Gene Summary

Gene:ACTA2; actin alpha 2, smooth muscle
Aliases: ACTSA
Summary:This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:actin, aortic smooth muscle
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ACTA2 (cancer-related)

Xu LH, Zhao F, Yang WW, et al.
MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma.
Int J Oncol. 2019; 54(5):1579-1590 [PubMed] Free Access to Full Article Related Publications
The incidence of recurrent t(6;9) translocation of the MYB proto‑oncogene to NFIB (the gene that encodes nuclear factor 1 B‑type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh‑frozen SACC tissues and 41 fresh‑frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial‑mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin‑1 (E‑cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin‑2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non‑obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

Sun C, Zhang G, Cheng S, et al.
URG11 promotes proliferation and induced apoptosis of LNCaP cells.
Int J Mol Med. 2019; 43(5):2075-2085 [PubMed] Free Access to Full Article Related Publications
von Willebrand factor C and EGF domain‑containing protein (URG11), a cell growth regulator, is involved in the progression of a variety of types of cancer, including prostate cancer (Pca). However, the functions of the URG11 gene in Pca cells require in‑depth investigation. The mRNA and protein levels of URG11 were measured by reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. Cell Counting kit‑8 (CCK‑8), wound‑healing and Transwell assays were used to detect cell viability, migration and invasion, respectively. Apoptosis and cell cycle analyses were performed using flow cytometry. The mRNA and protein expression levels of epithelial (E)‑cadherin, vimentin, α‑smooth muscle actin (α‑SMA), cyclin D1 and MYC proto‑oncogene protein (c‑Myc) were analyzed by RT‑qPCR and western blot analysis. In the present study, the mRNA and protein levels of URG11 were markedly upregulated in Pca cell lines compared with those in the normal prostate epithelial cell line. With functional experiments, the cell viability, migration and invasion of Pca cells were markedly promoted by URG11 overexpression. The cell cycle was effectively induced by URG11 and apoptosis was inhibited by the overexpression of URG11. Concomitantly, the epithelial marker E‑cadherin was downregulated, and the mesenchymal markers vimentin and α‑SMA were upregulated following URG11 overexpression. By contrast, genetic knockout of URG11 elicited the opposite effects. The present study also identified that the downstream effector genes of the Wnt/β‑catenin signal pathway, cyclin D1 and c‑Myc, were increased following the overexpression of endogenous URG11, which are known to regulate cell proliferation. In addition, the Wnt/β‑catenin inhibitor FH535 ameliorated the promotive effects of URG11 on LNCaP cells viability, migration and invasion, and the Wnt/β‑catenin agonist LiCl reversed the inhibitory effects of siURG11 in LNCaP cells on cell viability, migration and invasion. The present study demonstrated that URG11 served an oncogenic role in the development of Pca cells and provided evidence that URG11 has potential as a novel therapeutic target in Pca.

Zhao B, Baloch Z, Ma Y, et al.
Identification of Potential Key Genes and Pathways in Early-Onset Colorectal Cancer Through Bioinformatics Analysis.
Cancer Control. 2019 Jan-Dec; 26(1):1073274819831260 [PubMed] Free Access to Full Article Related Publications
This study was designed to identify the potential key protein interaction networks, genes, and correlated pathways in early-onset colorectal cancer (CRC) via bioinformatics methods. We selected microarray data GSE4107 consisting 12 patient's colonic mucosa and 10 healthy control mucosa; initially, the GSE4107 were downloaded and analyzed using limma package to identify differentially expressed genes (DEGs). A total of 131 DEGs consisting of 108 upregulated genes and 23 downregulated genes of patients in early-onset CRC were selected by the criteria of adjusted P values <.01 and |log2 fold change (FC)| ≥ 2. The gene ontology functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were accomplished to view the biological process, cellular components, molecular function, and the KEGG pathways of DEGs. Finally, protein-protein interactions (PPIs) were constructed, and the hub protein module was identified. Genes such as ACTA2, ACTG2, MYH11, CALD1, MYL9, TPM2, and LMOD1 were strongly implicated in CRC. In summary, in this study, we indicated that molecular mechanisms were involved in muscle contraction and vascular smooth muscle contraction signaling pathway, which improve our understanding of CRC and could be used as new therapeutic targets for CRC.

Goulet CR, Champagne A, Bernard G, et al.
Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling.
BMC Cancer. 2019; 19(1):137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer-associated fibroblasts (CAFs), activated by tumour cells, are the predominant type of stromal cells in cancer tissue and play an important role in interacting with neoplastic cells to promote cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. However, the mechanism by which CAFs induce EMT program in bladder cancer cells remains unclear.
METHODS: To investigate the role of CAFs in bladder cancer progression, healthy primary bladder fibroblasts (HFs) were induced into CAFs (iCAFs) by bladder cancer-derived exosomes. Effect of conditioned medium from iCAFs (CM
RESULTS: Cancer exosome-treated HFs showed CAFs characteristics with high expression levels of αSMA and FAP. We showed that the CM
CONCLUSIONS: We conclude that CAFs promote aggressive phenotypes of non-invasive bladder cancer cells through an EMT induced by the secretion of IL-6.

