Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response.

Gazdic, Marina; Simovic Markovic, Bojana; Jovicic, Nemanja; Misirkic-Marjanovic, Maja; Djonov, Valentin; Jakovljevic, Vladimir; Arsenijevic, Nebojsa; Lukic, Miodrag L; Volarevic, Vladislav (2017). Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response. Stem cells international, 2017, p. 6294717. Hindawi 10.1155/2017/6294717

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Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Topographical and Clinical Anatomy

UniBE Contributor:

Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1687-966X

Publisher:

Hindawi

Language:

English

Submitter:

David Christian Haberthür

Date Deposited:

18 Jan 2018 10:48

Last Modified:

23 Oct 2019 14:05

Publisher DOI:

10.1155/2017/6294717

PubMed ID:

28798777

BORIS DOI:

10.7892/boris.109003

URI:

https://boris.unibe.ch/id/eprint/109003

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