Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: VCAM1 (cancer-related)
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment.
BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.
METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.
RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.
CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.
Luo L, Xia L, Zha B, et al.miR-335-5p targeting ICAM-1 inhibits invasion and metastasis of thyroid cancer cells.
Biomed Pharmacother. 2018; 106:983-990 [PubMed
] Related Publications
miRNAs is a kind of noncoding small RNAs with negative regulation function. Some miRNAs play a crucial role in the growth of tumor cells. In this study, we analyzed the role of miR-335-5p and its target gene intercellular adhesion molecule 1 (ICAM-1) in thyroid cancer. Real-time polymerase chain reaction (PCR) results showed that the expression level of ICAM-1 in cancer tissues was higher than that in their adjacent tissues. The expression level of ICAM-1 in papillary thyroid carcinoma was also significantly higher than that in other types of tumors. However, the expression of miR-335-5p is opposite to that of ICAM-1. In human thyroid cancer cell lines TPC-1, FTC-133, TT and human thyroid follicular cell line Nthyori 3-1, the expression level of ICAM-1 in TPC-1 was significantly higher than that of other cells, while the expression level of miR-335-5p in TPC-1 was significantly lower than that of other cells. When ICAM-1 expression was downregulated and miR-335-5p expression was upregulated in TPC-1 cells, ICAM-1 expression was upregulated and miR-335-5p expression was downregulated in FTC-133 cells, we found that ICAM-1 could promote the proliferation of thyroid cancer cells, while miR-335-5p could inhibit the proliferation of thyroid cancer cells. miR-335-5p could combine with 3'UTR of ICAM-1 by bioinformatics prediction. Luciferase reporter gene analysis and Western blotting detection further confirmed that miR-335-5p could target ICAM-1 and inhibit its expression. The expression level of miR-335-5p was downregulated, while the expression level of ICAM-1 was upregulated in thyroid cancer. This study will help us better understand the pathogenesis of thyroid cancer and provide new insights into the treatment of this disease.
Luo D, Zhang X, Du R, et al.Low dosage of arsenic trioxide (As
J Biol Inorg Chem. 2018; 23(6):939-947 [PubMed
] Related Publications
Arsenic trioxide (As
Kriston C, Plander M, Márk Á, et al.In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment.
Ann Hematol. 2018; 97(11):2145-2152 [PubMed
] Related Publications
CD49d and CXCR4 are key determinants of interactions between chronic lymphocytic leukemia (CLL) tumor cells and their microenvironment. In this study, we investigated the effect of CD49d and CXCR4 expressions on survival of CLL cells. Primary CLL cells were cultured with CD49d ligand, VCAM-1, or bone marrow stromal cells (BMSCs); then, apoptosis and immunophenotype analyses were performed. VCAM-1 treatment could not induce direct apoptosis protection or immunophenotype change on the CD49d-expressing CLL cells, but resulted in actin reorganization. The BMSC-induced apoptosis protection was independent from the presence of CD49d expression of CLL cells, but showed an inverse correlation with their CXCR4 expression level. We suppose that CD49d contributes to enhanced survival of leukemic cells by mediating migration to the protective microenvironment, not by direct prevention of apoptosis. Moreover, CLL cells with low CXCR4 expression represent a subpopulation that is more dependent on the microenvironmental stimuli for survival, and show increased "death by neglect" when separated from the supportive niche.
Ruscito I, Cacsire Castillo-Tong D, Vergote I, et al.Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study).
Br J Cancer. 2018; 119(3):330-338 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: High-grade serous ovarian cancer (HGSOC) intratumoural vasculature evolution remains unknown. The study investigated changes in tumour microvessel density (MVD) in a large cohort of paired primary and recurrent HGSOC tissue samples and its impact on patients' clinico-pathological outcome.
METHODS: A total of 222 primary (pOC) and recurrent (rOC) intra-patient paired HGSOC were assessed for immunohistochemical expression of angiogenesis-associated biomarkers (CD31, to evaluate MVD, and VEGF-A). Expression profiles were compared between pOCs and rOCs and correlated with patients' data.
