Research IndicatorsGraph generated 27 February 2015 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 27 February, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
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
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: PDGFD (cancer-related)
BACKGROUND: Cytokine-induced killer (CIK) cells are an emerging approach of cancer treatment. Our previous study have shown that CIK cells stimulated with combination of IL-2 and IL-15 displayed improved proliferation capacity and tumor cytotoxicity. However, the mechanisms of CIK cell proliferation and acquisition of cytolytic function against tumor induced by IL-2 and IL-15 have not been well elucidated yet.
METHODS: CIK(IL-2) and CIK(IL-15) were generated from peripheral blood mononuclear cells primed with IFN-γ, and stimulated with IL-2 and IL-15 in combination with OKT3 respectively. RNA-seq was performed to identify differentially expressed genes, and gene ontology and pathways based analysis were used to identify the distinct roles of IL-2 and IL-15 in CIK preparation.
RESULTS: The results indicated that CIKIL-15 showed improved cell proliferation capacity compared to CIK(IL-2). However, CIK(IL-2) has exhibited greater tumor cytotoxic effect than CIKIL-15. Employing deep sequencing, we sequenced mRNA transcripts in CIK(IL-2) and CIK(IL-15). A total of 374 differentially expressed genes (DEGs) were identified including 175 up-regulated genes in CIK(IL-15) and 199 up-regulated genes in CIK(IL-2)). Among DEGs in CIK(IL-15), Wnt signaling and cell adhesion were significant GO terms and pathways which related with their functions. In CIK(IL-2, type I interferon signaling and cytokine-cytokine receptor interaction were significant GO terms and pathways. We found that the up-regulation of Wnt 4 and PDGFD may contribute to enhanced cell proliferation capacity of CIK(IL-15), while inhibitory signal from interaction between CTLA4 and CD80 may be responsible for the weak proliferation capacity of CIK(IL-2). Moreover, up-regulated expressions of CD40LG and IRF7 may make for improved tumor cytolytic function of CIK(IL-2) through type I interferon signaling.
CONCLUSIONS: Through our findings, we have preliminarily elucidated the cells proliferation and acquisition of tumor cytotoxicity mechanism of CIK(IL-15) and CIK(IL-2). Better understanding of these mechanisms will help to generate novel CIK cells with greater proliferation potential and improved tumor cytolytic function.
The platelet-derived growth factor-D (PDGF-D) was demonstrated to be able to promote tumor growth and invasion in human malignancies. However, little is known about its roles in endometrial cancer. In the present study, we investigated the expression and functions of PDGF-D in human endometrial cancer. Alterations of PDGF-D mRNA and protein were determined by real time PCR, western blot and immunohistochemical staining. Up-regulation of PDGF-D was achieved by stably transfecting the pcDNA3-PDGF-D plasmids into ECC-1 cells; and knockdown of PDGF-D was achieved by transient transfection with siRNA-PDGF-D into Ishikawa cells. The MTT assay, colony formation assay and Transwell assay were used to detect the effects of PDGF-D on cellular proliferation and invasion. The xenograft assay was used to investigate the functions of PDGF-D in vivo. Compared to normal endometrium, more than 50% cancer samples showed over-expression of PDGF-D (p < 0.001), and high level of PDGF-D was correlated with late stage (p = 0.003), deep myometrium invasion (p < 0.001) and lympha vascular space invasion (p = 0.006). In vitro, over-expressing PDGF-D in ECC-1 cells significantly accelerated tumor growth and promoted cellular invasion by increasing the level of MMP2 and MMP9; while silencing PDGF-D in Ishikawa cells impaired cell proliferation and inhibited the invasion, through suppressing the expression of MMP2 and MMP9. Moreover, we also demonstrated that over-expressed PDGF-D could induce EMT and knockdown of PDGF-D blocked the EMT transition. Consistently, in xenografts assay, PDGF-D over-expression significantly promoted tumor growth and tumor weights. We demonstrated that PDGF-D was commonly over-expressed in endometrial cancer, which was associated with late stage deep myometrium invasion and lympha vascular space invasion. Both in vitro and in vivo experiments showed PDGF-D could promote tumor growth and invasion through up-regulating MMP2/9 and inducing EMT. Thus, we propose targeting PDGF-D to be a potent strategy for endometrial cancer treatment.
