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Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression

Zhao, Kun ; Wang, Zhe ; Hackert, Thilo ; Pitzer, Claudia ; Zöller, Margot

In: Journal of Experimental & Clinical Cancer Research, 37 (2018), Nr. 312. pp. 1-23. ISSN 1756-9966

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Download (15MB) | Lizenz: Creative Commons LizenzvertragTspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression by Zhao, Kun ; Wang, Zhe ; Hackert, Thilo ; Pitzer, Claudia ; Zöller, Margot underlies the terms of Creative Commons Attribution 4.0

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Abstract

Background: The tetraspanins Tspan8 and CD151 promote metastasis, exosomes (Exo) being suggested to be important in the crosstalk between tumor and host. The contribution of Tspan8 and CD151 to host versus tumor-derived exosome (TEX) activities being not defined, we approached the questions using 3-methylcholanthrene-induced (MCA) tumors from wt, Tspan8ko, CD151ko and Tspan8/CD151 (db)ko mice, implanted into tetraspanin-competent and deficient hosts.

Methods: Tumor growth and dissemination, hematopoiesis and angiogenesis were surveyed in wild type (wt), Tspan8ko, CD151ko and dbko mice bearing tetraspanin-competent and -deficient MCA tumors. In vitro studies using tumor cells, bone marrow cells (BMC) and endothelial cells (EC) elaborated the mechanism of serum (s)Exo- and TEX-induced target modulation.

Results: Tumors grew in autochthonous and syngeneic hosts differing in Tspan8- and/or CD151-competence. However, Tspan8ko- and/or CD151ko-tumor cell dissemination and settlement in metastatic organs was significantly reduced in the autochthonous host, and less severely in the wt-host. Impaired wt-MCA tumor dissemination in the ko-host confirmed a contribution of host- and tumor-Tspan8/-CD151 to tumor cell dissemination, delivery of sExo and TEX being severely impaired by a Tspan8ko/CD151ko. Coculturing tumor cells, BMC and EC with sExo and TEX revealed minor defects in epithelial mesenchymal transition and apoptosis resistance of ko tumors. Strongly reduced migratory and invasive capacity of Tspan8ko/CD151ko-MCA relies on distorted associations with integrins and CAM and missing Tspan8/CD151-promoted recruitment of proteases. The defects, differing between Tspan8ko- and CD151ko-MCA, were rescued by wt-TEX and, less efficiently Tspan8ko- and CD151ko-TEX. Minor defects in hematopoietic progenitor maturation were based on the missing association of hematopoietic growth factors /− receptors with CD151 and, less pronounced, Tspan8. Rescue of impaired angiogenesis in ko mice by wt-sExo and promotion of angiogenesis by TEX depended on the association of Tspan8 and CD151 with GPCR and RTK in EC and tumor cells.

Conclusions: Tspan8-/CD151-TEX play central roles in tumor progression. Tspan8-/CD151-sExo and TEX contribute by stimulating angiogenesis. Tspan8 and CD151 fulfill these tasks by associating with function-relevant proteins, the additive impact of Tspan8 and CD151 relying on differences in preferred associations. The distinct Tspan8 and CD151 contributions suggest a blockade of TEX-Tspan8 and -CD151 promising for therapeutic intervention.

Item Type: Article
Journal or Publication Title: Journal of Experimental & Clinical Cancer Research
Volume: 37
Number: 312
Publisher: BioMed Central ; Springer
Place of Publication: London ; Berlin, Heidelberg
Date Deposited: 08 Feb 2019 09:29
Date: 2018
ISSN: 1756-9966
Page Range: pp. 1-23
Faculties / Institutes: Medizinische Fakultät Heidelberg > Chirurgische Universitätsklinik
Subjects: 610 Medical sciences Medicine
Uncontrolled Keywords: Tspan8 knockout, CD151 knockout, Exosomes, Metastasis, Angiogenesis, Hematopoiesis
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