RESULTS: High intratumoural MVD and VEGF-A expression were observed in 75.7% (84/111) and 20.7% (23/111) pOCs, respectively. MVD
CONCLUSIONS: HGSOC intratumoural vasculature did not undergo significant changes during disease progression. High concentration of CD31
Hou CH, Yang RS, Tsao YTConnective tissue growth factor stimulates osteosarcoma cell migration and induces osteosarcoma metastasis by upregulating VCAM-1 expression.
Biochem Pharmacol. 2018; 155:71-81 [PubMed
] Related Publications
Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. However, the detailed mechanism associated with CTGF-directed migration in bone neoplasms is still mostly unknown. Through the in vivo and in vitro examination of osteosarcoma cells, this study suggests that VCAM-1 up-regulation and increased osteosarcoma cell migration are involved in this process. Antagonizing αvβ3 integrin inhibited cell migration. Moreover, FAK, PI3K, Akt and NF-κB activation were also shown to be involved in CTGF-mediated osteosarcoma metastasis. Taken together, CTGF promotes VCAM-1 production and further induces osteosarcoma metastasis via the αvβ3 integrin/FAK/PI3K/Akt/NF-κB signaling pathway, which could represent a promising clinical target to improve patient outcome.
Rusak A, Jablonska K, Piotrowska A, et al.The Role of CHI3L1 Expression in Angiogenesis in Invasive Ductal Breast Carcinoma.
Anticancer Res. 2018; 38(6):3357-3366 [PubMed
] Related Publications
BACKGROUND/AIM: An increased level of chitinase 3 like 1 protein (CHI3L1) expression is observed in patients with cancer and may have potential prognostic value. The aim of this study was to evaluate the role of CHI3L1 in angiogenesis in invasive ductal breast carcinoma (IDC) (n=110).
MATERIALS AND METHODS: Immunohistochemistry was used to assess the expression of CHI3L1, CD31, CD34, vascular endothelial growth factor (VEGFA, VEGFC and VEGFD). Real-time polymerase chain reaction and western blot were used to determine the level of CHI3L1 mRNA and protein.
RESULTS: Immunohistochemistry demonstrated positive correlation between CHI3L1 expression and angiogenesis markers: CD31 (r=0.34, p=0.0003), CD34 (r=0.24, p=0.012), VEGFD (r=0.24, p=0.013). Higher CHI3L1 expression in estrogen receptor-negative (p=0.041) and progesterone receptor-negative (p=0.014) cancer was observed. Higher CHI3L1 expression was reported in cancer tissues in comparison to non-malignant breast lesions.
CONCLUSION: These results suggest a potential role of CHI3L1 in angiogenesis in IDC and may suggest its involvement in cancer progression.
Gao HY, Wang W, Luo XG, et al.Screening of prognostic risk microRNAs for acute myeloid leukemia.
Hematology. 2018; 23(10):747-755 [PubMed
] Related Publications
Objectives This study aimed to investigate the risk miRNAs (microRNAs) for AML (acute myeloid leukemia) prognosis and related regulatory mechanisms. Methods MiRNA and gene expression data, as well as clinical data of 176 patients were first downloaded from TCGA. Then miRNAs and genes significantly affecting the survival time based on KM survival curve were identified using Log Rank test. Next, COX proportional-hazard regression analysis was performed to screen the risk miRNAs (P-value < 0.05). Common genes from survival analysis and predicted by miRWalk were used to construct the miRNA regulatory network with the risk miRNAs. Finally, a protein-protein interaction (PPI) network was constructed, as well as functional annotation and pathway enrichment analysis. Results The survival analysis revealed 33 miRNAs and 1,377 genes significantly affecting the survival time. HR values of nine miRNAs (up-regulated hsa-mir-606, 520a, 137, 362, 599, 600, 202, 639and down-regulated 502) were either >1 or <1. The miRNA regulatory network contained 477 nodes and 944 edges. The top ten genes of the constructed PPI network were EGFR, EIF4G1, REL, TOP1, COL14A1, HDAC3, MRPL49, PSMA2, TOP2A and VCAM1 successively. According to pathway enrichment analysis, 6 KEGG pathways and 6 REACTOME pathways were obtained respectively. Conclusion Up-regulated hsa-mir-520a, 599, 606, 137 and 362 may increase the prognostic risk for AML patients via regulating the expression of corresponding target genes, especially COL14A1, HDAC3, REL, EGFR, PSMA2, EIF4G1, MRPL49 and TOP1.
