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The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding.

Yue S, Mu W, Erb U, Zöller M - Oncotarget (2015)

Bottom Line: Approaching to elaborate the underlying mechanism, we compared ASMLwt, -CD151kd and/or Tspan8kd clones.These effects are not seen or are weakened using ASML-CD151kd or -Tspan8kd exosomes, which is at least partly due to reduced binding/uptake of CD151- and/or Tspan8-deficient exosomes.Thus, CD151- and Tspan8-competent tumor exosomes support matrix degradation, reprogram stroma and hematopoietic cells and drive non-metastatic ASML-CD151/Tspan8kd cells towards a motile phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.

ABSTRACT
Tspan8 and CD151 are metastasis-promoting tetraspanins and a knockdown (kd) of Tspan8 or CD151 and most pronounced of both tetraspanins affects the metastatic potential of the rat pancreatic adenocarcinoma line ASML. Approaching to elaborate the underlying mechanism, we compared ASMLwt, -CD151kd and/or Tspan8kd clones. We focused on tumor exosomes, as exosomes play a major role in tumor progression and tetraspanins are suggested to be engaged in exosome targeting. ASML-CD151/Tspan8kd cells poorly metastasize, but regain metastatic capacity, when rats are pretreated with ASMLwt, but not ASML-CD151kd and/or -Tspan8kd exosomes. Both exosomal CD151 and Tspan8 contribute to host matrix remodelling due to exosomal tetraspanin-integrin and tetraspanin-protease associations. ASMLwt exosomes also support stroma cell activation with upregulation of cytokines, cytokine receptors and proteases and promote inflammatory cytokine expression in hematopoietic cells. Finally, CD151-/Tspan8-competent exosomes support EMT gene expression in poorly-metastatic ASML-CD151/Tspan8kd cells. These effects are not seen or are weakened using ASML-CD151kd or -Tspan8kd exosomes, which is at least partly due to reduced binding/uptake of CD151- and/or Tspan8-deficient exosomes. Thus, CD151- and Tspan8-competent tumor exosomes support matrix degradation, reprogram stroma and hematopoietic cells and drive non-metastatic ASML-CD151/Tspan8kd cells towards a motile phenotype.

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Leukocyte responses to exosomal CD151 and Tspan8(A-F) BMC and LNC were cocultured with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; (A,C,D,F) cytokine and activation marker expression as well as activation of the JAK/STAT signaling pathway and of NFAT and FoxP3 was evaluated by flow cytometry; mean percent±SD of stained cells; significant differences to BMC and LNC cultured in the absence of exosomes: * and representative examples; (B,E) representative examples of confocal microscopy (scale bar: 10μm). In BMC and LNC, ASML exosomes strengthen inflammatory cytokine expression; These effects are supported by, but not exclusively depending on exosomal CD151 and Tspan8.
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Figure 7: Leukocyte responses to exosomal CD151 and Tspan8(A-F) BMC and LNC were cocultured with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; (A,C,D,F) cytokine and activation marker expression as well as activation of the JAK/STAT signaling pathway and of NFAT and FoxP3 was evaluated by flow cytometry; mean percent±SD of stained cells; significant differences to BMC and LNC cultured in the absence of exosomes: * and representative examples; (B,E) representative examples of confocal microscopy (scale bar: 10μm). In BMC and LNC, ASML exosomes strengthen inflammatory cytokine expression; These effects are supported by, but not exclusively depending on exosomal CD151 and Tspan8.

Mentions: Tumor exosomes were reported to promote inflammation and immunosuppression [59-61,65]. Indeed, inflammatory TNFα and IL6 expression became upregulated in BMC and LNC. The latter also expressing C3 and HSP70 at an increased level. We also noted upregulated expression of the immunosuppressive cytokine IL10, but expression of the effector cytokines IL2 and IFNγ as well as of the activation markers CD44v6 and CD69 were unaltered or slightly reduced only in ASMwt exosome treated LNC. Upregulation of TGFβ was more pronounced in BMC than LNC cocultures, where it should be noted that ASML exosomes more strongly affected BMC than LNC. Confirming the exosome-induced shift towards inflammation / immunosuppression, TLR4, p-Stat3 and p-Stat4 expression were upregulated in BMC and LNC (data not shown) and FoxP3 expression was increased in LNC, but NFAT expression was not altered. Furthermore, while ASML-CD151/Tspan8kd exosomes hardly exerted any effect, in most instances ASMLwt exosomes had the strongest impact (Fig.7A-7F).


The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding.

