Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0961-6 |
| _version_ | 1819067698355634176 |
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| author | Kun Zhao Zhe Wang Thilo Hackert Claudia Pitzer Margot Zöller |
| author_facet | Kun Zhao Zhe Wang Thilo Hackert Claudia Pitzer Margot Zöller |
| author_sort | Kun Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T16:22:23Z |
| format | Article |
| id | doaj.art-715e889d14e4487e83c52b4ce79a387c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-21T16:22:23Z |
| publishDate | 2018-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-715e889d14e4487e83c52b4ce79a387c2022-12-21T18:57:32ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-12-0137112310.1186/s13046-018-0961-6Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progressionKun Zhao0Zhe Wang1Thilo Hackert2Claudia Pitzer3Margot Zöller4Pancreas Section, University Hospital of Surgery, Ruprecht-Karls-UniversityPancreas Section, University Hospital of Surgery, Ruprecht-Karls-UniversityPancreas Section, University Hospital of Surgery, Ruprecht-Karls-UniversityInterdisciplinary Neurobehavioral Core, Institute of Pharmacology, Ruprecht-Karls-UniversityPancreas Section, University Hospital of Surgery, Ruprecht-Karls-UniversityAbstract 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.http://link.springer.com/article/10.1186/s13046-018-0961-6Tspan8 knockoutCD151 knockoutExosomesMetastasisAngiogenesisHematopoiesis |
| spellingShingle | Kun Zhao Zhe Wang Thilo Hackert Claudia Pitzer Margot Zöller Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression Journal of Experimental & Clinical Cancer Research Tspan8 knockout CD151 knockout Exosomes Metastasis Angiogenesis Hematopoiesis |
| title | Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| title_full | Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| title_fullStr | Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| title_full_unstemmed | Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| title_short | Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| title_sort | tspan8 and tspan8 cd151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression |
| topic | Tspan8 knockout CD151 knockout Exosomes Metastasis Angiogenesis Hematopoiesis |
| url | http://link.springer.com/article/10.1186/s13046-018-0961-6 |
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