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER
Beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) is crucial for the degradation of IκBα. Our previous transcriptome sequencing analysis revealed that tetraspanin 15 (TSPAN15) was significantly upregulated in clinical oesophageal squamous cell carcinoma (OSCC) tissues. Here, we show that high TSPAN15 expression in OSCC tissues is significantly associated with lymph node and distant metastasis, advanced clinical stage, and poor prognosis. Elevated TSPAN15 expression is, in part, caused by the reduction of miR-339-5p. Functional studies demonstrate that TSPAN15 promotes metastatic capabilities of OSCC cells. We further show that TSPAN15 specifically interacts with BTRC to promote the ubiquitination and proteasomal degradation of p-IκBα, and thereby triggers NF-κB nuclear translocation and subsequent activation of transcription of several metastasis-related genes, including ICAM1, VCAM1, uPA, MMP9, TNFα, and CCL2. Collectively, our findings indicate that TSPAN15 may serve as a new biomarker and/or provide a novel therapeutic target to OSCC patients.
Chang AC, Chen PC, Lin YF, et al.Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin α4β1 system.
Cancer Lett. 2018; 426:47-56 [PubMed
] Related Publications
Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor-bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin α4β1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin α4β1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin α4β1 serves as a ligand that captures VCAM-1
Guo P, Wang B, Liu D, et al.Using Atomic Force Microscopy to Predict Tumor Specificity of ICAM1 Antibody-Directed Nanomedicines.
Nano Lett. 2018; 18(4):2254-2262 [PubMed
] Related Publications
Atomic force microscopy (AFM) is a powerful tool to detect in vitro antibody-antigen interactions. To date, however, AFM-measured antibody-antigen interactions have yet to be exploited to predict in vivo tumor specificity of antibody-directed nanomedicines. In this study, we have utilized AFM to directly measure the biomechanical interaction between live triple negative breast cancer (TNBC) cells and an antibody against ICAM1, a recently identified TNBC target. For the first time, we provide proof-of-principle evidence that in vitro TNBC cell-ICAM1 antibody binding force measured by AFM on live cells more precisely correlates with in vivo tumor accumulation and therapeutic efficacy of ICAM1 antibody-directed liposomes than ICAM1 gene and surface protein overexpression levels. These studies demonstrate that live cell-antibody binding force measurements may be used as a novel in vitro metric for predicting the in vivo tumor recognition of antibody-directed nanomedicines.
Amer R, Tiosano L, Pe'er JLeucine-Rich α-2-Glycoprotein-1 (LRG-1) Expression in Retinoblastoma.
Invest Ophthalmol Vis Sci. 2018; 59(2):685-692 [PubMed
] Related Publications
Purpose: Retinoblastomas' growth rate is dependent on their ability to induce neovascularization. Leucine-rich α-2-glycoprotein-1 (LRG-1) was recently reported to be upregulated in human retinal disease with neovascular pathology. The purpose of the study was to determine LRG-1 expression in human retinoblastoma and to correlate it with clinical and histopathologic parameters and to assess how its expression correlates with vascular endothelial growth factor (VEGF) expression.
Methods: LRG-1 expression was immunohistochemically evaluated in 34 retinoblastoma sections. Immunofluorescence for LRG-1/VEGF-A, LRG-1/TGF-β1/CD31, and LRG-1/Ki67 was performed. Quantitative RT-PCR analysis for the expression of LRG-1 was also done.
Results: LRG-1 was found to be extensively and robustly expressed in retinoblastoma tumors (88%) irrespective of the degree of invasiveness, differentiation, iris neovascularization, and anterior segment involvement. LRG-1 immunoreactivity was predominantly observed in the central tumor vasculature and in the surrounding rim of ischemia. The higher frequency of LRG-1 expression in the presence of optic nerve infiltration, vitreous seeding, and necrosis was not statistically significant. Colocalization was observed between LRG-1 and VEGF-A staining, and no difference in their counts was detected. Quantitative RT-PCR analysis showed that LRG-1 gene expression was significantly upregulated (4.8-fold increase, P = 0.01).
