Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy

Slany, Astrid; Bileck, Andrea; Muqaku, Besnik; Gerner, Christopher

doi:10.1016/j.breast.2015.06.009

Cited by 23 publications

(23 citation statements)

References 32 publications

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“…Interestingly, recently published data indicate an anti-fibrotic effect of ouabain through upregulation of COX-2 in lung fibroblasts, likely sharing a mechanism with our findings at the level of SMAD activity [55]. Given the abundance of published reports demonstrating that CAFs are able to facilitate the invasiveness of otherwise quiescent tumor cells, work toward the development of CAF-targeting therapeutic agents is warranted [8]. Although some drugs against stromal targets, such as angiogenesis inhibitors, have been developed, options for targeting fibroblast activation are greatly limited.…”

Section: Discussionsupporting

confidence: 68%

“…CAFs are characterized by increased expression of cancer-driving growth factors, including hepatocyte growth factor (HGF) and vascular endothelial growth factor; extracellular matrix (ECM) components, such as fibronectin, collagen, and tenascin C; and enhanced contractility that influences cancer cells through mechanotransduction and ECM remodeling [1, 7]. It is well documented that the cumulative effect of this CAF phenotype in the reactive stroma can be the promotion of invasive and metastatic cancer [8]. It has been shown that the presence of CAFs in the reactive stoma is correlated with poor prognosis for cancers of multiple origins [9, 10].…”

Section: Introductionmentioning

confidence: 99%

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Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation

et al. 2016

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The tumor microenvironment, primarily composed of myofibroblasts, directly influences the progression of solid tumors. Through secretion of growth factors, extracellular matrix deposition, and contractile mechanotransduction, myofibroblasts, or cancer-associated fibroblasts (CAFs), support angiogenesis and cancer cell invasion and metastasis. The differentiation of fibroblasts to CAFs is primarily induced by TGF-β from cancer cells. To discover agents capable of blocking CAF differentiation, we developed a high content immunofluorescence-based assay to screen repurposed chemical libraries utilizing fibronectin expression as an initial CAF marker. Screening of the Prestwick chemical library and NIH Clinical Collection repurposed drug library, totaling over 1700 compounds, identified cardiac glycosides as particularly potent CAF blocking agents. Cardiac glycosides are traditionally used to regulate intracellular calcium by inhibiting the Na+/K+ ATPase to control cardiac contractility. Herein, we report that multiple cardiac glycoside compounds, including digoxin, are able to inhibit TGF-β-induced fibronectin expression at low nanomolar concentrations without undesirable cell toxicity. We found this inhibition to hold true for multiple fibroblast cell lines. Using real-time qPCR, we determined that digoxin prevented induction of multiple CAF markers. Furthermore, we report that digoxin is able to prevent TGF-β-induced fibroblast contraction of extracellular matrix, a major phenotypic consequence of CAF differentiation. Assessing the mechanism of inhibition, we found digoxin reduced SMAD promoter activity downstream of TGF-β, and we provide data that the effect is through inhibition of its known target, the Na+/K+ ATPase. These findings support a critical role for calcium signaling during CAF differentiation and highlight a novel, repurposable modality for cancer therapy.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation

et al. 2016

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“…In this study, we also addressed a lively discussed topic in cancer biology, namely intercellular metabolism. Certain metabolic relationships, for example, between oxidative and glycolytic cancer cells or between CAFs and cancer cells, have been found to impact tumor growth, metastatic potential, patient survival, and even treatment success (Koukourakis et al, 2006;Martinez-Outschoorn et al, 2011;Slany et al, 2015;Sonveaux et al, 2008). Tools to assess such complex biological systems are mainly based on co-culturing cells or mouse models employing cell-type-specific gene targeting.…”

Section: Discussionmentioning

confidence: 99%

Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments

et al. 2017

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Over the past years, plenty of evidence has emerged illustrating how metabolism supports many aspects of cellular function and how metabolic reprogramming can drive cell differentiation and fate. Here, we present a method to assess the metabolic configuration of single cells within their native tissue microenvironment via the visualization and quantification of multiple enzymatic activities measured at saturating substrate conditions combined with subsequent cell type identification. After careful validation of the approach and to demonstrate its potential, we assessed the intracellular metabolic configuration of different human immune cell populations in healthy and tumor colon tissue. Additionally, we analyzed the intercellular metabolic relationship between cancer cells and cancer-associated fibroblasts in a breast cancer tissue array. This study demonstrates that the determination of metabolic configurations in single cells could be a powerful complementary tool for every researcher interested to study metabolic networks in situ.

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“…The crosstalk between cancer cells and CAFs is responsible for cancer cell proliferation, metastasis, invasion, and other critical oncological behaviors [21, 22]. CAFs necessitate targeted treatment, which improves anti-cancer therapy in vitro and animal experiments [23, 24]. …”

Section: Introductionmentioning

confidence: 99%

Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts

et al. 2017

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PurposeThe present review aimed to assess the role of exosomal miRNAs in cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized.MethodsAll relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer-associated fibroblasts, miRNA, exosomal, exosome, and similar terms.ResultsRecent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis.ConclusionsFinding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells.

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Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy

Cited by 23 publications

References 32 publications

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation

Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments

Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts

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