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IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition.

Walsh LA, Damjanovski S - Cell Commun. Signal (2011)

Bottom Line: Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways.In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7, Canada. sdamjano@uwo.ca.

ABSTRACT

Introduction: TGF-β signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of β-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.

Methods: MCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-β1 to determine if elevated levels of IGF-1 together with latent-TGF-β1 could cause EMT.

Results: Results showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

Conclusions: Taken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF-β signaling, and EMT in breast cancer cells.

No MeSH data available.


Related in: MedlinePlus

Schematic Model of IGF-1 and TGF-β1 signaling in MCF-7 breast cancer cells. 1) IGF-1 binds IGF-1 receptor. 2) IGF-1 receptor signals through the PI3K and MAPK pathways. 3) IGF-1 signaling causes transcriptional activation of unknown target genes (?). 4) Unknown target protein(s) (?) are secreted and activate MMPs. 5) Active MMPs are available to activate latent molecules in the ECM, such as TGF-β. 6) Active TGF-β1 binds TGF-β1 receptor. 7) TGF-β signaling causes nuclear localization of β-catenin. 8) TGF-β signaling causing transcriptional activation of genes that result in an EMT.
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Figure 6: Schematic Model of IGF-1 and TGF-β1 signaling in MCF-7 breast cancer cells. 1) IGF-1 binds IGF-1 receptor. 2) IGF-1 receptor signals through the PI3K and MAPK pathways. 3) IGF-1 signaling causes transcriptional activation of unknown target genes (?). 4) Unknown target protein(s) (?) are secreted and activate MMPs. 5) Active MMPs are available to activate latent molecules in the ECM, such as TGF-β. 6) Active TGF-β1 binds TGF-β1 receptor. 7) TGF-β signaling causes nuclear localization of β-catenin. 8) TGF-β signaling causing transcriptional activation of genes that result in an EMT.

Mentions: A major conclusion from our study is that IGF-1 signaling and TGF-β signaling work in concert to bring about an epithelial to mesenchymal transition in MCF-7 cells. TGF-β signaling has been widely studied in cancer for its ability to induce EMTs leading to metastasis [24]. Most studies describing the biological effects of TGF-β have been carried out in vitro using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted in vivo as a latent complex [8]. Thus the conditions for the activation of TGF-β are not addressed. In addition, although both IGF-1 levels and TGF-β signaling are associated with the metastatic potential of breast cancer, the mechanism of TGF-β activation and its effect on cell invasion is still poorly understood. Here for the first time we establish a critical link between these two pathways and their contribution to cancer progression. Based on our findings in MCF-7 cells, we present a model of putative latent TGF-β1 activation (Figure 6). We propose that IGF-1 transmits signals via both the PI3K and MAPK pathways that cause the transcription of unknown but specific genes. These gene products result in the extracellular activation of MMPs. This MMP activation is IGF-1 dependent and attenuated if the PI3K or MAPK signals are blocked. MMPs are then capable of working in the ECM to activate latent TGF-β1. Active TGF-β1 results in EMT characterized by the nuclear localization of β-catenin, changes in morphology and the transcription of EMT marker genes. The addition of a TGF-β inhibitor blocks this signaling cascade, demonstrating the specificity of TGF-β1 signaling. While our finding are based on studies using MCF-7 cells, the pathways and molecules examined are globally used in many cell types, developmental processes and diseases, and as such we believe that our model has broad relevance.


IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition.

Walsh LA, Damjanovski S - Cell Commun. Signal (2011)

Schematic Model of IGF-1 and TGF-β1 signaling in MCF-7 breast cancer cells. 1) IGF-1 binds IGF-1 receptor. 2) IGF-1 receptor signals through the PI3K and MAPK pathways. 3) IGF-1 signaling causes transcriptional activation of unknown target genes (?). 4) Unknown target protein(s) (?) are secreted and activate MMPs. 5) Active MMPs are available to activate latent molecules in the ECM, such as TGF-β. 6) Active TGF-β1 binds TGF-β1 receptor. 7) TGF-β signaling causes nuclear localization of β-catenin. 8) TGF-β signaling causing transcriptional activation of genes that result in an EMT.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104381&req=5

Figure 6: Schematic Model of IGF-1 and TGF-β1 signaling in MCF-7 breast cancer cells. 1) IGF-1 binds IGF-1 receptor. 2) IGF-1 receptor signals through the PI3K and MAPK pathways. 3) IGF-1 signaling causes transcriptional activation of unknown target genes (?). 4) Unknown target protein(s) (?) are secreted and activate MMPs. 5) Active MMPs are available to activate latent molecules in the ECM, such as TGF-β. 6) Active TGF-β1 binds TGF-β1 receptor. 7) TGF-β signaling causes nuclear localization of β-catenin. 8) TGF-β signaling causing transcriptional activation of genes that result in an EMT.
Mentions: A major conclusion from our study is that IGF-1 signaling and TGF-β signaling work in concert to bring about an epithelial to mesenchymal transition in MCF-7 cells. TGF-β signaling has been widely studied in cancer for its ability to induce EMTs leading to metastasis [24]. Most studies describing the biological effects of TGF-β have been carried out in vitro using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted in vivo as a latent complex [8]. Thus the conditions for the activation of TGF-β are not addressed. In addition, although both IGF-1 levels and TGF-β signaling are associated with the metastatic potential of breast cancer, the mechanism of TGF-β activation and its effect on cell invasion is still poorly understood. Here for the first time we establish a critical link between these two pathways and their contribution to cancer progression. Based on our findings in MCF-7 cells, we present a model of putative latent TGF-β1 activation (Figure 6). We propose that IGF-1 transmits signals via both the PI3K and MAPK pathways that cause the transcription of unknown but specific genes. These gene products result in the extracellular activation of MMPs. This MMP activation is IGF-1 dependent and attenuated if the PI3K or MAPK signals are blocked. MMPs are then capable of working in the ECM to activate latent TGF-β1. Active TGF-β1 results in EMT characterized by the nuclear localization of β-catenin, changes in morphology and the transcription of EMT marker genes. The addition of a TGF-β inhibitor blocks this signaling cascade, demonstrating the specificity of TGF-β1 signaling. While our finding are based on studies using MCF-7 cells, the pathways and molecules examined are globally used in many cell types, developmental processes and diseases, and as such we believe that our model has broad relevance.

Bottom Line: Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways.In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, University of Western Ontario, London, Ontario, N6A 5B7, Canada. sdamjano@uwo.ca.

ABSTRACT

Introduction: TGF-β signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of β-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.

Methods: MCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-β1 to determine if elevated levels of IGF-1 together with latent-TGF-β1 could cause EMT.

Results: Results showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.

Conclusions: Taken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF-β signaling, and EMT in breast cancer cells.

No MeSH data available.


Related in: MedlinePlus