The inhibitory effect of Gremlin-2 on adipogenesis suppresses breast cancer cell growth and metastasis

Breast Cancer Research

Research

World Gil¹  Youjin Kim¹  Dayeon Lim¹  Jayeon Park¹  Na Hui Kim²  Jiwoo Jung²  Minji Kwon²  Sin-Aye Park³  Ye Hwang Cheong⁴ 

[1] Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, 31538, Asan-si, Republic of Korea;Department of Medical Sciences, Graduate School, Soonchunhyang University, 31538, Asan-si, Republic of Korea;Department of Medical Sciences, Graduate School, Soonchunhyang University, 31538, Asan-si, Republic of Korea;Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, 31538, Asan-si, Republic of Korea;Drug Discovery Research Laboratories, Dong-A ST Co., Ltd., 17073, Yongin, Republic of Korea;

关键词: Gremlin-2;    3T3-L1 cells;    Adipocytes;    IL-6;    Breast cancer cells;    Cancer progression;    Metastasis;   

DOI  :  10.1186/s13058-023-01732-2

 received in 2023-05-22, accepted in 2023-10-17,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGremlin-1 (GREM1) and Gremlin-2 (GREM2) are bone morphogenetic protein antagonists that play important roles in organogenesis, tissue differentiation, and tissue homeostasis. Although GREM1 has been reported to be involved in promoting various cancers, little has been reported about effects of GREM2 on cancer. Recently, it has been reported that GREM2 can inhibit adipogenesis in adipose-derived stromal/stem cells. However, as an inhibitor of adipogenesis, the role of GREM2 in cancer progression is not well understood yet.MethodsPre-adipocyte 3T3-L1 cells overexpressing mock or Grem2 were established using a lentiviral transduction system and differentiated into adipocytes-mock and adipocytes-Grem2, respectively. To investigate the effect of adipocyte-Grem2 on breast cancer cells, we analyzed the proliferative and invasion abilities of spheroids using a 3D co-culture system of breast cancer cells and adipocytes or conditioned medium (CM) of adipocytes. An orthotopic breast cancer mouse model was used to examine the role of adipocytes-Grem2 in breast cancer progression.ResultsGrem2 overexpression suppressed adipogenesis of 3T3-L1 cells. Proliferative and invasion abilities of spheroids formed by co-culturing MTV/TM-011 breast cancer cells and adipocytes-Grem2 were significantly reduced compared to those of spheroids formed by co-culturing MTV/TM-011 cells and adipocytes-mock. Compared to adipocytes-mock, adipocytes-Grem2 showed decreased mRNA expression of several adipokines, notably IL-6. The concentration of IL-6 in the CM of these cells was also decreased. Proliferative and invasive abilities of breast cancer cells reduced by adipocytes-Grem2 were restored by IL-6 treatment. Expression levels of vimentin, slug, and twist1 in breast cancer cells were decreased by treatment with CM of adipocytes-Grem2 but increased by IL-6 treatment. In orthotopic breast cancer mouse model, mice injected with both MTV/TM-011 cells and adipocytes-Grem2 showed smaller primary tumors and lower lung metastasis than controls. However, IL-6 administration increased both the size of primary tumor and the number of metastatic lung lesions, which were reduced by adipocytes-Grem2.ConclusionsOur study suggests that GREM2 overexpression in adipocytes can inhibit adipogenesis, reduce the expression and secretion of several adipokines, including IL-6, and ultimately inhibit breast cancer progression.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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