Conclusions: LRG-1 was highly expressed in human retinoblastoma sections, thus providing new insights into the molecular mechanism of retinoblastoma pathogenesis, and suggests a possible new therapeutic target. LRG-1 is a novel oncogene-associated protein shown to be vital to the progression of human cancers. Inhibiting tumor vasculature is progressively evolving as a target in anticancer therapy.
BACKGROUND: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31.
METHODS: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients.
RESULTS: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio.
CONCLUSION: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.
Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. Temozolomide (TMZ) has been considered to be one of the most effective chemotherapeutic agents to prolong the survival of patients with glioblastoma. Many glioma cells develop drug-resistance against TMZ that is mediated by increasing
Li Y, Bai H, Wang H, et al.Reactive oxygen species (ROS)-responsive nanomedicine for RNAi-based cancer therapy.
Nanoscale. 2017; 10(1):203-214 [PubMed
] Related Publications
Although much effort has been dedicated to the development of efficient siRNA delivery for cancer therapy, delivery nanomaterials that can particularly respond to reactive oxygen species (ROS), which are overproduced in the tissue and mitochondria of cancer cells, are still rare for the clinical translation of RNA interference (RNAi)-based therapy. To this end, we developed a ROS-responsive boronic vehicle with a lipid envelope for systemic vascular endothelial growth factor (VEGF) siRNA delivery so as to improve RNAi cancer therapy. We found that the efficiency of siRNA delivery largely relied on the ROS responsiveness of the carrier we have developed to mediate timely siRNA release, the PEG-functionalized lipid layer to shield the surface charge of polyplexes as well as the ability of the phenylboronic moiety to stabilize siRNA. The unique carrier nanostructure provides the efficient systemic transportation of siRNA to the tumor site for effective knockdown of the VEGF, which resulted in a significant antiangiogenesis effect and the effective inhibition of tumor growth in vivo. The current study defines a new systemic delivery strategy for siRNA by cooperatively integrating multifunctional lipid coatings with the ROS-responsive boronic polymer, which may potentially benefit RNAi-based therapy in the dawning era of precision nanomedicine for cancer therapy.
BACKGROUND: The nuclear factor-kappa B (NF-κB) signalling pathway is a regulator of immune response and inflammation that has been implicated in the carcinogenic process. We examined differentially expressed genes in this pathway and miRNAs to determine associations with colorectal cancer (CRC).
METHODS: We used data from 217 CRC cases to evaluate differences in NF-κB signalling pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analysed. We evaluated genes most strongly associated and differentially expressed (fold change (FC) of > 1.5 or < 0.67) that were statistically significant after adjustment for multiple comparisons.
RESULTS: Of the 92 genes evaluated, 22 were significantly downregulated and nine genes were significantly upregulated in all tumours. Two additional genes (CD14 and CSNK2A1) were dysregulated in MSS tumours and two genes (CARD11 and VCAM1) were downregulated and six genes were upregulated (LYN, TICAM2, ICAM1, IL1B, CCL4 and PTGS2) in MSI tumours. Sixteen of the 21 dysregulated genes were associated with 40 miRNAs. There were 76 miRNA:mRNA associations of which 38 had seed-region matches. Genes were associated with multiple miRNAs, with TNFSRF11A (RANK) being associated with 15 miRNAs. Likewise several miRNAs were associated with multiple genes (miR-150-5p with eight genes, miR-195-5p with four genes, miR-203a with five genes, miR-20b-5p with four genes, miR-650 with six genes and miR-92a-3p with five genes).
CONCLUSIONS: Focusing on the genes and their associated miRNAs within the entire signalling pathway provides a comprehensive understanding of this complex pathway as it relates to CRC and offers insight into potential therapeutic agents.
Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG. Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms. However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies. In response to these limitations, we engineered a perfusable, vascularized
RESULTS: The bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells-TECs), and contained CSLC expressing SOX2 and NANOG. Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2. Our results suggest that CSLCs can transdifferentiate into drug resistant CD31
CONCLUSION: Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma.
Vastrad B, Vastrad C, Tengli A, Iliger SIdentification 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.
