UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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A global gene expression profiling specific to the early process of tumor promotion by fenbendazole (FB) or phenobarbital (PB) in a rat two-stage hepatocarcinogenesis model revealed 33 genes to show altered expression in common with both chemicals. The immunohistochemical distribution of transferrin receptor (Tfrc), nuclear receptor subfamily 0, group B, member 2 (Nr0b2) and minichromosome maintenance deficient 6 (MCM6), included in the altered expression profile, were therefore examined in FB- and PB-induced proliferative lesions at both early and late stages of tumor promotion. In addition, immunoexpression of transforming growth factor beta receptor (TGFbetaR) I, TGFbetaRII, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (pPTEN) was also examined. In the early stage, most hepatocellular foci positive for glutathione S-transferase placental form (GST-P) showed co-expression of TGFbetaRI and lack of PTEN and pPTEN, some GST-P-positive foci co-expressing Tfrc and Nr0b2. In the late stage, selective expression of TGFbetaRI, but not TGFbetaRII, was also observed in many adenomas and carcinomas consistently expressing GST-P. Nr0b2 was variably expressed in the proliferative lesions, irrespective of the carcinogenic stage. Like the GST-P-positive foci, adenomas and carcinomas consistently lacked PTEN and pPTEN. Expression of Tfrc and MCM6 was increased in parallel with the carcinogenic stage. In conclusion, loss of PTEN and dysregulation of transforming growth factor beta signaling can be considered to be involved in rat hepatocarcinogenesis from early stages. Selective expression of Tfrc in proliferative lesions suggests an involvement of changes in iron homeostasis during the process of tumor promotion/progression driven by FB or PB.
Carcinogenesis 2008 Nov
PMID:Cellular distributions of molecules with altered expression specific to the tumor promotion process from the early stage in a rat two-stage hepatocarcinogenesis model. 1858 88

Cancer cells differentiate along specific lineages that largely determine their clinical and biologic behavior. Distinct cancer phenotypes from different cells and organs likely result from unique gene expression repertoires established in the embryo and maintained after malignant transformation. We used comprehensive gene expression analysis to examine this concept in the prostate, an organ with a tractable developmental program and a high propensity for cancer. We focused on gene expression in the murine prostate rudiment at three time points during the first 48 h of exposure to androgen, which initiates proliferation and invasion of prostate epithelial buds into surrounding urogenital sinus mesenchyme. Here, we show that androgen exposure regulates genes previously implicated in prostate carcinogenesis comprising pathways for the phosphatase and tensin homolog (PTEN), fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), and Wnt signaling along with cellular programs regulating such 'hallmarks' of cancer as angiogenesis, apoptosis, migration and proliferation. We found statistically significant evidence for novel androgen-induced gene regulation events that establish and/or maintain prostate cell fate. These include modulation of gene expression through microRNAs, expression of specific transcription factors, and regulation of their predicted targets. By querying public gene expression databases from other tissues, we found that rather than generally characterizing androgen exposure or epithelial budding, the early prostate development program more closely resembles the program for human prostate cancer. Most importantly, early androgen-regulated genes and functional themes associated with prostate development were highly enriched in contrasts between increasingly lethal forms of prostate cancer, confirming a 'reactivation' of embryonic pathways for proliferation and invasion in prostate cancer progression. Among the genes with the most significant links to the development and cancer, we highlight coordinate induction of the transcription factor Sox9 and suppression of the proapoptotic phospholipid-binding protein Annexin A1 that link early prostate development to early prostate carcinogenesis. These results credential early prostate development as a reliable and valid model system for the investigation of genes and pathways that drive prostate cancer.
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PMID:Androgen-induced programs for prostate epithelial growth and invasion arise in embryogenesis and are reactivated in cancer. 1879 2

Synergistic effects of dysregulation of the WNT/CTNNB1 and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are thought to be important for the development and progression of many forms of cancer, including the granulosa cell tumor of the ovary. Sustained WNT/CTNNB1 signaling in Sertoli cells causes testicular degeneration and the formation of foci of poorly differentiated stromal cells in the seminiferous tubules in mice. To test if concomitant dysregulation of the WNT/CTNNB1 and PI3K/AKT pathways could synergize to cause testicular cancer, Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) mice that express a dominant, stable CTNNB1 mutant and lack the expression of phosphatase and tensin homolog (PTEN) in their Sertoli cells were generated. These mice developed aggressive testicular cancer with 100% penetrance by 5 weeks of age, and 44% of animals developed pulmonary metastases by 4 months, whereas Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) controls were phenotypically normal. Surprisingly, the tumors could not be classified as Sertoli cell tumors, but rather bore histologic and ultrastructural characteristics of granulosa cell tumors of the testis (GCTT). Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) testicular tumors did not express CYP17, CYP19, germ cell nuclear antigen, estrogen receptor 1 or progesterone receptor, but expressed the early granulosa cell markers WNT4 and FOXL2, confirming the diagnosis of GCTT. Immunohistochemical analyses of Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) GCTT demonstrated a tumor marker profile similar to that reported in human GCTT. Immunoblotting analyses revealed high levels of phosphorylation of AKT and the PI3K/AKT signaling effector FOXO1A in Pten(tm1Hwu/tm1Hwu);Ctnnb1(tm1Mmt/+);Amhr2(tm3(cre)Bhr/+) GCTT, suggesting the involvement of FOXO1A in the mechanism of GCTT development. Together, these data provide the first insights into the molecular etiology of GCTT and the first animal model for the study of GCTT biology.
Carcinogenesis 2009 May
PMID:Dysregulation of WNT/CTNNB1 and PI3K/AKT signaling in testicular stromal cells causes granulosa cell tumor of the testis. 1923 10