Yang TY, Hsu LI, Chiu AW, et al.Comparison of genome-wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure.
Environ Res. 2014; 128:57-63 [PubMed
] Related Publications
BACKGROUND: Arsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms.
OBJECTIVES: This study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure.
METHODS: Genome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels (β¯) in AsUC and non-AsUC were compared by their ratio (β¯ ratio) and difference (Δβ¯). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined.
RESULTS: Among 27,578 methylation sites analyzed, 231 sites had β¯ ratio >2 or <0.5 and 45 sites had Δβ¯ >0.2 or <-0.2. There were 13 sites showing statistically significant (q<0.05) differences in β¯ between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age.
CONCLUSIONS: Significant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose-response relation, remain to be validated by further studies with large sample sizes.
BACKGROUND: Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma.
METHODS: Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLN metastasis were estimated as ORs and 95% confidence intervals (CI) using logistic regression. Competing risk regression was used to estimate HRs and 95% CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma.
RESULTS: In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factor D (PDGFD), PIK3CA, and toll-like receptor (TLR)-3 were associated with the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666).
CONCLUSIONS: These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma.
IMPACT: Additional research attempting to replicate these results is warranted.
Newey PJ, Nesbit MA, Rimmer AJ, et al.Whole-exome sequencing studies of nonfunctioning pituitary adenomas.
J Clin Endocrinol Metab. 2013; 98(4):E796-800 [PubMed
] Related Publications
CONTEXT: The tumorigenic role of genetic abnormalities in sporadic pituitary nonfunctioning adenomas (NFAs), which usually originate from gonadotroph cells, is unknown.
OBJECTIVE: The objective of the study was to identify somatic genetic abnormalities in sporadic pituitary NFAs.
DESIGN: Whole-exome sequencing was performed using DNA from 7 pituitary NFAs and leukocyte samples obtained from the same patients. Somatic variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 24 pituitary NFAs.
RESULTS: Whole-exome sequencing achieved a high degree of coverage such that approximately 97% of targeted bases were represented by more than 10 base reads; 24 somatic variants were identified and confirmed in the discovery set of 7 pituitary NFAs (mean 3.5 variants/tumor; range 1-7). Approximately 80% of variants occurred as missense single nucleotide variants and the remainder were synonymous changes or small frameshift deletions. Each of the 24 mutations occurred in independent genes with no recurrent mutations. Mutations were not observed in genes previously associated with pituitary tumorigenesis, although somatic variants in putative driver genes including platelet-derived growth factor D (PDGFD), N-myc down-regulated gene family member 4 (NDRG4), and Zipper sterile-α-motif kinase (ZAK) were identified; however, DNA sequence analysis of these in the validation set of 24 pituitary NFAs did not reveal any mutations indicating that these genes are unlikely to contribute significantly in the etiology of sporadic pituitary NFAs.
CONCLUSIONS: Pituitary NFAs harbor few somatic mutations consistent with their low proliferation rates and benign nature, but mechanisms other than somatic mutation are likely involved in the etiology of sporadic pituitary NFAs.
Han Y, Guo XH, Zheng QF, et al.Down-regulation of platelet-derived growth factor-D expression blockades NF-κB pathway to inhibit cell proliferation and invasion as well as induce apoptosis in esophageal squamous cell carcinoma.
