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Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression.

ABSTRACT: Cancer-secreted exosomes are emerging mediators of cancer-associated cachexia. Here, we show that miR-155 secreted by breast cancer cells is a potent role on the catabolism of adipocytes and muscle cells through targeting the PPAR?. After cocultivated with mature adipocytes or C2C12, tumour cells exhibit an aggressive phenotype via inducing epithelial-mesenchymal transition while breast cancer-derived exosomes increased catabolism and release the metabolites in adipocytes and muscle cells. In adipocytes, cancer cell-secreted miR-155 promotes beige/brown differentiation and remodel metabolism in resident adipocytes by downregulating the PPAR? expression, but does not significantly affect biological conversion in C2C12. Likewise, propranolol ameliorates tumour exosomes-associated cachectic wasting through upregulating the PPAR? expression. In summary, we have demonstrated that the transfer of miR-155 from exosomes acts as an oncogenic signal reprograming systemic energy metabolism and leading to cancer-associated cachexia in breast cancer.

SUBMITTER: Wu Q

PROVIDER: S-EPMC6768245 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression.

Wu Qi Q Sun Si S Li Zhiyu Z Yang Qian Q Li Bei B Zhu Shan S Wang Lijun L Wu Juan J Yuan Jingping J Wang Changhua C Li Juanjuan J Sun Shengrong S

Adipocyte 20181211 1

Cancer-secreted exosomes are emerging mediators of cancer-associated cachexia. Here, we show that miR-155 secreted by breast cancer cells is a potent role on the catabolism of adipocytes and muscle cells through targeting the PPARγ. After cocultivated with mature adipocytes or C2C12, tumour cells exhibit an aggressive phenotype via inducing epithelial-mesenchymal transition while breast cancer-derived exosomes increased catabolism and release the metabolites in adipocytes and muscle cells. In ad ...[more]

PMID: 30474469

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Project description:Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Dataset Information

Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression.

Publications

Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression.

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