Wang X, Xu W, Wang S, et al.Transdifferentiation of human MNNG/HOS osteosarcoma cells into vascular endothelial cells in vitro and in vivo.
Oncol Rep. 2017; 38(5):3153-3159 [PubMed
] Related Publications
The transdifferentiation of cancer cells into other types of cells in several types of tissues or organs has been studied. However, whether human osteosarcoma MNNG/HOS cells can transdifferentiate into other types of cells has seldom been reported. Meanwhile, the mechanism of tumor angiogenesis is still disputed, and whether MNNG/HOS cells participate in angiogenesis in osteosarcoma remains unknown. In the present study, the investigation was divided into two parts: in vitro and in vivo. In vitro, we cultivated MNNG/HOS cells under hypoxic conditions for 4 days and found that they typically showed a characteristic 'flagstone' appearance as cultured vascular endothelial cells (VECs). MNNG/HOS cells that were cultivated on Matrigel under hypoxic conditions gradually formed tubular-like structures. Furthermore, when cultured under hypoxic conditions for 4 days, MNNG/HOS cells also transcribed and expressed several molecular markers of VECs (CD31, CD34 and vWF). In vivo, MNNG/HOS cells (1x106 cells) were cultivated under hypoxic conditions and subcutaneously injected into nude mice; the mice were sacrificed 49 days after inoculation. Immunohistochemical staining with anti-human CD31 antibody showed evidence of tumor angiogenesis in human osteosarcoma MNNG/HOS cells. The results demonstrated that MNNG/HOS cells can transdifferentiate into vascular endothelial cell-like cells in vitro and in vivo.
Mao CS, Yin H, Ning HB, et al.Levels of HBx, VEGF, and CEACAM1 in HBV-related hepatocellular carcinoma and their correlation with cancer prognosis.
Eur Rev Med Pharmacol Sci. 2017; 21(17):3827-3833 [PubMed
] Related Publications
OBJECTIVE: Hepatitis B virus X protein (HBx), vascular endothelial growth factor (VEGF) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), are related to HBV associated hepatocellular carcinoma (HCC). This study recruited HCC patients and employed the SMMC-7721 and L02 liver cell lines, to analyze the expression levels of HBx, VEGF and CEACAM1 in liver cancer and their correlation with the cancer prognosis.
PATIENTS AND METHODS: HBV-related HCC patients were recruited from our hospital. Immunohistochemistry (IHC) and Western blotting assay were used to detect the expression of HBx, VEGF and CEACAM1 in liver tissues. Multi-variant analysis and the correlation analysis between HBx, VEGF, CEACAM1 expression and clinical/pathological features of HCC were performed by using the Cox regression analysis.
RESULTS: In HBV-related HCC tissues, positive expression rates of HBx, CEACAM1, and VEGF, were 80%, 50%, and 65%, respectively. In HBx-positive group, positive rate for CEACAM1 and VEGF were 56.25% and 75%, while in HBx-negative group such figures were 75% and 25% (p<0.05). HCC cells had lower expression of CEACAM1 and higher VEGF levels compared to normal hepatocytes. Those HCC cells transfected with HBx had even lower CEACAM1 and higher VEGF levels compared to un-transfected cells. HBx was negatively correlated with CEACAM1 and positively correlated with VEGF. Expressions of these three factors were all independent risk factors as they were correlated with lesion size, venous infiltration, metastasis, and capsule.
CONCLUSIONS: HBx, VEGF and CEACAM1 were widely expressed in HBV-related HCC. HBx may facilitate occurrence and progression of HBV-related HCC via down-regulating CEACAM1 and up-regulating VEGF.
BACKGROUND: Breast cancer metastasis is a highly prevalent cause of death for European females. DNA microarray analysis has established that primary tumors, which remain localized, differ in gene expression from those that metastasize. Crossanalysis of these studies allow to revile the differences that may be used as predictive in the disease prognosis and therapy.
OBJECTIVE: The aim of the project was to validate suggested prognostic and therapeutic markers using meta-analysis of data on gene expression in metastatic and primary breast cancer tumors.
METHOD: Data on relative gene expression values from 12 studies on primary breast cancer and breast cancer metastasis were retrieved from Genevestigator (Nebion) database. The results of the data meta-analysis were compared with results of literature mining for suggested metastatic breast cancer markers and vectors and consistency of their reported differential expression.
