Abstract 47: Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response
| Autor: | Jennifer E. Koblinski, Madhavi Puchalapalli, Bin Hu, Megan R. Sayyad |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:47-47 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2018-47 |
| Popis: | Brain metastasis is a devastating, late-stage event affecting 10-30% of breast cancer patients, but it is unclear how breast cancer cells can cross the blood-brain barrier (BBB) and colonize the unique brain environment. Exosomes, endosomal-derived extracellular vesicles, have been reported to support premetastatic niche formation through recruitment of tumor growth-supporting cells, creating sites conducive to cancer development. Still, it is not known how exosomes might prime the distinctive brain environment for metastasis despite the ability of circulating exosomes to readily cross the BBB. Glial cells, namely astrocytes and microglia, are important contributors to brain metastasis, and astrocytes in particular secrete exosomes that promote tumor outgrowth in the brain. We therefore investigated the effects of breast cancer exosomes on astrocytes in promoting brain premetastatic niche formation. Using ultracentrifugation, we isolated exosomes from 4T1 metastatic and 67NR nonmetastatic mouse mammary carcinoma and MDA-MB-231 human triple-negative breast cancer cell-conditioned media. Exosomes were characterized using Western immunoblot, dynamic light scatter analysis, and transmission electron microscopy, and labeled with a fluorescent lipid dye. Mouse and human astrocytes were then treated with either 4T1 or MDA-MB-231 exosomes, respectively, and vesicle internalization was assessed using confocal microscopy. Astrocytes were indeed found to internalize cancer exosomes in vitro. Using qPCR analysis, we explored gene expression changes in mouse astrocytes treated with 4T1 exosomes compared to those treated with 67NR exosome nonmetastatic controls. 4T1 exosomes were found to significantly upregulate expression of tenascin C, an astrocyte-derived brain extracellular matrix protein, suggesting the brain matrix could be remodeled prior to cancer cell arrival. Further, astrocytes treated with 4T1 exosomes exhibited significant upregulation of inflammation-associated genes, namely COX-2, IL-6, CCL4 and PDGF-alpha, genes also associated with cancer and metastasis, specifically to the brain. Alternatively, 67NR exosome treated-astrocytes exhibited significant downregulation in these genes of interest, suggesting that there is a unique response profile associated with nonmetastatic versus metastatic breast cancer-derived exosomes. Taken together, these findings suggest that breast cancer exosomes could drive transformation of the brain environment towards a prometastatic site. Citation Format: Megan Sayyad, Madhavi Puchalapalli, Bin Hu, Jennifer Koblinski. Brain metastatic versus non-metastatic breast cancer exosomes influence astrocyte response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 47. |
| Databáze: | OpenAIRE |
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