Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

doi:10.1016/j.bbrc.2013.06.089

Cited by 150 publications

(123 citation statements)

References 38 publications

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“…In this regard, fibroblasts are known to express many protumorigenic factors, including IL-6, which has been previously found to enhance proliferation of ovarian carcinoma cells. 38,49,50 Consistent with these findings, our studies suggest that blocking IL-6 inhibited fibroblast CMinduced SKOV-3 cell growth. Given these findings and the high levels of IL-6 expressed by fibroblasts, our data are consistent with a mechanism by which targeting the HU177 epitope selectively limits accumulation of a-SMA fibroblasts, thereby reducing an important source of protumorigenic factors that enhance angiogenesis and tumor growth.…”

Section: Discussionsupporting

confidence: 89%

“…2,5,6,38 Although it is clear that most dermal fibroblast do not represent a fully accurate model of cancer-associated stromal cells found in vivo, following in vitro culture, our fibroblasts exhibited phosphorylated Erk and expressed a-SMA and platelet-derived growth factor receptor a, important markers of CAF-like stromal cells (data not shown). Therefore, we used these fibroblasts as a model of a-SMAeexpressing stromal cells and examined whether blocking the HU177 epitope could alter growth factoreinduced migration.…”

Section: Inhibition Of Growth Factoreinduced Fibroblast Migration By mentioning

confidence: 93%

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Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Caron

Ames

Contois

et al. 2016

The American Journal of Pathology

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Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of a-smooth muscle actineexpressing stromal cells. Integrin a10b1 can serve as a receptor for the HU177 epitope in a-smooth muscle actineexpressing stromal cells and subsequently regulates Erkdependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized a 10 b 1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors. (Am J Pathol 2016 http://dx

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Section: Discussionsupporting

confidence: 89%

Section: Inhibition Of Growth Factoreinduced Fibroblast Migration By mentioning

confidence: 93%

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Caron

Ames

Contois

et al. 2016

The American Journal of Pathology

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“…1A). We chose to focus on these genes as they were previously shown to be part of a proinflammatory gene signature expressed by CAFs in skin, breast, and pancreatic carcinomas (6,7,18), as well as by senescent fibroblasts (19,20). Moreover, their expression was shown to be functionally important for tumor progression supported by fibroblasts (6).…”

Section: Paracrine Signaling From Breast Tumor Cells Reprograms Mammamentioning

confidence: 99%

“…This proinflammatory gene signature was maintained in CAFs from skin carcinomas, and evident in mammary and pancreatic tumors in mice, and in cognate human cancers (6). Moreover, we recently demonstrated that CAFs express proinflammatory factors in human breast tumors, and this expression is enhanced with tumor progression (7). Nevertheless, despite growing evidence on the central role of CAFs in facilitating tumor progression, very little is known about the mechanisms by which resident fibroblasts become activated.…”

Section: Introductionmentioning

confidence: 99%

Tumor-Derived Osteopontin Reprograms Normal Mammary Fibroblasts to Promote Inflammation and Tumor Growth in Breast Cancer

et al. 2015

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Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAF) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. CAF also orchestrate tumor-promoting inflammation in multiple tumor types, including breast cancer. However, the mechanisms through which normal tissue fibroblasts are reprogrammed to tumor-promoting CAFs are mainly obscure. Here, we show that mammary fibroblasts can be educated by breast cancer cells to become activated to a proinflammatory state that supports malignant progression. Proteomic analysis of breast cancer cell-secreted factors identified the secreted proinflammatory mediator osteopontin, which has been implicated in inflammation, tumor progression, and metastasis. Osteopontin was highly secreted by mouse and human breast cancer cells, and tumor cell-secreted osteopontin activated a CAF phenotypes in normal mammary fibroblasts in vitro and in vivo. Osteopontin was sufficient to induce fibroblast reprogramming and neutralizing antibodies against osteopontinblocked fibroblast activation induced by tumor cells. The ability of secreted osteopontin to activate mammary fibroblasts relied upon its known receptors CD44 and a V b 3 integrin. Strikingly, osteopontin silencing in tumor cells in vivo attenuated stromal activation and inhibited tumor growth. Our findings establish a critical functional role for paracrine signaling by tumor-derived osteopontin in reprograming normal fibroblasts into tumor-promoting CAFs. Cancer Res; 75(6); 963-73. Ó2015 AACR.

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“…The CAFs secrete proangiogenic factors, such as IL‐8, SDF‐1, vascular endothelial factor (VEGF), and fibroblast growth factor (FGF), into an environment of other stromal cells including endothelial cells to promote tumor angiogenesis 30, 35, 38, 39. CAFs may enhance invasion of the cancer cells through expression of TGF β, potent EMT inducer, and HGF, which has been shown to promote breast tumorigenesis 39, 40. Since fibroblasts may alter the mRNA expression of structural and cell cycle‐associated genes in the presence of H. pylori ,9, 41 we have attempted to determine whether H. pylori can interact with fibroblasts by changing them not only into myofibroblasts, but also into CAFs, further being capable of inducing EMT program in normal RGM‐1 epithelial cell line.…”

Section: Introductionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

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Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

Cited by 150 publications

References 38 publications

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Tumor-Derived Osteopontin Reprograms Normal Mammary Fibroblasts to Promote Inflammation and Tumor Growth in Breast Cancer

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

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