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Fibroblast α11β1 integrin regulates tensional homeostasis in fibroblast/A549 carcinoma heterospheroids.

Lu N, Karlsen TV, Reed RK, Kusche-Gullberg M, Gullberg D - PLoS ONE (2014)

Bottom Line: Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids.Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5.In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.

ABSTRACT
We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.

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CXCL5 regulates heterospheroid invasion in 3D collagen gels.Six-day-old spheroids were embedded in 3D collagen gels (1 mg/ml collagen type I) in the presence of DMSO (control) or different concentrations of the CXCL5 receptor inhibitor SB225002 (upper graph) or recombinant CXCL5 (lower graph). Six spheroids were imbedded into the collagen gels under each condition. Invasion of the cells from the spheroids into the collagen gels was observed under an inverted phase contrast microscope and photographed after 48 h. Size bar  = 100 µm.
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pone-0103173-g007: CXCL5 regulates heterospheroid invasion in 3D collagen gels.Six-day-old spheroids were embedded in 3D collagen gels (1 mg/ml collagen type I) in the presence of DMSO (control) or different concentrations of the CXCL5 receptor inhibitor SB225002 (upper graph) or recombinant CXCL5 (lower graph). Six spheroids were imbedded into the collagen gels under each condition. Invasion of the cells from the spheroids into the collagen gels was observed under an inverted phase contrast microscope and photographed after 48 h. Size bar  = 100 µm.

Mentions: The CXCR2 inhibitor was furthermore added in experiments where cell migration onto a collagen I coated surface was analyzed. The inhibitor (at 2 µM) reduced cell migration in both types of spheroids. Furthermore, addition of recombinant CXCL5 increased cell migration from α11-/-/A549 spheroids to the same level as that seen from α11+/+/A549 spheroids (Fig.7).


Fibroblast α11β1 integrin regulates tensional homeostasis in fibroblast/A549 carcinoma heterospheroids.

Lu N, Karlsen TV, Reed RK, Kusche-Gullberg M, Gullberg D - PLoS ONE (2014)

CXCL5 regulates heterospheroid invasion in 3D collagen gels.Six-day-old spheroids were embedded in 3D collagen gels (1 mg/ml collagen type I) in the presence of DMSO (control) or different concentrations of the CXCL5 receptor inhibitor SB225002 (upper graph) or recombinant CXCL5 (lower graph). Six spheroids were imbedded into the collagen gels under each condition. Invasion of the cells from the spheroids into the collagen gels was observed under an inverted phase contrast microscope and photographed after 48 h. Size bar  = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4116160&req=5

pone-0103173-g007: CXCL5 regulates heterospheroid invasion in 3D collagen gels.Six-day-old spheroids were embedded in 3D collagen gels (1 mg/ml collagen type I) in the presence of DMSO (control) or different concentrations of the CXCL5 receptor inhibitor SB225002 (upper graph) or recombinant CXCL5 (lower graph). Six spheroids were imbedded into the collagen gels under each condition. Invasion of the cells from the spheroids into the collagen gels was observed under an inverted phase contrast microscope and photographed after 48 h. Size bar  = 100 µm.
Mentions: The CXCR2 inhibitor was furthermore added in experiments where cell migration onto a collagen I coated surface was analyzed. The inhibitor (at 2 µM) reduced cell migration in both types of spheroids. Furthermore, addition of recombinant CXCL5 increased cell migration from α11-/-/A549 spheroids to the same level as that seen from α11+/+/A549 spheroids (Fig.7).

Bottom Line: Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids.Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5.In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway; Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.

ABSTRACT
We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.

Show MeSH
Related in: MedlinePlus