Mol Biol Rep. 2013; 40(3):2473-83 [PubMed
] Related Publications
Substantial evidence has demonstrated that platelet-derived growth factor-D (PDGF-D) is tightly associated with the development and progression of tumors. However, its biological functions in esophageal squamous cell carcinoma (ESCC) remain to be delineated. In this study, we found that expressions of PDGF-D mRNA and protein in ESCC tissues and cells were significantly higher than that in normal esophageal epithelial tissues (P < 0.05), further investigation showed that PDGF-D protein level in EC1 cells was obviously higher than those in EC9706 and Eca109 cells (P < 0.05). Elevated PDGF-D level was closely associated with TNM staging, tumor differentiation and lymph node metastasis (P < 0.05), but not related to the patients' age and gender (P > 0.05). In addition, down-regulation of PDGF-D expression markedly inhibited proliferation, reduced invasion and induced apoptosis in EC1 cells. More importantly, reduced PDGF-D level evoked the down-regulation of p65 and p-IκBα proteins and elevation of IκBα protein of NF-κB pathway, accompanied with the decreases of bcl-2 and MMP-9 protein expressions and increases of bax protein level and caspase-3 activities. Correctively, our data suggest that PDGF-D plays pivotal roles in the development and progression of ESCC, and combinations with PDGF-D and NF-κB pathway may be effective and feasible molecular targets for therapy of ESCC.
Niini T, Scheinin I, Lahti L, et al.Homozygous deletions of cadherin genes in chondrosarcoma-an array comparative genomic hybridization study.
Cancer Genet. 2012; 205(11):588-93 [PubMed
] Related Publications
Chondrosarcoma is a malignant bone tumor that is often resistant to chemotherapy and radiotherapy. We applied high resolution oligonucleotide array comparative genomic hybridization to 46 tumor specimens from 44 patients with chondrosarcoma and identified several genes with potential importance for the development of chondrosarcoma. Several homozygous deletions were detected. The tumor suppressor genes CDKN2A and MTAP were each homozygously deleted in four of the cases, and the RB1 gene was homozygously deleted in one. Two homozygous deletions of MTAP did not affect CDKN2A. Deletions were also found to affect genes of the cadherin family, including CDH4 and CDH7, each of which had a targeted homozygous loss in one case, and CDH19, which had a targeted homozygous loss in two cases. Loss of the EXT1 and EXT2 genes was uncommon; EXT1 was homozygously deleted in none and EXT2 in two of the cases, and large heterozygous losses including EXT1 and/or EXT2 were seen in three cases. Targeted gains and amplifications affected the MYC, E2F3, CDK6, PDGFRA, KIT, and PDGFD genes in one case each. The data indicate that chondrosarcomas develop through a combination of genomic imbalances that often affect the RB1 signaling pathway. The inactivation of cadherin genes may also be critical in the pathogenesis of the tumor.
Wang Z, Ali S, Banerjee S, et al.Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype.
J Cell Physiol. 2013; 228(3):556-62 [PubMed
] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most frequently diagnosed cancers and the fourth leading cause of cancer-related death in the United States, suggesting that there is an urgent need to design novel strategies for achieving better treatment outcome of patients diagnosed with PDAC. Our previous study has shown that activation of Notch and NF-κB play a critical role in the development of PDAC in the compound K-Ras(G12D) and Ink4a/Arf deficient transgenic mice. However, the exact molecular mechanism by which mutated K-Ras and Ink4a/Arf deficiency contribute to progression of PDAC remains largely elusive. In the present study, we used multiple methods, such as real-time RT-PCR, Western blotting assay, and immunohistochemistry to gain further mechanistic insight. We found that the deletion of Ink4a/Arf in K-Ras(G12D) expressing mice led to high expression of PDGF-D signaling pathway in the tumor and tumor-derived cell line (RInk-1 cells). Furthermore, PDGF-D knock-down in RInk-1 cells resulted in the inhibition of pancreatosphere formation and down-regulation of EZH2, CD44, EpCAM, and vimentin. Moreover, we demonstrated that epithelial-mesenchymal transition (EMT) was induced in the compound mice, which is linked with aggressiveness of PDAC. In addition, we demonstrated that tumors from compound transgenic mice have higher expression of cancer stem cell (CSC) markers. These results suggest that the acquisition of EMT phenotype and induction of CSC characteristics could be linked with the aggressiveness of PDAC mediated in part through the activation of PDGF-D, signaling.