Zhou RJ, Lv HZ
Knockdown of ACTA2‑AS1 promotes liver cancer cell proliferation, migration and invasion.
Mol Med Rep. 2019; 19(3):2263-2270 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are important regulators of various cellular and biological processes. The present study aimed to investigate the functions of a novel lncRNA, ACTA2‑AS1:4, a transcript variant of smooth muscle α‑actin 2‑antisense 1 (ACTA2‑AS1), in regulating liver cancer progression. Expression of lncRNAs in liver cancer tissues and cell lines were analyzed by reverse transcription quantitative polymerase chain reaction (RT‑qPCR). Knockdown of ACTA2‑AS1:4 expression in LM3 liver cancer cells was achieved by transfection with small interfering RNAs (siRNAs) that specifically targeted ACTA2‑AS1:4. The proliferation and cell cycle progression of ACTA2‑AS1:4‑silenced LM3 cells were determined using MTS assay and flow cytometry, respectively. A Transwell system assay was used to evaluate the migration and invasion capacities of LM3 cells transfected with ACTA2‑AS1:4 siRNA. The expression levels of major genes associated with important cellular processes were finally determined by RT‑qPCR and western blot analysis. ACTA2‑AS1:4 expression in liver cancer tissues and multiple cell lines was markedly downregulated by specific siRNAs. This inhibition of ACTA2‑AS1:4 expression significantly promoted the proliferation, cell cycle progression, migration and invasion of LM3 cells. A decrease in ACTA2‑AS1:4 expression also suppressed E‑cadherin expression, increased N‑cadherin expression, decreased caspase 3 expression and increased cyclin D1 and matrix metalloproteinase expression in liver cancer cells. Downregulation of ACTA2‑AS1:4 affects a number of key mechanisms involved in liver cancer progression. These data may be important for the future of liver cancer diagnosis and subsequent treatments.

Gerashchenko GV, Grygoruk OV, Kononenko OA, et al.
Expression pattern of genes associated with tumor microenvironment in prostate cancer.
Exp Oncol. 2018; 40(4):315-322 [PubMed] Related Publications
AIM: To assess relative expression (RE) levels of CAF-, TAM-specific, immune defense-associated genes in prostate tumors and to show correlation of RE with clinical, pathological and molecular characteristics, with the aim to define clinically significant specific alterations in a gene expression pattern.
METHODS: RE of 23 genes was analyzed by a quantitative polymerase chain reaction in 37 freshly frozen samples of prostate cancer tissues of a different Gleason score (GS) and at various tumor stages, compared with RE in 37 paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas.
RESULTS: Differences in RE were shown for 11 genes out of 23 studied, when tumor samples were compared with corresponding CNTs. 7 genes, namely ACTA2, CXCL14, CTGF, THY1, FAP, CD163, CCL17 were upregulated in tumors. 4 genes, namely CCR4, NOS2A, MSMB, IL1R1 were downregulated in tumors. 14 genes demonstrated different RE in TNA at different stages: CXCL12, CXCL14, CTGF, FAP, HIF1A, THY1, CCL17, CCL22, CCR4, CD68, CD163, NOS2A, CTLA4, IL1R1. RE changes of 9 genes - CXCL12, CXCL14, HIF1A, CCR4, CCL17, NOS2A, CTLA4, IL1R1, IL2RA - were found in tumors with different GS. Moreover, 9 genes showed differences in RE in TNA, dependently on the presence or absence of the TMPRSS2/ERG fusion and 7 genes showed differences in RE of groups with differential PTEN expression. Significant correlations were calculated between RE of 9 genes in adenocarcinomas and the stage, and GS; also, between RE of 2 genes and the fusion presence; and between RE of 4 genes and PTEN expression.
CONCLUSIONS: Several gene expression patterns were identified that correlated with the GS, stage and molecular characteristics of tumors, i.e. presence of the TMPRSS2/ERG fusion and alterations in PTEN expression. These expression patterns can be used for molecular profiling of prostate tumors, with the aim to develop personalized medicine approaches. However, the proposed profiling requires a more detailed analysis and a larger cohort of patients with prostate tumor.

Kim S, You D, Jeong Y, et al.
TP53 upregulates α‑smooth muscle actin expression in tamoxifen‑resistant breast cancer cells.
Oncol Rep. 2019; 41(2):1075-1082 [PubMed] Related Publications
In a previous study, we reported that α‑smooth muscle actin (α‑SMA), one of the mesenchymal marker proteins, is highly expressed in tamoxifen‑resistant breast cancer (TamR) cells. However, the exact mechanism of α‑SMA expression in TamR cells is not fully understood. Here, we investigated the effect of TP53 on α‑SMA expression in breast cancer cells. The levels of α‑SMA mRNA and protein expression were analyzed by real‑time PCR and western blotting, respectively. In estrogen receptor‑positive [ER(+)] breast cancer patients, aberrant α‑SMA expression was found to be associated with a poor prognosis. The level of α‑SMA expression was significantly increased in established TamR cells compared to tamoxifen‑sensitive (TamS) cells. To verify the regulatory mechanism of α‑SMA expression, we analyzed diverse kinase activities between TamS and TamR cells. The activity of TP53 was markedly increased in the TamR cells. When TamS cells were treated with TP53 activator, Nutlin3 (Nut3), α‑SMA expression was increased in the TamS cells. In addition, α‑SMA expression was significantly increased by TP53 overexpression in breast cancer cells. On the contrary, the basal level of α‑SMA expression was decreased by the TP53 inhibitor, pifithrin‑α (PFT‑α). Taken together, we demonstrated that α‑SMA expression is regulated by TP53 activity in TamR cells.

