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GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response.

De Marco P, Lappano R, De Francesco EM, Cirillo F, Pupo M, Avino S, Vivacqua A, Abonante S, Picard D, Maggiolini M - Sci Rep (2016)

Bottom Line: Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1.Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2.This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.

ABSTRACT
Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of ligand-activated GPER that generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the induction of IL1β/IL1R1 target genes and biological responses as well as invasive features in breast cancer cells as fibroblastoid cytoarchitecture and F-actin reorganization.
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f9: Schematic representation of ligand-activated GPER that generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the induction of IL1β/IL1R1 target genes and biological responses as well as invasive features in breast cancer cells as fibroblastoid cytoarchitecture and F-actin reorganization.

Mentions: In the present study we have shown that estrogenic GPER signalling triggers a feedforward loop which couples IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the up-regulation of IL1β/IL1R1 target genes like PTGES, COX2, RAGE and ABCG2 and invasive features of breast cancer cells such as fibroblastoid cytoarchitecture and F-actin reorganization (see the schematic representation in Fig. 9). The aforementioned findings were confirmed, at least in part, in CAFs derived from a cutaneous metastasis of a breast malignancy. Altogether, these data provide novel insights into the potential of ligand-activated GPER to contribute to the functional interplay between cancer cells and the surrounding stroma toward the malignant progression.


GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response.

De Marco P, Lappano R, De Francesco EM, Cirillo F, Pupo M, Avino S, Vivacqua A, Abonante S, Picard D, Maggiolini M - Sci Rep (2016)

Schematic representation of ligand-activated GPER that generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the induction of IL1β/IL1R1 target genes and biological responses as well as invasive features in breast cancer cells as fibroblastoid cytoarchitecture and F-actin reorganization.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829876&req=5

f9: Schematic representation of ligand-activated GPER that generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the induction of IL1β/IL1R1 target genes and biological responses as well as invasive features in breast cancer cells as fibroblastoid cytoarchitecture and F-actin reorganization.
Mentions: In the present study we have shown that estrogenic GPER signalling triggers a feedforward loop which couples IL1β induction by CAFs to IL1R1 expression by cancer cells, toward the up-regulation of IL1β/IL1R1 target genes like PTGES, COX2, RAGE and ABCG2 and invasive features of breast cancer cells such as fibroblastoid cytoarchitecture and F-actin reorganization (see the schematic representation in Fig. 9). The aforementioned findings were confirmed, at least in part, in CAFs derived from a cutaneous metastasis of a breast malignancy. Altogether, these data provide novel insights into the potential of ligand-activated GPER to contribute to the functional interplay between cancer cells and the surrounding stroma toward the malignant progression.

Bottom Line: Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1.Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2.This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.

ABSTRACT
Cancer-associated fibroblasts (CAFs) contribute to the malignant aggressiveness through secreted factors like IL1β, which may drive pro-tumorigenic inflammatory phenotypes mainly acting via the cognate receptor named IL1R1. Here, we demonstrate that signalling mediated by the G protein estrogen receptor (GPER) triggers IL1β and IL1R1 expression in CAFs and breast cancer cells, respectively. Thereby, ligand-activation of GPER generates a feedforward loop coupling IL1β induction by CAFs to IL1R1 expression by cancer cells, promoting the up-regulation of IL1β/IL1R1 target genes such as PTGES, COX2, RAGE and ABCG2. This regulatory interaction between the two cell types induces migration and invasive features in breast cancer cells including fibroblastoid cytoarchitecture and F-actin reorganization. A better understanding of the mechanisms involved in the regulation of pro-inflammatory cytokines by GPER-integrated estrogen signals may be useful to target these stroma-cancer interactions.

No MeSH data available.


Related in: MedlinePlus