The platelet-derived growth factors (PDGF A, B, C, and D) and their receptors (α-PDGFR and β-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative β-PDGFR is overexpressed and activated during prostate cancer progression, but the identification and functional significance of its complementary ligand have not been elucidated. This study examined potential oncogenic functions of β-PDGFR ligands PDGF B and PDGF D, using nonmalignant prostate epithelial cells engineered to overexpress these ligands. In our models, PDGF D induced cell migration and invasion more effectively than PDGF B in vitro. Importantly, PDGF D supported prostate epithelial cell tumorigenesis in vivo and showed increased tumor angiogenesis compared with PDGF B. Autocrine signaling analysis of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways found PDGF D-specific activation of the c-jun-NH2-kinase (JNK) signaling cascade. Using short hairpin RNA and pharmacologic inhibitors, we showed that PDGFD-mediated phenotypic transformation is β-PDGFR and JNK dependent. Importantly, we made a novel finding of PDGF D-specific increase in the shedding and activation of the serine protease matriptase in prostate epithelial cells. Our study, for the first time to our knowledge, showed ligand-specific β-PDGFR signaling as well as PDGF D-specific regulation of matriptase activity and its spatial distribution through shedding. Taken together with our previous finding that matriptase is a proteolytic activator of PDGF D, this study provides a molecular insight into signal amplification of the proteolytic network and PDGF signaling loop during cancer progression.
Zhao Z, Liu Y, He H, et al.Candidate genes influencing sensitivity and resistance of human glioblastoma to Semustine.
Brain Res Bull. 2011; 86(3-4):189-94 [PubMed
] Related Publications
OBJECTIVE: The prognosis of glioblastoma (GBM) is poor. The therapeutic outcome of conventional surgical and adjuvant treatments remains unsatisfactory, and therefore individualized adjuvant chemotherapy has aroused more attention. Microarrays have been applied to study mechanism of GBM development and progression but it has difficulty in determining responsible genes from the plethora of genes on microarrays unrelated to outcome. The present study was attempted to use bioinformatics method to investigate candidate genes that may influence chemosensitivity of GBM to Semustine (Me-CCNU).
METHODS: Clinical data of 4 GBM patients in Affymetrix microarray were perfected through long-term follow-up study. Differential expression genes between the long- and short-survival groups were picked out, GO-analysis and pathway-analysis of the differential expression genes were performed. Me-CCNU-related signal transduction networks were constructed. The methods combined three steps before were used to screen core genes that influenced Me-CCNU chemosensitivity in GBM.
RESULTS: In Affymetrix microarray there were altogether 2018 differential expression genes that influenced survival duration of GBM. Of them, 934 genes were up-regulated and 1084 down-regulated. They mainly participated in 94 pathways. Me-CCNU-related signal transduction networks were constructed. The total number of genes in the networks was 466, of which 66 were also found in survival duration-related differential expression genes. Studied key genes through GO-analysis, pathway-analysis and in the Me-CCNU-related signal transduction networks, 25 core genes that influenced chemosensitivity of GBM to Me-CCNU were obtained, including TP53, MAP2K2, EP300, PRKCA, TNF, CCND1, AKT2, RBL1, CDC2, ID2, RAF1, CDKN2C, FGFR1, SP1, CDK6, IGFBP3, MDM4, PDGFD, SOCS2, CCNG2, CDK2, SDC2, STMN1, TCF7L1, TUBB.
CONCLUSION: Bioinformatics may help excavate and analyze large amounts of data in microarrays by means of rigorous experimental planning, scientific statistical analysis and collection of complete data about survival of GBM patients. In the present study, a novel differential gene expression pattern was constructed and advanced study will provide new targets for chemosensitivity of GBM.
