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Cancer-associated fibroblasts: activin A adds another string to their bow.

ABSTRACT: Non-melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer-associated fibroblasts (CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear. In this issue of EMBO Molecular Medicine, Cangkrama et al describe a new mechanism of fibroblast activation in squamous cell carcinoma. Cancer cell-secreted activin A induces a tumour-promoting phenotype in the fibroblast compartment, with distinct properties compared to TGF-?-activated fibroblasts. Activin A reprograms fibroblasts through transcriptional regulation of mDia2 and reduction of nuclear p53, which favours CAF marker expression, and increases tumour growth and migration. Inhibition of this pathway shows promising results in different models and could offer a new therapeutic strategy in NMSC.

SUBMITTER: Samain R

PROVIDER: S-EPMC7136955 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cancer-associated fibroblasts: activin A adds another string to their bow.

Samain Remi R Sanz-Moreno Victoria V

EMBO molecular medicine 20200326 4

Non-melanoma skin cancer (NMSC) is characterized by a strong desmoplastic reaction, largely responsible for cancer aggressiveness. Within the tumour microenvironment, cancer-associated fibroblasts (CAFs) play a key role in tumour progression, secretion of extracellular matrix proteins and recruitment of immunosuppressive cells. However, pathways involved in acquisition of CAF phenotype remain unclear. In this issue of EMBO Molecular Medicine, Cangkrama et al describe a new mechanism of fibroblas ...[more]

PMID: 32216089

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Project description:Recently, several studies have demonstrated that cancer cell?derived exosomes can facilitate tumor development and metastasis formation. However, the detailed function of exosomes released by cancer stem cells (CSCs) requires further investigation. The aim of the present study was to investigate the role of CSC?derived exosomes in tumor development. For this purpose, Piwil2?induced cancer stem cells (Piwil2?iCSCs) were used as exosome?generating cells, while fibroblasts (FBs) served as recipient cells. Exosomes were isolated by the ultracentrifugation of Piwil2?iCSC?conditioned medium and identified by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. To evaluate the effects of the exosomes on cell proliferation, migration and invasion, cell counting assay (CCK?8), a wound healing assay and a Transwell assay were performed. Protein expression [matrix metalloproteinase (MMP)2, MMP9, ??smooth muscle actin (??SMA) and vimentin and fibroblast?activating protein (FAP)] was examined in FBs by western blot analysis. It was found that the Piwil2?iCSC?derived exosomes (Piwil2?iCSC?Exo) were oval or spherical, membrane?coated vesicles with a uniform size (30?100 nm in diameter). They are characterized by the surface expression of CD9, CD63, Hsp70 and Piwil2 proteins. Additional results from functional analyses revealed that Piwil2?iCSC?Exo enhanced the proliferative, migratory and invasive abilities of FBs, accompanied by the upregulated expression of MMP2 and MMP9. In addition, the increased expression of ??SMA (P<0.05), vimentin (P<0.01 vs. control group, P<0.05 vs. PBS group) and FAP (P<0.001 vs. control group, P<0.01 vs. PBS group) following exposure to Piwil2?iCSC?Exo suggested that the exosomes induced FB transformation into cancer?associated fibroblasts (CAFs). On the whole, the findings of this study demonstrate that Piwil2?iCSC?Exo induce the cancer?associated phenotype in fibroblasts in vitro, suggesting that CSCs can promote tumor development through the modulation of the tumor microenvironment.

Project description:BackgroundOur independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate RORA in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of RORA may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate RORA are still unknown.MethodsHere we use functional knockdown of hormone receptors and coregulators with small interfering RNA (siRNA) to investigate their involvement in sex hormone regulation of RORA in human neuronal cells. Luciferase assays using a vector containing various RORA promoter constructs were first performed to identify the promoter regions required for inverse regulation of RORA by male and female hormones. Sequential chromatin immunoprecipitation methods followed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses of RORA expression in hormone-treated SH-SY5Y cells were then utilized to identify coregulators that associate with hormone receptors on the RORA promoter. siRNA-mediated knockdown of interacting coregulators was performed followed by qRT-PCR analyses to confirm the functional requirement of each coregulator in hormone-regulated RORA expression.ResultsOur studies demonstrate the direct involvement of androgen receptor (AR) and estrogen receptor (ER) in the regulation of RORA by male and female hormones, respectively, and that the promoter region between -10055 bp and -2344 bp from the transcription start site of RORA is required for the inverse hormonal regulation. We further show that AR interacts with SUMO1, a reported suppressor of AR transcriptional activity, whereas ERα interacts with the coactivator NCOA5 on the RORA promoter. siRNA-mediated knockdown of SUMO1 and NCOA5 attenuate the sex hormone effects on RORA expression.ConclusionsAR and SUMO1 are involved in the suppression RORA expression by androgen, while ERα and NCOA5 collaborate in the up-regulation of RORA by estrogen. While this study offers a better understanding of molecular mechanisms involved in sex hormone regulation of RORA, it also reveals another layer of complexity with regard to gene regulation in ASD. Inasmuch as coregulators are capable of interacting with a multitude of transcription factors, aberrant expression of coregulator proteins, as we have seen previously in lymphoblasts from individuals with ASD, may contribute to the polygenic nature of gene dysregulation in ASD.

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Cancer-associated fibroblasts: activin A adds another string to their bow.

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Cancer-associated fibroblasts: activin A adds another string to their bow.

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