Role of cancer-associated fibroblasts in breast cancer development and prognosis

Aboussekhra, Abdelilah

doi:10.1387/ijdb.113362aa

Cited by 99 publications

(80 citation statements)

References 102 publications

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“…7,8 It was also shown that CAFs support the malignant properties of cancer spreading by secreting soluble factors such as pro-angiogenic factors, matrix metalloproteinases (MMPs), cytokines as well as chemokines and growth factors. 9 Among these cytokines, CCL2 and CCL5, which are known inflammatory mediators, were demonstrated to play important role in the mediation of the interaction between CAFs and breast cancer cells beyond SDF-1 [10][11][12][13] Dovitinib (formerly CHIR-258, TKI-258, Novartis pharmaceuticals) is an investigational new inhibitor of multiple tyrosine kinases that has in vitro inhibitory activity against basic fibroblast growth factor receptor (bFGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) kinases with IC 50 values of approximately 10 nM. Further in vivo and in vitro data indicate that this drug blocked PDGFR/FGFR/VEGFR signaling in advanced melanoma, 4 pancreatic cancer, 14 breast carcinoma, 15 urothelial carcinoma, 16 impaired tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in vitro.…”

Section: Introductionmentioning

confidence: 99%

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

et al. 2015

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A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.

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Section: Introductionmentioning

confidence: 99%

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

et al. 2015

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“…Recent findings have shown that the transformation of breast stromal fibroblasts to myofibroblasts is under the control of tumor suppressor proteins, such as p21 WAF (p21), p53, PTEN, and CAV-1 (27). Furthermore, we have recently shown that the expression of the cyclin-dependent kinase inhibitor p16…”

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confidence: 99%

The Cytokine IL-6 Reactivates Breast Stromal Fibroblasts through Transcription Factor STAT3-dependent Up-regulation of the RNA-binding Protein AUF1

Hendrayani

Al‐Khalaf

Aboussekhra

2014

Journal of Biological Chemistry

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Background: Cancer cells activate their microenvironment through secreting several cytokines. Results:The cytokine IL-6 activates breast stromal fibroblasts through STAT3-dependent up-regulation of the RNA binding protein AUF1, which stabilizes the SDF-1, ␣-SMA, TGF-␤1, and IL-6 mRNAs. Conclusion: Up-regulation of AUF1 enhances the procarcinogenic effects of breast stromal fibroblasts. Significance: The IL-6/STAT3/AUF1 pathway could constitute an important prognostic and/or therapeutic target.

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“…In many cases, tumors with abundant CAFs have a poorer prognosis than those of tumors with less CAFs, since CAFs have significant roles in the tumor microenvironment for promotion of cell growth and invasion. 11,12 It has also been suggested that CSCs/CICs might preferentially interact with CAFs, which serve as a niche in the CSC/CIC microenvironment. 13 In this study, we show evidence that fibroblasts can induce expression of stemness-associated genes and fibroblast growth factor 4 (FGF4) in ovarian carcinoma CSCs/CICs, leading enhancement of tumor-initiating capacity.…”

mentioning

confidence: 99%

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

Yasuda

Torigoe

Mariya

et al. 2014

Laboratory Investigation

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Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/ CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1 high ) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1 high cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1 high cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1 high cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1 high cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1 high cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1 high cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.

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Role of cancer-associated fibroblasts in breast cancer development and prognosis

Cited by 99 publications

References 102 publications

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

The Cytokine IL-6 Reactivates Breast Stromal Fibroblasts through Transcription Factor STAT3-dependent Up-regulation of the RNA-binding Protein AUF1

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity

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