BACKGROUND: Current management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumor recurrence with Castrate Resistant Prostate Cancer (CRPC) and subsequent metastasis lead to poor survival outcome, suggesting that there is a dire need for novel mechanistic understanding of tumor recurrence, which would be critical for designing novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancer stem cells or cancer-initiating cells that is reminiscent of the acquisition of Epithelial to Mesenchymal Transition (EMT) phenotype. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that PCa cells with EMT phenotype displayed stem-like cell features characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhanced clonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreased expression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-forming ability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7 expression, which was consistent with repressed self-renewal capability.
CONCLUSIONS/SIGNIFICANCE: These results suggest that miR-200 played a pivotal role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention of tumor recurrence especially by eliminating those cells that are the "Root Cause" of tumor development and recurrence.
BACKGROUND: Members of the PDGF family have been suggested as potential biomarkers for papillary thyroid carcinomas (PTC). However, it is known that both expression and stimulatory effect of PDGF ligands can be affected by inflammatory cytokines. We have performed a microarray study in a collection of PTCs, of which about half the biopsies contained tumour-infiltrating lymphocytes or thyroiditis. To investigate the expression level of PDGF ligands and receptors in PTC we measured the relative mRNA expression of all members of the PDGF family by qRT-PCR in 10 classical PTC, eight clinically aggressive PTC, and five non-neoplastic thyroid specimens, and integrated qRT-PCR data with microarray data to enable us to link PDGF-associated gene expression profiles into networks based on recognized interactions. Finally, we investigated potential influence on PDGF mRNA levels by the presence of tumour-infiltrating lymphocytes.
METHODS: qRT-PCR was performed on PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA PDGFRB and a selection of lymphocyte specific mRNA transcripts. Semiquantitative assessment of tumour-infiltrating lymphocytes was performed on the adjacent part of the biopsy used for RNA extraction for all biopsies, while direct quantitation by qRT-PCR of lymphocyte-specific mRNA transcripts were performed on RNA also subjected to expression analysis. Relative expression values of PDGF family members were combined with a cDNA microarray dataset and analyzed based on clinical findings and PDGF expression patterns. Ingenuity Pathway Analysis (IPA) was used to elucidate potential molecular interactions and networks.
RESULTS: PDGF family members were differentially regulated at the mRNA level in PTC as compared to normal thyroid specimens. Expression of PDGFA (p = 0.003), PDGFB (p = 0.01) and PDGFC (p = 0.006) were significantly up-regulated in PTCs compared to non-neoplastic thyroid tissue. In addition, expression of PDGFC was significantly up-regulated in classical PTCs as compared to clinically aggressive PTCs (p = 0.006), and PDGFRB were significantly up-regulated in clinically aggressive PTCs (p = 0.01) as compared to non-neoplastic tissue. Semiquantitative assessment of lymphocytes correlated well with quantitation of lymphocyte-specific gene expression. Further more, by combining TaqMan and microarray data we found a strong inverse correlation between PDGFC expression and the expression of lymphocyte specific mRNAs.
CONCLUSION: At the mRNA level, several members of the PDGF family are differentially expressed in PTCs as compared to normal thyroid tissue. Of these, only the PDGFC mRNA expression level initially seemed to distinguish classical PTCs from the more aggressive PTCs. However, further investigation showed that PDGFC expression level correlated inversely to the expression of several lymphocyte specific genes, and to the presence of lymphocytes in the biopsies. Thus, we find that PDGFC mRNA expression were down-regulated in biopsies containing infiltrated lymphocytes or thyroiditis. No other PDGF family member could be linked to lymphocyte specific gene expression in our collection of PTCs biopsies.
Fèvre-Montange M, Champier J, Durand A, et al.Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype.
