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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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Stroma and endothelial cell responses to exosomal CD151 and Tspan8(A-C) Flow cytometry analysis of LnStr, RAEC and LuFb after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; mean percent±SD (3 assays) of stained cells; significant differences to untreated cells: *; (D) representative examples of SDF1, CXCR4, VEGFR1 and VEGFR3 expression in LnStr and RAEC after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 10μm) and (E) in draining LN after repeated application of ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 150μm). Exosomal CD151 and Tspan8 promote upregulated expression of several growth factors and their receptors, which varies depending on the target cell. Upregulated expression of some markers, e.g. bFGF and VEGFR1 essentially depends on the presence of both CD151 and Tspan8, whereas SDF1 and FGFR expression is independent of exosomal CD151 and Tspan8. However, exosomal Tspan8 is essential for VEGFR3 upregulation.
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Figure 6: Stroma and endothelial cell responses to exosomal CD151 and Tspan8(A-C) Flow cytometry analysis of LnStr, RAEC and LuFb after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; mean percent±SD (3 assays) of stained cells; significant differences to untreated cells: *; (D) representative examples of SDF1, CXCR4, VEGFR1 and VEGFR3 expression in LnStr and RAEC after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 10μm) and (E) in draining LN after repeated application of ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 150μm). Exosomal CD151 and Tspan8 promote upregulated expression of several growth factors and their receptors, which varies depending on the target cell. Upregulated expression of some markers, e.g. bFGF and VEGFR1 essentially depends on the presence of both CD151 and Tspan8, whereas SDF1 and FGFR expression is independent of exosomal CD151 and Tspan8. However, exosomal Tspan8 is essential for VEGFR3 upregulation.

Mentions: Premetastatic niches are frequently characterized by changes in chemokines and their receptors [64], where we controlled for a selective impact of exosomal CD151 and Tspan8 in LnStr, RAEC and LuFb after 48h coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes. LnStr, LuFb and RAEC did not uniformly respond to ASML exosome treatment. Only SDF1 and VEGFR1 were upregulated in all three cell populations after treatment with ASMLwt exosomes. However, SDF1 depended more on CD151 than Tspan8, whereas VEGFR1 stimulation required CD151 and Tspan8. CXCR4 and VEGFR3 expression, stimulated in LnStr and LuFb, respectively in LnStr and RAEC, required Tspan8-competent exosomes. FGFR upregulation in LnStr and LuFb was independent of exosomal CD151 and Tspan8 (Fig.6A-6D). These findings could be confirmed by staining LN of ASML exosome-treated rats (Fig.6E).


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)

Stroma and endothelial cell responses to exosomal CD151 and Tspan8(A-C) Flow cytometry analysis of LnStr, RAEC and LuFb after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; mean percent±SD (3 assays) of stained cells; significant differences to untreated cells: *; (D) representative examples of SDF1, CXCR4, VEGFR1 and VEGFR3 expression in LnStr and RAEC after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 10μm) and (E) in draining LN after repeated application of ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 150μm). Exosomal CD151 and Tspan8 promote upregulated expression of several growth factors and their receptors, which varies depending on the target cell. Upregulated expression of some markers, e.g. bFGF and VEGFR1 essentially depends on the presence of both CD151 and Tspan8, whereas SDF1 and FGFR expression is independent of exosomal CD151 and Tspan8. However, exosomal Tspan8 is essential for VEGFR3 upregulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Stroma and endothelial cell responses to exosomal CD151 and Tspan8(A-C) Flow cytometry analysis of LnStr, RAEC and LuFb after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes; mean percent±SD (3 assays) of stained cells; significant differences to untreated cells: *; (D) representative examples of SDF1, CXCR4, VEGFR1 and VEGFR3 expression in LnStr and RAEC after coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 10μm) and (E) in draining LN after repeated application of ASMLwt, -CD151kd and/or -Tspan8kd exosomes (scale bar: 150μm). Exosomal CD151 and Tspan8 promote upregulated expression of several growth factors and their receptors, which varies depending on the target cell. Upregulated expression of some markers, e.g. bFGF and VEGFR1 essentially depends on the presence of both CD151 and Tspan8, whereas SDF1 and FGFR expression is independent of exosomal CD151 and Tspan8. However, exosomal Tspan8 is essential for VEGFR3 upregulation.
Mentions: Premetastatic niches are frequently characterized by changes in chemokines and their receptors [64], where we controlled for a selective impact of exosomal CD151 and Tspan8 in LnStr, RAEC and LuFb after 48h coculture with ASMLwt, -CD151kd and/or -Tspan8kd exosomes. LnStr, LuFb and RAEC did not uniformly respond to ASML exosome treatment. Only SDF1 and VEGFR1 were upregulated in all three cell populations after treatment with ASMLwt exosomes. However, SDF1 depended more on CD151 than Tspan8, whereas VEGFR1 stimulation required CD151 and Tspan8. CXCR4 and VEGFR3 expression, stimulated in LnStr and LuFb, respectively in LnStr and RAEC, required Tspan8-competent exosomes. FGFR upregulation in LnStr and LuFb was independent of exosomal CD151 and Tspan8 (Fig.6A-6D). These findings could be confirmed by staining LN of ASML exosome-treated rats (Fig.6E).

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