RESULTS: Our analysis suggested that transcriptional expression of the COX2 gene is significantly downregulated in metastatic tissue compared to normal breast tissue, but is not downregulated in primary tumors compared with normal breast tissue and may be used as a differential marker in metastatic breast cancer diagnostics. RRM2 gene expression decreases in metastases when compared to primary breast cancer and could be suggested as a marker to trace breast cancer evolution. Our study also supports MMP1, VCAM1, FZD3, VEGFC, FOXM1 and MUC1 as breast cancer onset markers, as these genes demonstrate significant differential expression in breast neoplasms compared with normal breast tissue.
CONCLUSION: COX2 and RRM2 are suggested to be prominent markers for breast cancer metastasis. The crosstalk between upstream regulators of genes differentially expressed in primary breast tumors and metastasis also suggests pathways involving p53, ER1, ERB-B2, TNF and WNT, as the most promising regulators that may be considered for new complex drug therapeutic interventions in breast cancer metastatic progression.
Cao Y, Zhao D, Li P, et al.MicroRNA-181a-5p Impedes IL-17-Induced Nonsmall Cell Lung Cancer Proliferation and Migration through Targeting VCAM-1.
Cell Physiol Biochem. 2017; 42(1):346-356 [PubMed
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AIM: The contribution of the inflammatory mediator interleukin-17 (IL-17) in nonsmall cell lung cancer (NSCLC) malignancy has been reported in the literature. MicroRNA-181a-5p (miR-181a-5p) acts as a tumor suppressor which can regulate target gene at the posttranscriptional level. Our study aimed to investigate the interaction between IL-17 and miR-181a-5p in NSCLC.
METHODS: 35 patients with NSCLC and 24 COPD controls were selected and examined in our study. In vitro, H226 and H460 cell lines were exposed to different doses (20, 40, 60, and 80 ng/mL) of IL-17 to examine the effect of IL-17 on miR-181a-5p and vascular cell adhesion molecule 1 (VCAM-1) expression. MiR-181 mimic and miR-181a-5p inhibitor were transfected to explore the regulation of VCAM-1 as well as tumor cell proliferation and migration.
RESULTS: miR-181a-5p expression was downregulated, and IL-17 and VCAM-1 expression was upregulated in NSCLC tissues. Furthermore, IL-17 decreased miR-181a-5p expression but increased VCAM-1 expression in H226 and H460 cells. MiR-181 regulated VCAM-1 expression through binding to 3'-UTR sequence. MiR-181 attenuated tumor cell proliferation and migration. IL-17 modulated miR-181a-5p expression through activating NF-κB but not Stat3.
CONCLUSION: Taken together, our data show the regulation of VCAM-1 expression by miR-181a-5p under IL-17 exposure, predicting a potential way for counteracting cancer metastasis.
Wang Y, Liu P, Wang X, Mao HRole of X‑linked inhibitor of apoptosis‑associated factor‑1 in vasculogenic mimicry in ovarian cancer.
Mol Med Rep. 2017; 16(1):325-330 [PubMed
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X-linked inhibitor of apoptosis‑associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that may reverse the anti‑apoptotic effect of XIAP. Previous studies have revealed that XAF1 serves an important role in cancer angiogenesis. Vasculogenic mimicry (VM) describes the formation of fluid‑conducting channels by highly invasive and genetically dysregulated tumor cells. VM is critical for tumor blood supply and is associated with aggressive actions and metastasis. The aim of present study was to investigate the potential association between XAF1 expression with VM of ovarian cancer, and evaluate the role of XAF1 in tumor cell migration and invasion of SKOV3 cells. VM structure and XAF1 expression were detected in 94 tissue samples of advanced epithelial ovarian cancer (EOC). Invasion and migration of the SKOV3 human ovarian carcinoma cell line were identified by Transwell assay. It was revealed that the presence of VM was associated with high grade advanced ovarian cancer. Reduced XAF1 expression was significantly associated with presence of VM. Overexpression of XAF1 significantly reduced invasion and migration of SKOV3 cells, and inhibited vascular endothelial growth factor protein expression. Furthermore, vasculature was suppressed by overexpression of XAF1 in vivo in xenograft models. In conclusion, XAF1 expression was associated with VM in ovarian cancer, suggesting a potential role of XAF1 in the formation of VM in EOC. These ﬁndings may facilitate the development of novel therapeutic agents for the treatment of ovarian cancer.
