Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression
Abstract Background Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer. However, the mediators and mechanisms remain unclear. Methods Survival...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-05-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1210-3 |
| _version_ | 1828415674518601728 |
|---|---|
| author | Qi Wu Juanjuan Li Zhiyu Li Si Sun Shan Zhu Lijun Wang Juan Wu Jingping Yuan Yimin Zhang Shengrong Sun Changhua Wang |
| author_facet | Qi Wu Juanjuan Li Zhiyu Li Si Sun Shan Zhu Lijun Wang Juan Wu Jingping Yuan Yimin Zhang Shengrong Sun Changhua Wang |
| author_sort | Qi Wu |
| collection | DOAJ |
| description | Abstract Background Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer. However, the mediators and mechanisms remain unclear. Methods Survival probabilities were estimated using the Kaplan–Meier method based on immunohistochemistry results. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes. Results We show that tumour-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumour cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by exosomes from the co-culture system that carry high levels of miRNA-144 and miRNA-126. miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis, and exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte–induced tumour growth. Conclusions These results demonstrate that by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes, exosomal miRNA-144 and miRNA-126 from the tumour-adipocyte interaction reprogram systemic energy metabolism to facilitate tumour progression. |
| first_indexed | 2024-12-10T13:50:21Z |
| format | Article |
| id | doaj.art-4d2adc29cc304570a83a13e19b49a909 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T13:50:21Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-4d2adc29cc304570a83a13e19b49a9092022-12-22T01:46:13ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-05-0138112010.1186/s13046-019-1210-3Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progressionQi Wu0Juanjuan Li1Zhiyu Li2Si Sun3Shan Zhu4Lijun Wang5Juan Wu6Jingping Yuan7Yimin Zhang8Shengrong Sun9Changhua Wang10Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Clinical Laboratory, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Pathology, Renmin Hospital of Wuhan UniversityDepartment of Pathology, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Breast and Thyroid Surgery, Renmin Hospital of Wuhan UniversityDepartment of Pathophysiology, Wuhan University School of Basic Medical SciencesAbstract Background Emerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer. However, the mediators and mechanisms remain unclear. Methods Survival probabilities were estimated using the Kaplan–Meier method based on immunohistochemistry results. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes. Results We show that tumour-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumour cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by exosomes from the co-culture system that carry high levels of miRNA-144 and miRNA-126. miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis, and exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte–induced tumour growth. Conclusions These results demonstrate that by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes, exosomal miRNA-144 and miRNA-126 from the tumour-adipocyte interaction reprogram systemic energy metabolism to facilitate tumour progression.http://link.springer.com/article/10.1186/s13046-019-1210-3Breast cancerExosomesAdipocytesTumour progression |
| spellingShingle | Qi Wu Juanjuan Li Zhiyu Li Si Sun Shan Zhu Lijun Wang Juan Wu Jingping Yuan Yimin Zhang Shengrong Sun Changhua Wang Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression Journal of Experimental & Clinical Cancer Research Breast cancer Exosomes Adipocytes Tumour progression |
| title | Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| title_full | Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| title_fullStr | Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| title_full_unstemmed | Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| title_short | Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| title_sort | exosomes from the tumour adipocyte interplay stimulate beige brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression |
| topic | Breast cancer Exosomes Adipocytes Tumour progression |
| url | http://link.springer.com/article/10.1186/s13046-019-1210-3 |
| work_keys_str_mv | AT qiwu exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT juanjuanli exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT zhiyuli exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT sisun exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT shanzhu exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT lijunwang exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT juanwu exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT jingpingyuan exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT yiminzhang exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT shengrongsun exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression AT changhuawang exosomesfromthetumouradipocyteinterplaystimulatebeigebrowndifferentiationandreprogrammetabolisminstromaladipocytestopromotetumourprogression |