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Exosomal ?v?6 integrin is required for monocyte M2 polarization in prostate cancer.

ABSTRACT: Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described ?v?6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel ?v?6-mediated signaling pathway that has profound effects on the microenvironment. We show that ?v?6 is transferred from cancer cells to monocytes, including ?6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express ?v?6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas ?v?6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, ?v?6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc-/- prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that ?v?6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of ?v?6 from cancer cells to monocytes through exosomes.

SUBMITTER: Lu H

PROVIDER: S-EPMC6081240 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer.

Lu Huimin H Bowler Nicholas N Harshyne Larry A LA Craig Hooper D D Krishn Shiv Ram SR Kurtoglu Senem S Fedele Carmine C Liu Qin Q Tang Hsin-Yao HY Kossenkov Andrew V AV Kelly William K WK Wang Kerith K Kean Rhonda B RB Weinreb Paul H PH Yu Lei L Dutta Anindita A Fortina Paolo P Ertel Adam A Stanczak Maria M Forsberg Flemming F Gabrilovich Dmitry I DI Speicher David W DW Altieri Dario C DC Languino Lucia R LR

Matrix biology : journal of the International Society for Matrix Biology 20180309

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvβ ...[more]

PMID: 29530483

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Project description:BackgroundEmerging evidence has revealed that tumor-associated macrophages (TAMs) and exosomes play a crucial role in the microenvironment for tumor growth. However, the mechanisms through which exosomal miRNAs modulate TAMs and tumor development in breast cancer are not fully understood.MethodsWe constructed a macrophage model and an indirect coculture system consist of breast cancer cells and macrophages. Exosomes were isolated from BC cells culture supernatant and identified by transmission electron microscopy, Western blot and Nanosight LM10 system. The expression of miR-148b-3p in exosomes was determined by qRT-PCR and the effect of exosomal miR-148b-3p on macrophage polarization was measured using qRT-PCR and ELISA. The proliferation, migration and invasion of BC cells were estimated by EdU, wound healing assay and transwell assay. We employed bioinformatics, luciferase reporter assay and Western blot to identify the target gene of miR-148b-3p. Western blot was used to clarify the mechanism of exosomal miR-148b-3p mediated the crosstalk between BC cells and M2 macrophages.ResultsCancer-derived exosomes could induce M2 polarization of macrophages, which promoted the migration and invasion of breast cancer cells. We found that exosomal miR-148b-3p was overexpressed in breast cancer cell-derived exosomes and correlated with lymph node metastasis, late tumor stage and worse prognosis. Upregulated miR-148b-3p expression in exosomes modulated macrophage polarization by targeting TSC2, which promoted the proliferation and might affect migration and invasion of breast cancer cells. Interestingly, we found that exosomal miR-148b-3p could induce M2 macrophage polarization via the TSC2/mTORC1 signaling pathway in breast cancer.ConclusionOverall, our study elucidated that miR-148b-3p could be transported by exosomes from breast cancer cells to surrounding macrophages and induced M2 polarization by targeting TSC2, providing novel insights for breast cancer therapy.

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Exosomal ?v?6 integrin is required for monocyte M2 polarization in prostate cancer.

Publications

Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer.

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