Zhang Q, Wang C, Cliby WA
Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer.
Gynecol Oncol. 2019; 152(2):368-374 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
OBJECTIVE: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from 'tumor', consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC.
METHODS: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites.
RESULTS: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma.
CONCLUSIONS: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

Eriksson BO, Gahm C, Halle M
Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients.
Mediators Inflamm. 2018; 2018:4058986 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Background: Clinical studies have shown that radiotherapy can induce vascular disease at the site of exposure but is usually not clinically evident until years after treatment. We have studied irradiated human arteries and veins to better understand the underlying biology in search of future treatments. The aim was to investigate whether radiotherapy contributed to a sustained expression of plasminogen activator inhibitor-1 (PAI-1) in human arteries and veins.
Methods: Irradiated arteries and veins were harvested, together with unirradiated control vessels, from patients undergoing free tissue transfer reconstruction at a median time of 90 weeks [5-650] following radiation exposure. Differential gene expression of PAI-1 was analysed, together with immunohistochemistry (IHC) and immunofluorescence (IF).
Results: PAI-1 gene expression was increased in both arteries (
Conclusion: The current study shows a sustained upregulation of PAI-1 in both arteries and veins after exposure to ionizing radiation, indicating a chronic inflammation mainly in the adventitia. We believe that the results contribute to further understanding of radiation-induced vascular disease, where targeting PAI-1 may be a potential treatment.

Nanchahal J, Ball C, Davidson D, et al.
Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.
EBioMedicine. 2018; 33:282-288 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor.
METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with (NCT03180957) and the EudraCT (2015-001780-40).
FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug.
INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease.
FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Wang JP, Yu HM, Chiang ER, et al.
Corticosteroid inhibits differentiation of palmar fibromatosis-derived stem cells (FSCs) through downregulation of transforming growth factor-β1 (TGF-β1).
PLoS One. 2018; 13(6):e0198326 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Treatment for musculoskeletal fibromatosis remains challenging. Surgical excision for fibromatosis is the standard therapy but recurrence remains high. Corticosteroids, an anti-fibrogenic compound, have been used to treat early stage palmar fibromatosis, but the mechanism is unknown. We investigated the inhibitory mechanism effect of corticosteroids in the murine model of fibromatosis nodule as well as in cultured FSCs. Quantitative reverse transcription/polymerase chain reaction (PCR) analysis and immunofluorescence (IF) staining for markers of myofibroblasts (α-smooth muscle actin and type III collagen) were used to examine the effect of dexamethasone on myofibroblasic differentiation of FSCs both in vitro and in vivo. Transforming growth factor-β1 (TGF-β1) signaling and its downstream targets were examined using western blot analysis. TGF-β1 expression in FSCs before and after dexamethasone treatment was compared. In addition, inhibition of TGF-β1 expression was examined using RNA interference (RNAi) on FSCs, both in vitro and in vivo. Treating FSCs with dexamethasone inhibited FSCs' myofibroblastic differentiation in vitro. Treating FSCs with dexamethasone before or after implantation further inhibited formation of fibromatosis nodules. Dexamethasone suppressed expression of TGF-β1 and pSmad2/3 by FSCs in vitro. TGF-β1 knockdown FSCs showed reducing myofibroblastic differentiation both in vitro and in vivo. Finally, addition of TGF-β1 abolished dexamethasone-mediated inhibition of myofibroblastic differentiation. Dexamethasone inhibits the myofibroblastic differentiated potential of FSCs both in vitro and in vivo through inhibition of TGF-β1 expression in FSCs. TGF-β1 plays a key role in myofibroblastic differentiation.