Int J Oncol. 2009; 35(6):1395-407 [PubMed
] Related Publications
Meningiomas, one of the largest subgroup of intracranial tumours are generally benign, but can progress to malignancy. They are classified into the three World Health Organization grades: benign, atypical and anaplastic meningiomas. Various histopathological features have been associated with aggressiveness or recurrence. Several genes have been suggested as prognostic factors, but molecular signatures have not permitted the classification of the tumours into the three grades. We have performed a microarray transcriptomic study on 17 meningiomas of different malignancy using CodeLink Uniset Human Whole Genome Bioarrays to try to distinguish the different grades and histopathological subtypes. Unsupervised hierarchical clustering classified the meningiomas into groups A, B and C, which corresponded to the three grades except for 3 benign meningiomas with higher proliferation indexes and/or recurrence, included in the atypical group. Several genes involved in cell adhesion (CD44, LOX), cell division (CKS2, BIRC5 and UBE2C), cell differentiation (Notch1) or signal transduction (ARHGAP28) were upregulated, whereas tumour suppressor genes (LR1B, DRR1, PLZF, GPX3, SYNPO, TIMP3 and HOPS) and genes involved in cell adhesion (PROS1), proliferation (SERPINF1 and PDGFD) and differentiation (AOX1) were downregulated in groups B and C compared to group A. In the benign tumours, we identified genes with signatures specific for fibroblastic meningiomas (FBLN1, Tenascin C and MMP2 encoding extracellular matrix proteins) and for meningothelial meningiomas (MLPH, DEFB1 and FAT3), suggesting different mechanisms involved in the tumorigenesis of these subtypes. This microarray-based expression profiling study revealed candidate genes and pathways that may contribute to a better understanding of the recurrence of a benign meningioma. Our results might make it possible to determine which benign meningiomas might recur despite complete resection, and will provide helpful information for neurosurgeons in the follow-up of the patients.
MicroRNAs have been implicated in tumor progression. Recent studies have shown that the miR-200 family regulates epithelial-mesenchymal transition (EMT) by targeting zinc-finger E-box binding homeobox 1 (ZEB1) and ZEB2. Emerging evidence from our laboratory and others suggests that the processes of EMT can be triggered by various growth factors, such as transforming growth factor beta and platelet-derived growth factor-D (PDGF-D). Moreover, we recently reported that overexpression of PDGF-D in prostate cancer cells (PC3 PDGF-D cells) leads to the acquisition of the EMT phenotype, and this model offers an opportunity for investigating the molecular interplay between PDGF-D signaling and EMT. Here, we report, for the first time, significant downregulation of the miR-200 family in PC3 PDGF-D cells as well as in PC3 cells exposed to purified active PDGF-D protein, resulting in the upregulation of ZEB1, ZEB2, and Snail2 expression. Interestingly, re-expression of miR-200b in PC3 PDGF-D cells led to reversal of the EMT phenotype, which was associated with the downregulation of ZEB1, ZEB2, and Snail2 expression, and these results were consistent with greater expression levels of epithelial markers. Moreover, transfection of PC3 PDGF-D cells with miR-200b inhibited cell migration and invasion, with concomitant repression of cell adhesion to the culture surface and cell detachment. From these results, we conclude that PDGF-D-induced acquisition of the EMT phenotype in PC3 cells is, in part, a result of repression of miR-200 and that any novel strategy by which miR-200 could be upregulated would become a promising approach for the treatment of invasive prostate cancer.
Ammoun S, Flaiz C, Ristic N, et al.Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma.
Cancer Res. 2008; 68(13):5236-45 [PubMed
] Related Publications
Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor beta (PDGFRbeta), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRbeta-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRbeta-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials.
Wågsäter D, Zhu C, Björck HM, Eriksson PEffects of PDGF-C and PDGF-D on monocyte migration and MMP-2 and MMP-9 expression.
Atherosclerosis. 2009; 202(2):415-23 [PubMed
] Related Publications
BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory process involving the activity of several cytokines and growth factors. Platelet-derived growth factor-A (PDGF-A) and PDGF-B are important mitogens and chemoattractants for monocytes as well as smooth muscle cells. We sought to identify the role of PDGF-C and PDGF-D, two new members of the PDGF family, in monocyte migration and differentiation. We also assessed their effects in regulating matrix metalloproteinase-2 (MMP-2) and MMP-9, which are important for cell migration.
