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C-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion.

ABSTRACT: Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression in immortalized breast normal fibroblasts (NFs) induces conversion to breast CAFs by repressing p53 and thereby upregulating SDF-1 in NFs. SDF-1 treatment or p53 knockdown in NFs had similar effects on the activation of NFs as c-Ski overexpression. The c-Ski-activated CAFs show increased proliferation, migration, invasion and contraction compared with NFs. Furthermore, c-Ski-activated CAFs facilitated the migration and invasion of MDA-MB-231 breast cancer cells. Our data suggest that c-Ski is an important regulator in the activation of CAFs and may serve as a potential therapeutic target to block breast cancer progression.

SUBMITTER: Wang L

PROVIDER: S-EPMC3864893 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion.

Wang Liyang L Hou Yixuan Y Sun Yan Y Zhao Liuyang L Tang Xi X Hu Ping P Yang Jiajia J Zeng Zongyue Z Yang Guanglun G Cui Xiaojiang X Liu Manran M

Molecular oncology 20130827 6

Aberrant expression of c-Ski oncoprotein in some tumor cells has been shown to be associated with cancer development. However, the role of c-Ski in cancer-associated fibroblasts (CAFs) of tumor microenvironment has not been characterized. In the current study, we found that c-Ski is highly expressed in CAFs derived from breast carcinoma microenvironment and this CAF-associated c-Ski expression is associated with invasion and metastasis of human breast tumors. We showed that c-Ski overexpression ...[more]

PMID: 24011664

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Project description:BackgroundCancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors. These myofibroblasts promote invasion and metastasis of cancer cells. Mechanisms regulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumor invasion.Principal findingsPalladin expression in stromal fibroblasts occurs very early in tumorigenesis. In vivo, concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (?-SMA), occurs early at the dysplastic stages in peri-tumoral stroma and progressively increases in pancreatic tumorigenesis. In vitro introduction of exogenous 90 kD palladin into normal human dermal fibroblasts (HDFs) induces activation of stromal fibroblasts into myofibroblasts as marked by induction of ?-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expression in the fibroblasts enhances cellular migration, invasion through the extracellular matrix, and creation of tunnels through which cancer cells can follow. The fibroblast invasion and creation of tunnels results from the development of invadopodia-like cellular protrusions which express invadopodia proteins and proteolytic enzymes. Palladin expression in fibroblasts is triggered by the co-culture of normal fibroblasts with k-ras-expressing epithelial cells.ConclusionsOverall, palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.

Project description:BackgroundThe molecular mechanisms involved in the invasion of bone by oral squamous cell carcinomas (OSCC) are poorly understood, and little is known about the role of cancer-associated fibroblasts (CAF), the presence of which confers a poor prognosis.MethodsClinicopathological data from 277 OSCC cases involving bone resections were reviewed, and 32 cases thoroughly analysed histologically. Immunohistochemistry was used to examine αSMA, RANKL and OPG. Western blotting and qPCR were used to assess myofibroblast (CAF-like) differentiation, RANKL and OPG expression in vitro, and RANKL secretion was analysed by ELISA. Osteoclastogenesis was examined using TRAP staining, multinucleation and pit forming assays.ResultsFibrous stroma intervened between tumour and bone in the majority of cases, with no direct contact between cancer cells and bone. RANKL and OPG, two proteins key to regulating bone resorption, were expressed in tumour cells as well as fibrous stroma adjacent to bone and αSMA-positive myofibroblastic CAF were consistently seen infiltrating into bone ahead of tumour cells. Human primary osteoblasts cultured with conditioned media from human OSCC-derived cells and human primary CAF showed a significant increase in RANKL and a decline in OPG mRNA expression. RANKL secretion was significantly increased in primary oral fibroblasts induced to differentiate into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) treatment and in primary CAF. Indirect co-culture of murine macrophages with conditioned media from CAF (experimentally derived and isolated from OSCCs) resulted in a marked increase in osteoclastogenesis (in excess of that provoked by cancer cells) determined by tartrate-resistant acid phosphatase activity, multinucleation and resorption pit formation.ConclusionsThis study is the first to describe a functional role for CAFs in bone invasion and turnover, identifying a novel potential therapeutic target and diagnostic indicator in this difficult to treat bone invasive malignancy.

Project description:Objective:Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in cancer development and progression, including breast cancer (BC). Up-regulation of CCL17 was observed in BC and predicted a decrease in overall survival, suggesting an important role of CCL17 in BC development. Nonetheless, little is known about the role of CCL17 in the interaction between CAFs and BC. Materials and methods:Real-time quantitative PCR, Western blot, and enzyme-linked immunosorbent assay were performed to examine C-C motif chemokine ligand 17 (CCL17) and C-C motif chemokine receptor 4 (CCR4) levels in BC tissues and CAFs. Cell proliferation, migration, and invasion of CAFs co-cultured with or without BC cell lines were measured by Cell Counting Kit-8 and Transwell analysis. Expression of CCL17, CCR4, dual specificity phosphatase 6 (DUSP6), matrix metallopeptidase 13 (MMP13), extracellular signal-regulated kinase (ERK) 1/2, and phosphor-ERK1/2 (p-ERK1/2) in BC cell lines co-cultured with or without CAFs was measured by Western blotting. Results:We found that BC tissues and CAFs demonstrated higher levels of CCL17 compared with adjacent-normal breast tissues and adjacent-normal fibroblasts (NFs), respectively. CCL17 expression is correlated with lymph nodes, TNM stage and tumor size of BC patients. CCL17 knockdown significantly inhibited CCL17 release, CCR4 expression, and the cell proliferation of CAFs, while CCL17 overexpression demonstrated an inverse effect in NFs. Co-culture with CAFs induced the increases in cell proliferation, migration, invasion, and the expression of CCL17, CCR4, MMP13, and p-ERK1/2 in MCF-7 and MDA-MB-231 cells were markedly reversed by CCL17 knockdown in CAFs. Meanwhile, co-culture with NFs induced the malignant phenotype of MCF-7 cells was markedly enhanced by CCL17 overexpression in NFs. Moreover, DUSP6, a negative regulator of ERK1/2, was dose-dependent decrease in response to recombinant CCL17 and inhibited cell migration, invasion, MMP13 expression, and ERK1/2 activation in MCF-7 cells. Conclusion:The findings of this study suggest that CCL17 may function as a novel biomarker as well as potential therapeutic target against BC and CAF-secreted CCL17 promotes BC cell migration and invasion through the DUSP6-dependent ERK1/2 pathway.

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C-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion.

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c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion.

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