Pucci A, Mattioli C, Matteucci M, et al.
Cell differentiation in cardiac myxomas: confocal microscopy and gene expression analysis after laser capture microdissection.
Heart Vessels. 2018; 33(11):1403-1410 [PubMed] Related Publications
Cardiac myxomas are rare tumors with a heterogeneous cell population including properly neoplastic (lepidic), endothelial and smooth muscle cells. The assessment of neoplastic (lepidic) cell differentiation pattern is rather difficult using conventional light microscopy immunohistochemistry and/or whole tissue extracts for mRNA analyses. In a preliminary study, we investigated 20 formalin-fixed and paraffin-embedded cardiac myxomas by means of conventional immunohistochemistry; in 10/20 cases, cell differentiation was also analyzed by real-time RT-PCR after laser capture microdissection of the neoplastic cells, whereas calretinin and endothelial antigen CD31 immunoreactivity was localized in 4/10 cases by double immunofluorescence confocal microscopy. Gene expression analyses of α-smooth muscle actin, endothelial CD31 antigen, alpha-cardiac actin, matrix metalloprotease-2 (MMP2) and tissue inhibitor of matrix metalloprotease-1 (TIMP1) was performed on cDNA obtained from either microdissected neoplastic cells or whole tumor sections. We found very little or absent CD31 and α-Smooth Muscle Actin expression in the microdissected cells as compared to the whole tumors, whereas TIMP1 and MMP2 genes were highly expressed in both ones, greater levels being found in patients with embolic phenomena. α-Cardiac Actin was not detected. Confocal microscopy disclosed two different signals corresponding to calretinin-positive myxoma cells and to endothelial CD31-positive cells, respectively. In conclusion, the neoplastic (lepidic) cells showed a distinct gene expression pattern and no consistent overlapping with endothelial and smooth muscle cells or cardiac myocytes; the expression of TIMP1 and MMP2 might be related to clinical presentation; larger series studies using also systematic transcriptome analysis might be useful to confirm the present results.

Desantis V, Frassanito MA, Tamma R, et al.
Rhu-Epo down-regulates pro-tumorigenic activity of cancer-associated fibroblasts in multiple myeloma.
Ann Hematol. 2018; 97(7):1251-1258 [PubMed] Related Publications
We have previously demonstrated that recombinant human erythropoietin (rHuEpo) is involved in the regulation of the angiogenic response in multiple myeloma (MM) through a direct effect on macrophages and endothelial cells isolated from the bone marrow of patients with MM. The aim of the present study was designed to determine the effects of rHuEpo on cancer-associated fibroblasts (CAFs) from monoclonal gammopathy of undetermined significance (MGUS) and MM patients by means of in vitro and in vivo assays. rHuEpo treatment reduces the expression of mRNA levels of fibroblast activation markers, namely alpha smooth actin (αSMA) and fibroblast activation protein (FAP) in MGUS and MM CAFs, and of pro-inflammatory and pro-angiogenic cytokines, including interleukin (IL)-6 and IL-8, vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) in MM CAFs. Moreover, rHuEpo inhibits the proliferative activity of MM CAFs and increased the apoptosis of MGUS and MM CAFs. Overall, these data suggest that rHu-Epo down-regulates CAFs pro-tumorigenic activity. Moreover, these results are not suggestive for a pro-angiogenic activity of rHuEpo on CAFs. In fact, rHuEpo pre-treatment induces a low angiogenic response in vivo in the chorioallantoic membrane (CAM) assay of MGUS and MM CAFs conditioned medium, not comparable to that of a well-known angiogenic cytokine, VEGF-A, tested in the same assay.

Liang L, Luo H, He Q, et al.
Investigation of cancer-associated fibroblasts and p62 expression in oral cancer before and after chemotherapy.
J Craniomaxillofac Surg. 2018; 46(4):605-610 [PubMed] Related Publications
PURPOSE: The aim of this study is to investigate the expression of the autophagy protein p62 in oral squamous cell carcinoma (OSCC) cells before and after chemotherapy. We also detected cancer-associated fibroblasts (CAFs) in these OSCC samples to explore the roles of p62 and CAFs in chemotherapy.
MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expression of p62 and α-SMA in 26 paired OSCC samples before and after chemotherapy. The relationships between clinicopathological features, clinical outcome and the expression of these proteins were analyzed.
RESULTS: Our results indicated an increased stromal α-SMA expression after chemotherapy in OSCC samples. High p62 expression of OSCC cells closely correlated with stromal α-SMA expression after chemotherapy. Furthermore, the post-chemotherapy p62 expression was associated with the prognosis for OSCC patients.
CONCLUSION: These results suggest that chemotherapy may increase CAFs in OSCC. High cytoplasmic p62 expression may serve as a poor prognostic marker for OSCC patients.

Song H, Zhang Y
Regulation of pancreatic stellate cell activation by Notch3.
BMC Cancer. 2018; 18(1):36 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC.
METHODS: The expression of Notch signaling pathway components in human PDAC was examined via immunohistochemical staining and assessed in mouse PaSCs using RT-qPCR and western blotting. Notch3 expression in both PDAC stromal cells and activated mouse PaSCs was evaluated using immunofluorescence, RT-qPCR and western blotting. The impact of siRNA-mediated Notch3 knockdown on PaSC activation was detected with RT-qPCR and western blotting, and the impact on PaSC proliferation and migration was detected using CCK-8 assays and scratch experiments. The effect of conditioned medium from PaSCs activated with Notch3 siRNA on pancreatic cancer (LTPA) cells was also detected with CCK-8 assays and scratch experiments. The data were analyzed for statistical significance using Student's t-test.
RESULTS: Notch3 was overexpressed in both human PDAC stromal cells and activated mouse PaSCs, and Notch3 knockdown with Notch3 siRNA decreased the proliferation and migration of mouse PaSCs. The levels of markers related to PaSC activation, such as α-smooth muscle actin (α-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells.
CONCLUSIONS: Notch3 inhibition in PaSCs can inhibit the activation, proliferation and migration of PaSCs and reduce the PaSC-induced pro-tumorigenic effect. Therefore, Notch3 silencing in PaSCs is a potential novel therapeutic option for patients with PDAC.

