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Tumor-derived Exosome Promotes Metastasis via Altering its Phenotype and Inclusions.

ABSTRACT: Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC8176431 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Tumor-derived Exosome Promotes Metastasis via Altering its Phenotype and Inclusions.

Zhou Yu Y Chen Fan F Xie Xiaodong X Nie Huifang H Lian Shu S Zhong Chunlian C Fu Chengbin C Shen Weiyu W Li Bifei B Ye Yongqing Y Lu Yusheng Y Jia Lee L

Journal of Cancer 20210519 14

Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression o ...[more]

PMID: 34093824

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Project description:The angiopoietin (Angpt)-TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1-TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell-expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell-expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma. SIGNIFICANCE: This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.

Project description:BackgroundBreast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear.MethodsAdipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes.ResultsIt was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer.ConclusionIn summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

Dataset Information

Tumor-derived Exosome Promotes Metastasis via Altering its Phenotype and Inclusions.

Publications

Tumor-derived Exosome Promotes Metastasis via Altering its Phenotype and Inclusions.

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