癌細胞以Oct-4經由巨噬細胞生長激素調控腫瘤相關巨噬細胞的分化
謝嘉興a、盧佳杏b、蕭璦莉c、吳昭良b
衛生福利部 台南醫院 泌尿科a, 國立成功大學醫學院 生化所b，國立成功大學醫學院 微免所c
Oct4 modulates M2 polarization of tumor associated macrophages by upregulation of macrophage colony-stimulating factor in cancers
Gia-Shing Shieha, Chia-Sing Lub, Ai-Li Shiauc, and Chao-Liang Wub
a Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Taiwan,
b Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan,
c Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan
Purpose: Oct4 overexpression in cancers is correlated with poor prognosis. Oct4 expression increased tumorigenic properties of colorectal cancer cells through IL-8 and IL-32 secretion. IL-8 secreted by cancer cells had been showed to induce monocytes, neutrophils and other leukocytes recruitment. However, the linkage between the expression of Oct4 of cancer cells and tumor associated macrophages within the tumor microenvironments remained unclear. We explored the role of Oct4 on tumor associated macrophages (TAM) polarization and its effect on the expression of cytokines and patient outcome in cancers
Methods: A549, CL1-0, CL1-1 and CL1-5F4 cancer cells and THP-1 human monocytic cells were used in the study. ELISAs were performed using kits and procedures for cytokine assays. Migrations of cancer cells were measured using transwell inserts with an 8 μm porous membrane. Immunohistochemistry and immunoblotting were performed for Oct4, M-CSF, or CD206 expressions. Group differences were determined by Student t test. All statistical tests were two-sided.
Result: Oct4-overexpressing A549 cancer cells expressed higher levels of M-CSF. Secreting M-CSF contributed to increasing of M2 macrophages and tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival in mice, which was correlated with the number of M2 macrophages in cancers. Patients with high expression of CD206, a marker of M2 macrophages, were associated with inferior recurrence-free survival. High expressions in Oct4, M-CSF and CD206 posed most poor recurrence-free survival in cancers that emerged the findings of Oct4 expression and M2 macrophage infiltration in microenvironment disadvantaged toward cancer cells. We also demonstrated that all-trans retinoic acid (ARTA), an inhibitor of Oct4, exerted anti-tumor effects and reduced CD206 macrophages in tumor-bearing mice.
Conclusion: M2-polarized TAMs promoted cancer cell migration is mediated by M-CSF in Oct4-overexpressing cancer cells, suggesting M2 macrophages triggered by cancer cells and MCSF could be a therapeutic target in cancers. Furthermore, ATRA treatment, which contributes to interfere the pathway involved Oct4/M2 macrophages axis, could be a potential therapeutic agent in cancers