Luo Q, Wang CQ, Yang LY, et al.
FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells.
Cancer Lett. 2018; 417:21-34 [PubMed] Related Publications
Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC.

Li Y, Wang M, Huang BW, et al.
Transcriptome-wide elucidation of liposomal formulations for anticancer drug delivery.
Int J Nanomedicine. 2017; 12:8557-8572 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery.

Wu J, Hong Y, Wu T, et al.
Stromal-epithelial lactate shuttle induced by tumor‑derived interleukin‑1β promotes cell proliferation in oral squamous cell carcinoma.
Int J Mol Med. 2018; 41(2):687-696 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Stromal-epithelial lactate shuttle is an essential process to support fast‑growing tumor cells, however, the underlying mechanism remains ambiguous. Interleukin‑1β (IL‑1β), which is a key node gene in both stromal and epithelial cells of oral squamous cell carcinoma (OSCC), may participate in this metabolic reprogramming. In the present study, anaerobic glycolysis of cancer‑associated fibroblasts (CAFs) was evaluated and the role of IL‑1β in regulating stromal‑epithelial lactate shuttle was determined. A co‑culture system of primary fibroblasts and OSCC cell lines (CAL27, UM1 or SCC25) was created to investigate the stromal‑epithelial interaction. α‑smooth muscle actin (α‑SMA) expression of fibroblasts, IL‑1β expression and cell proliferation of OSCC cells, and a series of glycolytic genes were measured. Recombinant IL‑1β treatment and IL‑1β knockdown in UM1 cells were also used to evaluate the effect of IL‑1β. Expression of α‑SMA, glucose transporter 1, hexokinase 2, lactic dehydrogenase and mono‑carboxylate transporter (MCT) 4 were significantly overexpressed in activated fibroblasts, while IL‑1β and MCT1 were upregulated in OSCC cells, indicating enhanced glycolysis in cells of the tumor stroma and a lactate shuttle to the tumor cells. Furthermore, exogenous IL‑1β induced fibroblasts to present similar expression profiles as that in the co‑culture system. Silencing of IL‑1β significantly abrogated the regulatory effect of UM1 cells on stromal glycolysis. Additionally, carboxy‑fluorescein succinimidyl ester cell tracing indicated that OSCC cell proliferation was accelerated during co‑cultivation with fibroblasts. These results indicate that tumor‑derived IL‑1β enhanced stromal glycolysis and induced one‑way lactate flow from the tumor mesenchyme to transformed epithelium, which promotes OSCC proliferation.

Masamune A, Yoshida N, Hamada S, et al.
Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells.
Biochem Biophys Res Commun. 2018; 495(1):71-77 [PubMed] Related Publications
Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of α-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor β1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.

Vastrad B, Vastrad C, Tengli A, Iliger S
Identification of differentially expressed genes regulated by molecular signature in breast cancer-associated fibroblasts by bioinformatics analysis.
Arch Gynecol Obstet. 2018; 297(1):161-183 [PubMed] Related Publications
OBJECTIVE: Breast cancer is a severe risk to public health and has adequately convoluted pathogenesis. Therefore, the description of key molecular markers and pathways is of much importance for clarifying the molecular mechanism of breast cancer-associated fibroblasts initiation and progression. Breast cancer-associated fibroblasts gene expression dataset was downloaded from Gene Expression Omnibus database.
METHODS: A total of nine samples, including three normal fibroblasts, three granulin-stimulated fibroblasts and three cancer-associated fibroblasts samples, were used to identify differentially expressed genes (DEGs) between normal fibroblasts, granulin-stimulated fibroblasts and cancer-associated fibroblasts samples. The gene ontology (GO) and pathway enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by NetworkAnalyst software.
RESULTS: Totally, 190 DEGs were identified, including 66 up-regulated and 124 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell-cell signalling and negative regulation of cell proliferation; molecular function (MF), including insulin-like growth factor II binding and insulin-like growth factor I binding; cellular component (CC), including insulin-like growth factor binding protein complex and integral component of plasma membrane; the down-regulated DEGs were significantly enriched in BP, including cell adhesion and extracellular matrix organization; MF, including N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase activity and calcium ion binding; CC, including extracellular space and extracellular matrix. WIKIPATHWAYS analysis showed the up-regulated DEGs were enriched in myometrial relaxation and contraction pathways. WIKIPATHWAYS, REACTOME, PID_NCI and KEGG pathway analysis showed the down-regulated DEGs were enriched endochondral ossification, TGF beta signalling pathway, integrin cell surface interactions, beta1 integrin cell surface interactions, malaria and glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulphate. The top 5 up-regulated hub genes, CDKN2A, MME, PBX1, IGFBP3, and TFAP2C and top 5 down-regulated hub genes VCAM1, KRT18, TGM2, ACTA2, and STAMBP were identified from the PPI network, and subnetworks revealed these genes were involved in significant pathways, including myometrial relaxation and contraction pathways, integrin cell surface interactions, beta1 integrin cell surface interaction. Besides, the target hsa-mirs for DEGs were identified. hsa-mir-759, hsa-mir-4446-5p, hsa-mir-219a-1-3p and hsa-mir-26a-5p were important miRNAs in this study.
CONCLUSIONS: We pinpoint important key genes and pathways closely related with breast cancer-associated fibroblasts initiation and progression by a series of bioinformatics analysis on DEGs. These screened genes and pathways provided for a more detailed molecular mechanism underlying breast cancer-associated fibroblasts occurrence and progression, holding promise for acting as molecular markers and probable therapeutic targets.

Kikuchi K, McNamara KM, Miki Y, et al.
Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma.
Breast Cancer Res Treat. 2017; 166(3):709-723 [PubMed] Related Publications
PURPOSE: The tumor microenvironment plays pivotal roles in promotion of many malignancies. Cancer-associated fibroblasts (CAFs) have been well-known to promote proliferation, angiogenesis, and metastasis but mechanistic understanding of tumor-stroma interactions is not yet complete. Recently, estrogen synthetic enzymes were reported to be upregulated by co-culture with stromal cells in ER positive breast carcinoma (BC) but effects of co-culture on androgen metabolism have not been extensively examined. Therefore, we evaluated roles of CAFs on androgen metabolism in ER-negative AR-positive BC through co-culture with CAFs.
METHODS: Concentrations of steroid hormone in supernatant of co-culture of MDA-MB-453 and primary CAFs were measured using GC-MS. Cytokines derived from CAFs were determined using Cytokine Array. Expressions of androgen synthetic enzymes were confirmed using RT-PCR and Western blotting. Correlations between CAFs and androgen synthetic enzymes were analyzed using triple-negative BC (TNBC) patient tissues by immunohistochemistry.
RESULTS: CAFs were demonstrated to increase expressions and activities of 17βHSD2, 17βHSD5, and 5α-Reductase1. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17βHSD2, 17βHSD5, and 5α-Reductase1 expression. Underlying mechanisms of IL-6 paracrine regulation of 17βHSD2 and 17βHSD5 could be partially dependent on phosphorylated STAT3, while phosphorylated ERK could be involved in HGF-mediated 5α-Reductase1 induction. α-SMA status was also demonstrated to be significantly correlated with 17βHSD2 and 17βHSD5 status in TNBC tissues, especially AR-positive cases.
CONCLUSIONS: Results of our present study suggest that both IL-6 and HGF derived from CAFs could contribute to the intratumoral androgen metabolism in ER-negative BC patients.

Yi L, Shen H, Zhao M, et al.
Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G
Sci Rep. 2017; 7(1):7953 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Tumor-associated inflammation plays a critical role in facilitating tumor growth, invasion and metastasis. Our previous study showed Aflatoxin G

Kocabayoglu P, Piras-Straub K, Gerken G, et al.
Expression of Fibrogenic Markers in Tumor and Tumor-Surrounding Tissue at Time of Transplantation Correlates with Recurrence of Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation.
Ann Transplant. 2017; 22:446-454 [PubMed] Related Publications
BACKGROUND Liver transplantation (LT) remains the only curative treatment option for patients with defined stages of hepatocellular carcinoma (HCC). Up to 25% of patients show a tumor recurrence following transplantation. The correlation of fibrogenic markers prior to LT with HCC recurrence has not been characterized. We explored the expression of fibrogenic markers in tumor tissue and tumor-surrounding liver tissue of patients undergoing LT and correlated these findings with tumor recurrence. MATERIAL AND METHODS Fibrogenic marker expression in explanted livers was assessed using tumor and tumor-surrounding liver tissue from patients who recently underwent liver transplantation at our center with a follow-up period of at least 3 years. Tissue was analyzed for the expression of fibrogenic proteins and genes, as well as collagen deposition into the extracellular matrix. Results were correlated with HCC recurrence. RESULTS Patients with recurrent HCC following LT exhibited increased levels of fibrogenic markers on both protein and RNA level within the non-tumorous liver tissue in comparison to the tumor tissue itself. Patients who did not develop tumor recurrence up to 4 years after LT showed a reversed expression pattern of fibrogenic markers with decreased levels of β-PDGFR, Collagen 1, and α-SMA in their non-tumorous liver tissue versus the tumor tissue at time of LT as assessed in protein and mRNA expression analysis. These findings correlated with analysis of collagen deposition in the liver. CONCLUSIONS Fibrogenic markers exhibit a differential expression pattern in HCC versus non-tumorous tissue in explanted livers of patients undergoing LT, showing a correlation with HCC recurrence.

