Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells

Soon, Patsy; Kim, Edward; Pon, Cindy K.; Gill, Anthony J.; Moore, Katrina; Spillane, Andrew J.; Benn, Diana E.; Baxter, Robert C.

doi:10.1530/erc-12-0227

Cited by 112 publications

(88 citation statements)

References 25 publications

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“…Chemotherapeutic DNA-damaging agents have also been reported to cause stromal fibroblasts senescence and CAF activation. 19 As in response to the other insults, treatment with doxorubicin resulted in downregulation of CSL and opposite CDKN1A induction (Fig. 2E).…”

Section: Stress/dna Damaging Conditions As Negative Regulators Of Cslmentioning

confidence: 76%

Negative control of CSL gene transcription by stress/DNA damage response and p53

Menietti

Ostano

et al. 2016

Cell Cycle

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CSL is a key transcriptional repressor and mediator of Notch signaling. Despite wide interest in CSL, mechanisms responsible for its own regulation are little studied. CSL down-modulation in human dermal fibroblasts (HDFs) leads to conversion into cancer associated fibroblasts (CAF), promoting keratinocyte tumors. We show here that CSL transcript levels differ among HDF strains from different individuals, with negative correlation with genes involved in DNA damage/repair. CSL expression is negatively regulated by stress/DNA damage caused by UVA, Reactive Oxygen Species (ROS), smoke extract, and doxorubicin treatment. P53, a key effector of the DNA damage response, negatively controls CSL gene transcription, through suppression of CSL promoter activity and, indirectly, by increased p21 expression. CSL was previously shown to bind p53 suppressing its activity. The present findings indicate that p53, in turn, decreases CSL expression, which can serve to enhance p53 activity in acute DNA damage response of cells.

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Section: Stress/dna Damaging Conditions As Negative Regulators Of Cslmentioning

confidence: 76%

Negative control of CSL gene transcription by stress/DNA damage response and p53

Menietti

Ostano

et al. 2016

Cell Cycle

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“…However, CAFs are different from normal fibroblasts, including a more rapid proliferation rate, as well as several actions promoting tumor phenotypes such as survival, proliferation, general metabolic reprogramming, angiogenic shift, ECM remodeling, EMT activation, the acquisition of stem cell traits, metabolic reprogramming toward a reverse Warburg phenotype, or inflammatory cell recruitment. [24][25][26][27] All of these actions are due to the fact that CAFs produce a repertoire of growth factors and cytokines that influence the behavior of the epithelium, such as hepatocyte growth factor (HGF), epidermal growth factor (EGF), insulin growth factors (IGFs), IGF binding protein (IGFBPs), fibroblast growth factor (bFGF) or transforming growth factor b (TGFb). 2,28,29 In addition, there are data indicating that CAFs contribute to both chemotherapy and endocrine resistance.…”

Section: Discussionmentioning

confidence: 99%

A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer

et al. 2015

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Keywords: Breast cancer, cancer-associated fibroblast, matrix-metalloproteases, mononuclear inflammatory cell, tumor stroma Abbreviations: bFGF, fibroblast growth factor; CAF, cancer-associated fibroblast; CI, confidence interval; ECM, extracellular matrix; EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; EGF, epidermal growth factor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IGFs, insulin growth factors; IGFBPs, IGF binding protein; IL, interleukin; MIC, mononuclear inflammatory cell; MMP, matrix metalloprotease; NFkB, nuclear factor kappa B; PgR, progesterone receptor, TA, tissue array; TGFß, transforming growth factor ß; TIMP, tissue inhibitors of metalloproteases.The objective of the present work was to evaluate the impact of the phenotype of both mononuclear inflammatory cells (MICs) and cancer-associated fibroblast (CAFs) in early breast cancer patients, specifically assessed as to their expression of MMP/TIMP relative to their position within the tumor (i.e., localization at the tumor center or invasive front) and the occurrence of distant metastases.. An immunohistochemical study was performed using tissue arrays and specific antibodies against matrix metalloproteinase (MMP)¡1, ¡2, ¡7, ¡9, ¡11, ¡13 and ¡14, tissue inhibitors of metalloproteinase (TIMP)¡1, ¡2 and ¡3, both at tumor center and at invasive front, in 107 patients with primary ductal invasive breast tumors. Data were analyzed by unsupervised hierarchical clustering analysis. Our results indicated that MMP-11 expression by MICs, and TIMP-2 expression by CAFs at either the tumor center or the invasive front, were the most potent independent prognostic factors for predicting the clinical outcome of patients. Using the unsupervised hierarchical clustering analysis, we found well-defined clusters of cases identifying subgroups of tumors showing a high molecular profile of MMPs/TIMPs expression by stromal cells (CAFs and MICs), both at the tumor center and at the invasive front, which were strongly associated with a higher prevalence of distant metastasis. In addition, we found combinations of these clusters defining subpopulations of breast carcinomas differing widely in their clinical outcome. The results presented here identify biologic markers useful to categorize patients into different subgroups based on their tumor stroma, which may contribute to improved understanding of the prognosis of breast cancer patients.

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“…There is evidence that CAF can affect cancer cells more potently than normal fibroblasts (42)(43)(44). Consequently, mRNA expression of EMT markers as well as proliferation and migration were also measured in co-cultures with KYSE-410 cells and CAF.…”

Section: Secretion Of Chemokines Ccl5 and Ccl11 By Fibroblastsmentioning

confidence: 99%

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

Kretschmer

Freudenberger

Twarock

et al. 2016

Journal of Biological Chemistry

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The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less ␣-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4 ؉ but not CD8 ؉ cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.

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Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells

Cited by 112 publications

References 25 publications

Negative control of CSL gene transcription by stress/DNA damage response and p53

Negative control of CSL gene transcription by stress/DNA damage response and p53

A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

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