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Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.

Knuchel S, Anderle P, Werfelli P, Diamantis E, Rüegg C - Oncotarget (2015)

Bottom Line: These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2.Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects.Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland.

ABSTRACT
Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.

No MeSH data available.


Related in: MedlinePlus

Cultured dermal, colon and colon cancer associated fibroblasts induce similarly cancer cell elongation and motility and have equivalent gene expression and activation profilesA. Representative images of SW620-GFP co-cultured with dermal fibroblasts (FB), normal colon fibroblasts (CFB) and colon cancer associated fibroblasts (CAF). B. Quantification of cancer cell elongation with CFB and CAF, represented as mean +/− SD. C. Quantification of SW620 motility during 48 hours culture with CFB and CAF, represented as mean +/− SD. D. Self-organizing heat-maps of the top 100 genes with greatest variability across all samples, showing similar expression profile for Colon Normal Fibroblasts (cFB_N), Colon Cancer Fibroblasts (cFB_T) and Dermal Fibroblasts (dFB_N), but highly different profiles compare to HUVEC (HU). E. PCA plot demonstrating that Colon Normal Fibroblasts (n), Colon Cancer Fibroblasts (t) and Dermal Fibroblasts (d) are similar, while they greatly diverge from HUVEC (e). F. PCR expression analysis of fibroblast activation markers.
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Figure 2: Cultured dermal, colon and colon cancer associated fibroblasts induce similarly cancer cell elongation and motility and have equivalent gene expression and activation profilesA. Representative images of SW620-GFP co-cultured with dermal fibroblasts (FB), normal colon fibroblasts (CFB) and colon cancer associated fibroblasts (CAF). B. Quantification of cancer cell elongation with CFB and CAF, represented as mean +/− SD. C. Quantification of SW620 motility during 48 hours culture with CFB and CAF, represented as mean +/− SD. D. Self-organizing heat-maps of the top 100 genes with greatest variability across all samples, showing similar expression profile for Colon Normal Fibroblasts (cFB_N), Colon Cancer Fibroblasts (cFB_T) and Dermal Fibroblasts (dFB_N), but highly different profiles compare to HUVEC (HU). E. PCA plot demonstrating that Colon Normal Fibroblasts (n), Colon Cancer Fibroblasts (t) and Dermal Fibroblasts (d) are similar, while they greatly diverge from HUVEC (e). F. PCR expression analysis of fibroblast activation markers.

Mentions: Next we tested whether fibroblasts isolated from normal colon (CFB) or colon cancer (CAF) tissues were also able to induce cancer cell elongation and motility. Indeed, CFB and CAF induced SW620 and HT29 elongation and motility to extents comparable to those exerted by dermal fibroblasts (Fig. 2A-2C). The fact that dermal fibroblasts and CFB were able to induce these effects on CRC cells was unexpected, as previous studies demonstrated that only freshly isolated CAF, but not normal fibroblasts, induced cancer progression in vivo [21, 22].


Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.

Knuchel S, Anderle P, Werfelli P, Diamantis E, Rüegg C - Oncotarget (2015)

Cultured dermal, colon and colon cancer associated fibroblasts induce similarly cancer cell elongation and motility and have equivalent gene expression and activation profilesA. Representative images of SW620-GFP co-cultured with dermal fibroblasts (FB), normal colon fibroblasts (CFB) and colon cancer associated fibroblasts (CAF). B. Quantification of cancer cell elongation with CFB and CAF, represented as mean +/− SD. C. Quantification of SW620 motility during 48 hours culture with CFB and CAF, represented as mean +/− SD. D. Self-organizing heat-maps of the top 100 genes with greatest variability across all samples, showing similar expression profile for Colon Normal Fibroblasts (cFB_N), Colon Cancer Fibroblasts (cFB_T) and Dermal Fibroblasts (dFB_N), but highly different profiles compare to HUVEC (HU). E. PCA plot demonstrating that Colon Normal Fibroblasts (n), Colon Cancer Fibroblasts (t) and Dermal Fibroblasts (d) are similar, while they greatly diverge from HUVEC (e). F. PCR expression analysis of fibroblast activation markers.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546468&req=5

Figure 2: Cultured dermal, colon and colon cancer associated fibroblasts induce similarly cancer cell elongation and motility and have equivalent gene expression and activation profilesA. Representative images of SW620-GFP co-cultured with dermal fibroblasts (FB), normal colon fibroblasts (CFB) and colon cancer associated fibroblasts (CAF). B. Quantification of cancer cell elongation with CFB and CAF, represented as mean +/− SD. C. Quantification of SW620 motility during 48 hours culture with CFB and CAF, represented as mean +/− SD. D. Self-organizing heat-maps of the top 100 genes with greatest variability across all samples, showing similar expression profile for Colon Normal Fibroblasts (cFB_N), Colon Cancer Fibroblasts (cFB_T) and Dermal Fibroblasts (dFB_N), but highly different profiles compare to HUVEC (HU). E. PCA plot demonstrating that Colon Normal Fibroblasts (n), Colon Cancer Fibroblasts (t) and Dermal Fibroblasts (d) are similar, while they greatly diverge from HUVEC (e). F. PCR expression analysis of fibroblast activation markers.
Mentions: Next we tested whether fibroblasts isolated from normal colon (CFB) or colon cancer (CAF) tissues were also able to induce cancer cell elongation and motility. Indeed, CFB and CAF induced SW620 and HT29 elongation and motility to extents comparable to those exerted by dermal fibroblasts (Fig. 2A-2C). The fact that dermal fibroblasts and CFB were able to induce these effects on CRC cells was unexpected, as previous studies demonstrated that only freshly isolated CAF, but not normal fibroblasts, induced cancer progression in vivo [21, 22].

Bottom Line: These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2.Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects.Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, CH-1700, Switzerland.

ABSTRACT
Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.

No MeSH data available.


Related in: MedlinePlus