METHODS AND RESULTS: PDGF-C and PDGF-D were expressed in macrophages, smooth muscle cells, and endothelial cells in human atherosclerotic plaques, as shown by immunohistochemical analysis. PDGF-C and PDGF-D mRNA and protein expression was induced after differentiation of THP-1 monocytes to macrophages, and both PDGF-C and PDGF-D induced MMP-9 mRNA expression in a concentration-dependent manner. Treatment of cells with PDGF-C or PDGF-D enhanced the secretion of MMP-2 and MMP-9 in a cell-dependent manner. In a migration assay using a Boyden chamber with 8 microm pore size, PDGF-C and PDGF-D attracted THP-1 monocytes in a concentration-dependent manner.
CONCLUSIONS: Our data suggest that PDGF-C and PDGF-D, like PDGF-A and PDGF-B, play important roles in atherosclerosis by stimulating MMP activity and influencing monocyte migration.
The majority of human malignancies are believed to have epithelial origin, and the progression of cancer is often associated with a transient process named epithelial-mesenchymal transition (EMT). EMT is characterized by the loss of epithelial markers and the gain of mesenchymal markers that are typical of "cancer stem-like cells," which results in increased cell invasion and metastasis in vivo. Therefore, it is important to uncover the mechanistic role of factors that may induce EMT in cancer progression. Studies have shown that platelet-derived growth factor (PDGF) signaling contributes to EMT, and more recently, PDGF-D has been shown to regulate cancer cell invasion and angiogenesis. However, the mechanism by which PDGF-D promotes invasion and metastases and whether it is due to the acquisition of EMT phenotype remain elusive. For this study, we established stably transfected PC3 cells expressing high levels of PDGF-D, which resulted in the significant induction of EMT as shown by changes in cellular morphology concomitant with the loss of E-cadherin and zonula occludens-1 and gain of vimentin. We also found activation of mammalian target of rapamycin and nuclear factor-kappaB, as well as Bcl-2 overexpression, in PDGF-D PC3 cells, which was associated with enhanced adhesive and invasive behaviors. More importantly, PDGF-D-overexpressing PC3 cells showed tumor growth in SCID mice much more rapidly than PC3 cells. These results provided a novel mechanism by which PDGF-D promotes EMT, which in turn increases tumor growth, and these results further suggest that PDGF-D could be a novel therapeutic target for the prevention and/or treatment of prostate cancer. Disclosure of potential conflicts of interest is found at the end of this article.
Wang Z, Kong D, Banerjee S, et al.Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.
Cancer Res. 2007; 67(23):11377-85 [PubMed
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Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-kappaB (NF-kappaB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-kappaB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-kappaB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA-transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-kappaB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.
Yang S, Shin J, Park KH, et al.Molecular basis of the differences between normal and tumor tissues of gastric cancer.
Biochim Biophys Acta. 2007; 1772(9):1033-40 [PubMed
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To be able to describe the differences between the normal and tumor tissues of gastric cancer at a molecular level would be essential in the study of the disease. We investigated the gene expression pattern in the two types of tissues from gastric cancer by performing expression profiling of 86 tissues on 17K complementary DNA microarrays. To select for the differentially expressed genes, class prediction algorithm was employed. For predictor selection, samples were first divided into a training (n=58), and a test set (n=28). A group of 894 genes was selected by a t-test in a training set, which was used for cross-validation in the training set and class (normal or tumor) prediction in the test set. Smaller groups of 894 genes were individually tested for their ability to correctly predict the normal or tumor samples based on gene expression pattern. The expression ratios of the 5 genes chosen from microarray data can be validated by real time RT-PCR over 6 tissue samples, resulting in a high level of correlation, individually or combined. When a representative predictor set of 92 genes was examined, pathways of 'focal adhesion' (with gene components of THBS2, PDGFD, MAPK1, COL1A2, COL6A3), 'ECM-receptor interaction' pathway (THBS2, COL1A2, COL6A3, FN1) and 'TGF-beta signaling' (THBS2, MAPK1, INHBA) represent some of the main differences between normal and tumor of gastric cancer at a molecular level.