Shih YL, Chou HM, Chou HC, et al.Casticin impairs cell migration and invasion of mouse melanoma B16F10 cells via PI3K/AKT and NF-κB signaling pathways.
Environ Toxicol. 2017; 32(9):2097-2112 [PubMed
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Casticin, a polymethoxyflavone, is one of the major active components obtained from Fructus viticis, which have been shown to have anticancer activities including induce cell apoptosis in human cancer cells. The aim of this study was to investigate the molecular mechanisms by which casticin inhibits cell migration and invasion of mouse melanoma B16F10 cells. Cell viability was examined by MTT assay and the results indicated that casticin decreased the total percentages of viable cells in dose-dependent manners. Casticin affected cell migration and invasion in B16F10 cells were examined by wound healing mobility assay and Boyden chamber migration and invasion assay and results indicated that casticin inhibited cell migration and invasion in dose-dependent manners. Western blotting was used to examine the protein expression of B16F10 cells after exposed to casticin and the results showed that casticin decreased the expressions of MMP-9, MMP-2, MMP-1, FAK, 14-3-3, GRB2, Akt, NF-κB p65, SOS-1, p-EGFR, p-JNK 1/2, uPA, and Rho A in B16F10 cells. Furthermore, cDNA microarray assay was used to show that casticin affected associated gene expression of cell migration and invasion and the results indicated that casticin affected some of the gene expression such as increased SCN1B (cell adhesion molecule 1) and TIMP2 (TIMP metallopeptidase inhibitor 2) and decreased NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S protein4), VEGFA (vascular endothelial growth factor A), and DDIT3 (DNA-damage-inducible transcript 3) which associated cell migration and invasion in B16F10 cells. Based on those observations, we suggest that casticin could be used as a novel anticancer metastasis of melanoma cancer in the future.
CONTEXT: Clove (Eugenia caryophyllata Thunb. [Myrtaceae]) essential oil (CEO) has been shown to possess antimicrobial, antifungal, antiviral, antioxidant, anti-inflammatory and anticancer properties. However, few studies have focused on its topical use.
OBJECTIVE: We investigated the biological activity of a commercially available CEO in a human skin disease model.
MATERIALS AND METHODS: We evaluated the effect of CEO on 17 protein biomarkers that play critical roles in inflammation and tissue remodelling in a validated human dermal fibroblast system, which was designed to model chronic inflammation and fibrosis. Four concentrations of CEO (0.011, 0.0037, 0.0012, and 0.00041%, v/v) were studied. The effect of 0.011% CEO on genome-wide gene expression was also evaluated.
RESULTS AND DISCUSSION: CEO at a concentration of 0.011% showed robust antiproliferative effects on human dermal fibroblasts. It significantly inhibited the increased production of several proinflammatory biomarkers such as vascular cell adhesion molecule-1 (VCAM-1), interferon γ-induced protein 10 (IP-10), interferon-inducible T-cell α chemoattractant (I-TAC), and monokine induced by γ interferon (MIG). CEO also significantly inhibited tissue remodelling protein molecules, namely, collagen-I, collagen-III, macrophage colony-stimulating factor (M-CSF), and tissue inhibitor of metalloproteinase 2 (TIMP-2). Furthermore, it significantly modulated global gene expression and altered signalling pathways critical for inflammation, tissue remodelling, and cancer signalling processes. CEO significantly inhibited VCAM-1 and collagen III at both protein and gene expression levels.
CONCLUSIONS: This study provides important evidence of CEO-induced anti-inflammatory and tissue remodelling activity in human dermal fibroblasts. This study also supports the anticancer properties of CEO and its major active component eugenol.
Desbourdes L, Javary J, Charbonnier T, et al.Alteration Analysis of Bone Marrow Mesenchymal Stromal Cells from De Novo Acute Myeloid Leukemia Patients at Diagnosis.