Zhou Q, Sun E, Ling L, et al.
Bioinformatic analysis of computational identified differentially expressed genes in tumor stoma of pregnancy‑associated breast cancer.
Mol Med Rep. 2017; 16(3):3345-3350 [PubMed] Related Publications
The present study aimed to screen the differentially expressed genes (DEGs) in tumor‑associated stroma of pregnancy‑associated breast cancer (PABC). By analyzing Affymetrix microarray data (GSE31192) from the Gene Expression Omnibus database, DEGs between tumor asso-ciated stromal cells and normal stromal cells in PABC were identified. Gene Ontology (GO) function and pathway enrichment analyses for the DEGs were then performed, followed by construction of a protein‑protein interaction (PPI) network. A total of 94 upregulated and 386 downregulated DEGs were identified between tumor associated stromal cells and normal stromal cells in patients with PABC. The upregulated DEGs were primarily enriched in the cytokine‑cytokine receptor interaction pathway and GO terms associated with the immune response, which included the DEGs of interleukin 18 (IL18) and cluster of differentiation 274 (CD274). The downregulated DEGs were primarily involved in GO terms associated with cell surface receptor linked signal transduction and pathways of focal adhesion and pathways in cancer. In the PPI network, nodes of jun proto‑oncogene (JUN), FBJ murine osteosarcoma viral oncogene homolog (FOS), V‑myc avian myelocytomatosis viral oncogene homolog (MYC), and alpha‑smooth muscle actin (ACTA2) had higher degrees. The hub genes of JUN, FOS, MYC and ACTA2, as well as the DEGs IL18 and CD274 that were associated with the immune response in GO terms may exert important functions in the molecular mechanisms of PABC. These genes may be used as new molecular targets in the treatment of this disease.

Wu Z, Wang S, Jiang F, et al.
Mass spectrometric detection combined with bioinformatic analysis identified possible protein markers and key pathways associated with bladder cancer.
Gene. 2017; 626:407-413 [PubMed] Related Publications
We aimed to find possible protein markers and key pathways related to bladder cancer. In total, we extracted three bladder cancer tissues and three paracancerous tissues from Jiangsu Provincial People's Hospital Urology Department, and performed mass spectrometric detection with Q Exactive. Subsequently, we screened the differentially expressed proteins in the disease group and the normal group using the LIMMA package, and performed functional enrichment analyses using DAVID. Further, we constructed protein-protein interaction (PPI) networks with Cytoscape software, and analyzed modules with ClusterONE. In total, 165 differentially expressed proteins including 19 upregulated and 146 downregulated ones were obtained. ACTA2 (Actin, Alpha 2, Smooth Muscle, Aorta), ACTN1 (Actinin, Alpha 1), and VCL (Vinculin) were significant nodes with higher degrees in the PPI network. These three nodes were also hub nodes in module 2. Besides, functional enrichment analysis suggested that ECM-receptor interaction and focal adhesion were significant pathways, and these two pathways were also enriched in three network modules. In addition, ACTN1 and VCL were enriched in the focal adhesion pathway in module 2. Thus, ACTA2, ACTN1, and VCL may play important roles in bladder cancer progression and may be protein markers for this disease. The ECM-receptor interaction pathway and the focal adhesion pathway may be involved in the progression of bladder cancer. Furthermore, ACTN1 and VCL may play roles in bladder cancer development, partly via the focal adhesion pathway.

Sanchez-Diaz PC, Chang JC, Moses ES, et al.
Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma.
PLoS One. 2017; 12(5):e0176879 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Pediatric high-grade gliomas represent 8-12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15-35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i.e. self-renewal measure). A 70% reduction in Wnt signaling was also observed in the SF188 and SJ-GBM2 UCHL1 knockdowns (KDs) using a TCF-dependent TOPflash reporter assay. Transcriptome comparisons of UCHL1 KDs versus vector control identified a list of 306 differentially expressed genes (at least 2-fold change; p <0.05) which included genes known to be involved in cancer like ACTA2, POSTN, LIF, FBXL7, FBXW11, GDF15, HEY2, but also potential novel genes such us IGLL5, ABCA4, AQP3, AQP4, CALB1, and ALK. Bioinformatics gene ontology (GO) analysis of these 306 genes revealed significant enrichment in "signal peptides", "extracellular matrix"and "secreted proteins" GO Terms. "Angiogenesis and blood vessel development", "neuron differentiation/development", cell adhesion", and "cell migration" also showed significant enrichment in our GO analysis. Top canonical pathways identified by Ingenuity Pathway Analysis (IPA) included "Clathrin-mediated Endocytosis Signaling" (p = 5.14x10-4), "Virus Entry via Endocytic Pathways" (p = 6.15x 10-4), and "High Mobility Group-Box 1 (HMGB1) Signaling" (p = 6.15x10-4). While FGF2, IL1B, TNF and PDGFB were predicted as top upstream regulators (p < 2x10-16) of the UCHL1 KD-associated transcriptome. Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt/Beta catenin activity. UCHL1 might act as an oncogene in glioma within the gene network that imparts stem-like characteristics to these cancer cells.

