Dataset Information

Fibroblast ER? promotes bladder cancer invasion via increasing the CCL1 and IL-6 signals in the tumor microenvironment.

ABSTRACT: Epidemiological studies indicate that women have a higher chance of developing muscle invasive bladder cancer (BCa) than men, suggesting that estrogen and estrogen receptors (ERs) may play critical roles in BCa progression. However, the ERs roles in the bladder tumor microenvironment and impacts on BCa progression remain largely unclear. Using IHC staining in human BCa samples, we found that higher ER? expression in the stromal compartment of BCa may be correlated with unfavorable clinical outcomes. Results from cell line studies revealed that co-culturing with fibroblasts could promote BCa T24, UMUC3 and 5637 cells invasion. Importantly, addition of ER? in fibroblasts further enhanced the BCa cell invasion and knock-down of ER? in fibroblasts could then partially reduce the fibroblasts-enhanced BCa invasion. Mechanism dissection suggested that ER? could function through modulating the CCL cytokines expression in fibroblasts to increase the BCa IL-6 expression. An interruption approach using IL-6 neutralizing antibody then reversed the fibroblast ER?-enhanced BCa cell invasion. Together, these data suggest that the higher expression of ER? in fibroblasts may be the result of modulating the CCL1 expression in fibroblasts and/or IL-6 production in BCa cells to enhance BCa cells invasion. Targeting these individual molecules in this newly identified ER?-stimulated CCL1 and IL-6 signal pathways may become an alternative therapy to better suppress the BCa cell invasion.

SUBMITTER: Yeh CR

PROVIDER: S-EPMC4449442 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Fibroblast ERα promotes bladder cancer invasion via increasing the CCL1 and IL-6 signals in the tumor microenvironment.

Yeh Chiuan-Ren CR Hsu Iawen I Song Wenbin W Chang Hongchiang H Miyamoto Hiroshi H Xiao Guang-Qian GQ Li Lei L Yeh Shuyuan S

American journal of cancer research 20150215 3

Epidemiological studies indicate that women have a higher chance of developing muscle invasive bladder cancer (BCa) than men, suggesting that estrogen and estrogen receptors (ERs) may play critical roles in BCa progression. However, the ERs roles in the bladder tumor microenvironment and impacts on BCa progression remain largely unclear. Using IHC staining in human BCa samples, we found that higher ERα expression in the stromal compartment of BCa may be correlated with unfavorable clinical outco ...[more]

PMID: 26045993

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Project description:BackgroundTumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer.MethodsIn this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings.ResultsA total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial-mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis.ConclusionKRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial-mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.

Project description:Purpose: TIAM2 (T-cell lymphoma invasion and metastasis 2), a RAC1 guanine nucleotide exchange factor, plays crucial roles in human cancer cells. Its homolog, TIAM1, has been reported to promote the migration and invasion of cancer cells through regulating the functions of cancer associated fibroblasts (CAFs). However, the functions of TIAM2 in CAFs have not been investigated. In this study, we explored how fibroblast TIAM2 influences the migration and invasion of lung cancer cells. Methods: We cultured primary lung CAFs and adjacent normal lung fibroblasts (NFs) from 12 non-small cell lung cancer (NSCLC) patients. RT-PCR and western blot were used to compare TIAM2 levels between CAFs and NFs. Two co-culture systems were designed, in which cancer cells were directly co-cultured with fibroblasts and indirectly co-cultured with conditional medium (CM) from fibroblasts. Subsequently, the wound healing and transwell tests were conducted to assess the migration and invasion ability of fibroblasts and co-cultured cancer cells. Finally, cytokine antibody arrays were used to screen differentially secreted cytokines in the CM. Results: The expression levels of TIAM2 were significantly higher in CAFs than NFs, and TIAM2-silenced fibroblasts showed decreased migration and invasion ability. In the direct co-culture system, the migration and invasion of cancer cells were retarded when co-culturing with TIAM2-silenced fibroblasts, and the expression levels of EMT-related genes also changed in cancer cells. Decreased migration and invasion of cancer cells were also observed when culturing with the CM from TIAM2-silenced fibroblasts. In addition, the cytokine antibody arrays revealed that Osteoprotegerin (OPG) was significantly decreased in the CM of TIAM2-silenced fibroblasts. This result suggested that OPG might be one of the main cytokines contributing to the migration and invasion of cancer cells in co-culture systems. Conclusion: Our results suggest that fibroblast TIAM2 promotes the invasion and migration of lung cancer cell, and OPG might be one of the main cytokines contributing to this pro-cancer process.

Dataset Information

Fibroblast ER? promotes bladder cancer invasion via increasing the CCL1 and IL-6 signals in the tumor microenvironment.

Publications

Fibroblast ERα promotes bladder cancer invasion via increasing the CCL1 and IL-6 signals in the tumor microenvironment.

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