Stem Cells Dev. 2017; 26(10):709-722 [PubMed
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Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) frequently display alterations in several hematologic disorders, such as acute lymphoid leukemia, acute myeloid leukemia (AML), and myelodysplastic syndromes. In acute leukemias, it is not clear whether MSC alterations contribute to the development of the malignant clone or whether they are simply the effect of tumor expansion on the microenvironment. We extensively investigated the characteristics of MSCs isolated from the BM of patients with de novo AML at diagnosis (L-MSCs) in terms of phenotype (gene and protein expression, apoptosis and senescence levels, DNA double-strand break formation) and functions (proliferation and clonogenic potentials, normal and leukemic hematopoiesis-supporting activity). We found that L-MSCs show reduced proliferation capacity and increased apoptosis levels compared with MSCs from healthy controls. Longer population doubling time in L-MSCs was not related to the AML characteristics at diagnosis (French-American-British type, cytogenetics, or tumor burden), but was related to patient age and independently associated with poorer patient outcome, as was cytogenetic prognostic feature. Analyzing, among others, the expression of 93 genes, we found that proliferative deficiency of L-MSCs was associated with a perivascular feature at the expense of the osteo-chondroblastic lineage with lower expression of several niche factors, such as KITLG, THPO, and ANGPT1 genes, the cell adhesion molecule VCAM1, and the developmental/embryonic genes, BMI1 and DICER1. L-MSC proliferative capacity was correlated positively with CXCL12, THPO, and ANGPT1 expression and negatively with JAG1 expression. Anyway, these changes did not affect their in vitro capacity to support normal hematopoiesis and to modify leukemic cell behavior (protection from apoptosis and quiescence induction). Our findings indicate that BM-derived MSCs from patients with newly diagnosed AML display phenotypic and functional alterations such as proliferative deficiency that could be attributed to tumor progression, but does not seem to play a special role in the leukemic process.
Takada S, Hojo M, Tanigaki K, Miyamoto SContribution of Endothelial-to-Mesenchymal Transition to the Pathogenesis of Human Cerebral and Orbital Cavernous Malformations.
Neurosurgery. 2017; 81(1):176-183 [PubMed
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BACKGROUND: The analysis of gene-targeted mouse mutants has demonstrated that endothelial-to-mesenchymal transition (EndMT) is crucial to the onset and progression of cerebral cavernous malformations (CMs). It has also been shown that Notch and ephrin/Eph signaling are involved in EndMT. However, their roles in the pathogenesis of human intracranial CMs remain unclear.
OBJECTIVE: To elucidate the contribution of EndMT, the Notch pathway, and ephrin-B2/EphB4 signaling to the pathogenesis of human intracranial CMs.
METHODS: Eight human intracranial CMs (5 cerebral and 3 orbital CMs) were immunohistochemically investigated.
RESULTS: CD31 (an endothelial marker) and EndMT markers, such as α-smooth muscle actin (a mesenchymal marker) and CD44 (a mesenchymal stem cell marker), were expressed in the endothelial layer of vascular sinusoids in all cases, suggesting that endothelial cells (ECs) have acquired mesenchymal and stem-cell-like characteristics and undergone EndMT in all cerebral and orbital CMs. EndMT was observed in about 70% and 35% of ECs in cerebral and orbital CMs, respectively. In all cases, Notch3 was expressed in the endothelial layer, indicating that ECs of vascular sinusoids have acquired mesenchymal features. In all cases, both ephrin-B2 and EphB4 were detected in the endothelial layer, suggesting that ECs of vascular sinusoids are immature or malformed cells and have both arterial and venous characteristics.
CONCLUSION: EndMT plays a critical role in the pathogenesis of human cerebral and orbital CMs. Modulating EndMT is expected to be a new therapeutic strategy for cerebral and orbital CMs.
We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig, was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n = 228) and TCGA datasets (n = 547) and can separate GBM patients from control individuals with a Matthew's correlation coefficient value of 0.87 in a lock-down test. Functionally, 17/33 GBMSig proteins are associated with transforming growth factor β signaling pathways, including CD47, SLC16A1, HMOX1, and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy control individuals (area under the curve is 0.98 in receiver operating characteristic). In addition, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers.