisms for this ;;seed and soil” hypothesis are unclear. Here we report that CCL9 was significantly produced and secreted by Gr-1+CD11b+ cells when co-cultured with tumor cells, and in the premetastatic lung. CCL9 knockdown (KD) in myeloid cells decreased metastasis, and this process signaled through its sole receptor CCR1. Overexpression of CCR1 lost the metastasis-promoting function in the context of CCL9 KD. CCL9 enhanced tumor cell survival in the premetastatic organs. The underlying molecular mechanisms included activation of cell survival factors phosphorylated AKT and BCL-2, as well as inhibition of Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis pathway. Additionally, CCL9/CCR1 had autocrine effects, which enhanced CCL9 secretion and the survival of Gr-1+CD11b+ cells.We found that CCL9 was a key effector of myeloid transforming growth factor β (TGF-β) pathway that promotes metastasis. Decreased metastasis in mice with myeloid specific TGF-β receptor II deletion (Tgfbr2MyeKO) correlated with lower CCL9 expression in TGF-β deficient myeloid cells. Importantly, CCL9 over-expression in theses cells rescued metastasis deficiency. Furthermore, inhibition or KD of p38, a downstream molecule in TGF-β singling pathway, decreased CCL9 expression in wild type but not TβRII-deficient Gr-1+CD11b+ cells. Our findings likely had clinic significance as human data paralleled those from mouse studies. CCL23, the human orthologue for mouse CCL9, was elevated in the supernatant by peripheral blood mononuclear cells (PBMCs) when co-cultured with human tumor cells. Publicly available databases showed a negative correlation between CCL23/CCR1 expressions and metastasis free survival of cancer patients. Our work indicates that CCL9 may serve as a target for treating cancer patients with metastasis. This approach may bypass the complexity of TGF-β treatment that results from its dual pro- and anti-cancer function.