Shao JB, Gao ZM, Huang WY, Lu ZB
The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells.
Int J Oncol. 2017; 50(5):1623-1633 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-β1 induces EMT in human neuroblastoma cells. Using quantitative RT-qPCR and western blot analyses, we found that the mRNA and protein expression levels of E-cadherin were significantly decreased, whereas that of α-SMA was significantly increased after neuroblastoma cells were treated with different concentrations of TGF-β1. A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-β1 indicating that TGF-β1 induced EMT in neuroblastoma cells and led to their migration. Inhibiting Smad2/3 expression did not affect the expression of the key molecules involved in EMT. Further investigation found that the expression of the glioblastoma transcription factor (Gli) significantly increased in TGF-β1-stimulated neuroblastoma cells undergoing EMT, accordingly, interfering with Gli1/2 expression inhibited TGF-β1-induced EMT in neuroblastoma cells. GANT61, which is a targeted inhibitor of Gli1 and Gli2, decreased cell viability and promoted cell apoptosis. Thus, TGF-β1 induced EMT in neuroblastoma cells to increase their migration. Specifically, EMT induced by TGF-β1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-β1-induced EMT independent of Smad signaling.

Ni WD, Yang ZT, Cui CA, et al.
Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer.
Biochem Biophys Res Commun. 2017; 486(3):607-612 [PubMed] Related Publications
Tenascin-C (TNC), as a member of the extracellular matrix (ECM), plays an important role in cancer cell proliferation and migration and tumor invasion in various types of cancer. Here, we attempted to investigate the role of TNC as a prognostic factor in prostate cancer. We studied TNC expression via immunohistochemistry in 145 prostate cancer tissue samples. The clinicopathological relevance of TNC expression was examined, as well as other cancer-associated fibroblasts (CAFs)-related factors. Our results showed that the high levels of TNC expression in prostate cancer stroma was significantly associated with lymph node metastasis (P = 0.024) and clinical stage (P = 0.032). Furthermore, TNC was positively correlated with increased micro-vessel density (MVD) (P = 0.017) and tumor associated macrophage (TAM) population (P = 0.025). In both univariate and multivariate Cox regression analyses, TNC (P < 0.001) was an independent poor prognostic factor for overall survival in prostate cancer patients. Moreover, over-expression of TNC (P < 0.001), SMA (P = 0.042) and vimentin (P = 0.010) were significantly correlated with the lower overall survival. In addition, TNC expression in prostate cancer stroma was significantly associated with FSP1 (P = 0.011), SMA (P = 0.021), and vimentin (P = 0.002). In conclusion, our study revealed that high level of TNC as a potential biomarker of CAFs was significantly correlated with the poor prognosis for prostate cancer patients.

Alves MJ, Figuerêdo RG, Azevedo FF, et al.
Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.
BMC Cancer. 2017; 17(1):190 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Cancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients.
METHODS: After signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay.
RESULTS: There was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue.
CONCLUSIONS: Cancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.

Shan T, Chen S, Chen X, et al.
Cancer-associated fibroblasts enhance pancreatic cancer cell invasion by remodeling the metabolic conversion mechanism.
Oncol Rep. 2017; 37(4):1971-1979 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
We investigated the mechanism of cancer-associated fibroblasts (CAFs) in promoting the invasion and metastasis of pancreatic cancer cells in a non-vascular manner. We verified the original generation of isolated cultured CAFs and normal fibroblasts (NFs) based on the expression of α-SMA and vimentin, and we examined the cell glycolysis level through glucose consumption and lactate production experiments. The mRNA and protein expression of CAF glycolytic enzymes, lactate dehydrogenase and pyruvate kinase m2, were examined by RT-PCR and western blotting, respectively. In vitro culture first-generation pancreatic CAFs were collected and cultured together with pancreas cancer BxPc-3 and Panc-1 cells. Cell invasion and migration were assessed using a Transwell assay and scratch test, respectively. Mitochondrial activity was assessed by experimentally determining oxidative phosphorylation (OP) activity. The aerobic oxidation index of cancer cells was also examined. Succinate dehydrogenase, fumarate hydratase (FH), and monocarboxylate transporter 1 (MCT1) expression were examined using an MCT1-specific inhibitor to remove 'tumor-stromal' metabolic coupling to observe the influence of cell interstices on pancreas cancer progression. First-generation isolated cultured CAFs and NFs both grew well, and showed active proliferation. Glucose absorption and lactate production were significantly enhanced in CAFs compared with that in NFs. PCR and western blotting showed that the lactate dehydrogenase and pyruvate kinase m2 mRNA and protein expression levels were increased in the CAFs. After indirect co-culture, OP was increased in the BxPc-3 and Panc-1 cells; correspondingly, succinate dehydrogenase, FH and MCT expression were increased. After the MCT1-specific inhibitor removed 'tumor-stromal' metabolic coupling, the migration and invasion abilities of the pancreatic cancer cells were decreased. Pancreatic CAFs can alter metabolism as well as communicate with and respond to cancer cell migration and invasion. This may be an important mechanism for promoting tumor progression in a non-vascular manner in the tumor microenvironment. The mechanism by which CAFs reshape metabolic transition requires further analysis.

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