Yue S, Mu W, Erb U, Zöller M - Oncotarget (2015)

Leukocyte responses to exosomal CD151 and Tspan8(A-F) BMC and LNC were cocultured with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; (A,C,D,F) cytokine and activation marker expression as well as activation of the JAK/STAT signaling pathway and of NFAT and FoxP3 was evaluated by flow cytometry; mean percent±SD of stained cells; significant differences to BMC and LNC cultured in the absence of exosomes: * and representative examples; (B,E) representative examples of confocal microscopy (scale bar: 10μm). In BMC and LNC, ASML exosomes strengthen inflammatory cytokine expression; These effects are supported by, but not exclusively depending on exosomal CD151 and Tspan8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385857&req=5

Figure 7: Leukocyte responses to exosomal CD151 and Tspan8(A-F) BMC and LNC were cocultured with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; (A,C,D,F) cytokine and activation marker expression as well as activation of the JAK/STAT signaling pathway and of NFAT and FoxP3 was evaluated by flow cytometry; mean percent±SD of stained cells; significant differences to BMC and LNC cultured in the absence of exosomes: * and representative examples; (B,E) representative examples of confocal microscopy (scale bar: 10μm). In BMC and LNC, ASML exosomes strengthen inflammatory cytokine expression; These effects are supported by, but not exclusively depending on exosomal CD151 and Tspan8.
Mentions: Tumor exosomes were reported to promote inflammation and immunosuppression [59-61,65]. Indeed, inflammatory TNFα and IL6 expression became upregulated in BMC and LNC. The latter also expressing C3 and HSP70 at an increased level. We also noted upregulated expression of the immunosuppressive cytokine IL10, but expression of the effector cytokines IL2 and IFNγ as well as of the activation markers CD44v6 and CD69 were unaltered or slightly reduced only in ASMwt exosome treated LNC. Upregulation of TGFβ was more pronounced in BMC than LNC cocultures, where it should be noted that ASML exosomes more strongly affected BMC than LNC. Confirming the exosome-induced shift towards inflammation / immunosuppression, TLR4, p-Stat3 and p-Stat4 expression were upregulated in BMC and LNC (data not shown) and FoxP3 expression was increased in LNC, but NFAT expression was not altered. Furthermore, while ASML-CD151/Tspan8kd exosomes hardly exerted any effect, in most instances ASMLwt exosomes had the strongest impact (Fig.7A-7F).

Bottom Line: Approaching to elaborate the underlying mechanism, we compared ASMLwt, -CD151kd and/or Tspan8kd clones.These effects are not seen or are weakened using ASML-CD151kd or -Tspan8kd exosomes, which is at least partly due to reduced binding/uptake of CD151- and/or Tspan8-deficient exosomes.Thus, CD151- and Tspan8-competent tumor exosomes support matrix degradation, reprogram stroma and hematopoietic cells and drive non-metastatic ASML-CD151/Tspan8kd cells towards a motile phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.

ABSTRACT
Tspan8 and CD151 are metastasis-promoting tetraspanins and a knockdown (kd) of Tspan8 or CD151 and most pronounced of both tetraspanins affects the metastatic potential of the rat pancreatic adenocarcinoma line ASML. Approaching to elaborate the underlying mechanism, we compared ASMLwt, -CD151kd and/or Tspan8kd clones. We focused on tumor exosomes, as exosomes play a major role in tumor progression and tetraspanins are suggested to be engaged in exosome targeting. ASML-CD151/Tspan8kd cells poorly metastasize, but regain metastatic capacity, when rats are pretreated with ASMLwt, but not ASML-CD151kd and/or -Tspan8kd exosomes. Both exosomal CD151 and Tspan8 contribute to host matrix remodelling due to exosomal tetraspanin-integrin and tetraspanin-protease associations. ASMLwt exosomes also support stroma cell activation with upregulation of cytokines, cytokine receptors and proteases and promote inflammatory cytokine expression in hematopoietic cells. Finally, CD151-/Tspan8-competent exosomes support EMT gene expression in poorly-metastatic ASML-CD151/Tspan8kd cells. These effects are not seen or are weakened using ASML-CD151kd or -Tspan8kd exosomes, which is at least partly due to reduced binding/uptake of CD151- and/or Tspan8-deficient exosomes. Thus, CD151- and Tspan8-competent tumor exosomes support matrix degradation, reprogram stroma and hematopoietic cells and drive non-metastatic ASML-CD151/Tspan8kd cells towards a motile phenotype.

Show MeSH
Related in: MedlinePlus