Li X, Eriksson UNovel PDGF family members: PDGF-C and PDGF-D.
Cytokine Growth Factor Rev. 2003; 14(2):91-8 [PubMed
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Platelet-derived growth factors (PDGFs) were discovered almost two decades ago. The classical PDGF polypeptide chains, PDGF-A and PDGF-B, are well studied and they regulate a number of physiological and pathophysiological processes in many types of mesenchymal cells via two receptor tyrosine kinases, PDGF receptors alpha and beta. Recently, two additional PDGF polypeptide chains were discovered, namely PDGF-C and PDGF-D. The discovery of two additional ligands for the two PDGF receptors suggests that PDGF-mediated signaling is more complex than previously anticipated.
Li H, Fredriksson L, Li X, Eriksson UPDGF-D is a potent transforming and angiogenic growth factor.
Oncogene. 2003; 22(10):1501-10 [PubMed
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Platelet-derived growth factors (PDGFs) are important for normal tissue growth and maintenance. Overexpression of the classical PDGFs, PDGF-A and PDGF-B, has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Recently, two novel PDGFs, PDGF-C and PDGF-D, were discovered. It has not yet been established whether PDGF-C and PDGF-D are linked to disease phenotypes like the classical PDGFs. PDGF-B, the cellular homologue of the viral simian sarcoma oncogene v-sis, is known to potently induce cellular transformation through activation of PDGF receptor (PDGFR)-beta. In this work, we have determined the transformation efficacy of PDGF-D in comparison with that of PDGF-C and PDGF-B. PDGF-D is a potent transforming growth factor for NIH/3T3 cells, and the transformed cells displayed stress fibre reorganization, increased proliferation rate, anchorage-independent growth in soft agar, ability to induce tumours in nude mice, and upregulation of vascular endothelial growth factor. Morphological analyses of the vasculatures from the PDGF-isoform-expressing tumours revealed marked differences suggesting differential signalling through the two PDGF receptors in tumour vessel development and remodelling. In summary, these results suggest that PDGF-D induce cellular transformation and promote tumour growth by accelerating the proliferation rate of the tumour cells, and by stimulation of tumour neovascularization.
Uutela M, Laurén J, Bergsten E, et al.Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFD genes.
Circulation. 2001; 103(18):2242-7 [PubMed
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BACKGROUND: Platelet-derived growth factor (PDGF), which is a major mitogen for vascular smooth muscle cells and has been implicated in the pathogenesis of arteriosclerosis, is composed of dimers of PDGF-A and PDGF-B polypeptide chains, encoded by different genes. Here, we have analyzed the chromosomal localization, structure, and expression of 2 newly identified human genes of the PDGF family, called PDGFC and PDGFD.
METHODS AND RESULTS: We used fluorescence in situ hybridization to locate PDGFC and PDGFD in chromosomes 4q32 and 11q22.3 to 23.2, respectively. Exon structures of PDGFC and PDGFD were determined by sequencing from genomic DNA clones. The coding region of PDGFC consists of 6 and PDGFD of 7 exons, of which the last 2 encode the C-terminal PDGF cystine knot growth factor homology domain. An N-terminal CUB domain is encoded by exons 2 and 3 of both genes, and a region of proteolytic cleavage involved in releasing and activating the growth factor domain is located in exon 4 in PDGFC and exon 5 in PDGFD. PDGF-C was expressed predominantly in smooth muscle cells and PDGF-D in fibroblastic adventitial cells, and both genes were active in cultured endothelial cells and in a variety of tumor cell lines. Both PDGF-C and PDGF-D also stimulated human coronary artery smooth muscle cells.
CONCLUSIONS: PDGFC and PDGFD have similar genomic structures, which resemble those of the PDGFA and PDGFB genes. Their expression in the arterial wall and cultured vascular cells suggests that they can transduce proliferation/migration signals to pericytes and smooth muscle cells.