Skin cancer is the most common cancer in the United States. UV radiation in sunlight is the major environmental factor causing skin cancer development. PTEN (phosphatase and tensin homolog deleted on chromosome 10), a recently discovered tumor suppressor gene, is frequently mutated, deleted, or epigenetically silenced in various human cancers. PTEN negatively regulates the oncogenic phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. PTEN is clearly a critical tumor suppressor for skin cancer in humans and in mice. This review summarizes the recent progress in the function of PTEN in the development of skin cancer, including basal-cell carcinoma, squamous-cell carcinoma, and melanoma. The regulation of PTEN by UV radiation is also discussed in association with skin carcinogenesis. Understanding the fundamental mechanisms that lead to the reduction of PTEN function in skin carcinogenesis and the essential association with UV radiation opens up new opportunities for molecular chemoprevention and therapy of skin cancer by targeting PTEN pathways.
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PMID:PTEN: new insights into its regulation and function in skin cancer. 1934 9

MicroRNAs (miRNAs) are small, non-protein-coding RNAs that can function as tumor suppressors or oncogenes. Deregulation of miRNA expression has been reported in lung cancer. However, modulation of miRNA expression by chemopreventive agents remains to be defined. In the present study, we examined if the chemopreventive agent indole-3-carbinol (I3C) reversed vinyl carbamate (VC)-induced deregulation of miRNA levels in lung tissues of female A/J mice. Lung tissues were obtained from a previous chemoprevention study, in which mice were treated with VC and given I3C in the diet for 15 weeks. Microarray studies revealed alterations in the expression of a number of miRNAs in lung tumors relative to that of normal lungs. miR-21, mir-31, miR-130a, miR-146b and miR-377 were consistently upregulated, whereas miR-1 and miR-143 were downregulated in lung tumors relative to normal lungs. In mice treated with VC and given I3C in the diet, levels of miR-21, mir-31, miR-130a, miR-146b and miR-377 were reduced relative to the level in mice treated with the carcinogen only. The results of the microarray study were confirmed by quantitative reverse transcription-polymerase chain reaction and gel analysis of polymerase chain reaction products. Further studies with miR-21 indicated that phosphatase and tensin homolog, programmed cell death 4 and rich protein with Kazal motifs are potential targets for the oncogenic effect of miR-21 and the chemopreventive activity of I3C. Taken together, we showed here that miRNAs are deregulated during VC-induced mouse lung tumorigenesis and their levels are modulated by I3C. Therefore, miRNAs and their target genes are promising biomarkers for the diagnosis of lung cancer and efficacy of chemopreventive/chemotherapeutic agents.
Carcinogenesis 2010 Feb
PMID:Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. 1974 27

Development of three-dimensional (3D) cultures that mimic in vivo tissue organization has a pivotal role in the investigation of the involvement of cell adhesion and polarity genes in the pathogenesis of epithelial cancers. Here we describe a novel 3D culture model with primary mouse endometrial epithelial cells. In this model, isolated endometrial epithelial cells develop single-lumened, polarized glandular structures resembling those observed in endometrial tissue. Our in vitro 3D culture model of endometrial glands requires the use of serum-free defined medium with only epidermal growth factor and insulin as growth supplements and 3% Matrigel as reconstituted extracellular matrix. Under these culture conditions, glands of epithelial cells displaying typical apicobasal polarity and proper positioning of tight and adherent junctions are formed by hollowing as early as 7 to 8 days in culture. Addition of the phosphatidylinositol 3-kinase inhibitor LY294002 completely inhibits bromodeoxyuridine incorporation and cyclinD1 expression, confirming that in vitro growth of endometrial glands depends on phosphatidylinositol 3-kinase/Akt signaling. To prove that our culture method is a good model to study endometrial carcinogenesis, we knocked down E-cadherin or phosphatase and tensin homolog expression by lentivirus-delivered short hairpin RNAs. Down-regulation of E-cadherin resulted in complete loss of epithelial cell polarity and glandular formation, whereas phosphatase and tensin homolog down-regulation resulted in increased proliferation of glandular epithelial cells. These properties indicate that our 3D culture model is suitable to study the effect of growth factors, drugs, and gene alterations in endometrial carcinogenesis and to study normal endometrial biology/physiology.
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PMID:A novel three-dimensional culture system of polarized epithelial cells to study endometrial carcinogenesis. 2039 48

Hepatocellular carcinoma (HCC) is a typical hypervascular tumor, and increased levels of vascular endothelial growth factor (VEGF) are associated with progression of HCC. Tumor suppression gene PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important antagonist of the phosphoinositide-3-kinase (PI3K)/adenosine triphosphate-dependent tyrosine kinase (Akt) pathway, is also commonly lost or mutated in HCC. However, the effect of PTEN on VEGF-mediated angiogenesis in HCC remains unknown. To explore this relationship, we expressed a panel of PTEN mutants in human HCC cells with low expression of PTEN (HepG2 cells). Overexpression of PTEN in HepG2 cells resulted in the downregulation of proliferation and migration of cocultured endothelial cells and decreased expression of hypoxia-inducible factor 1 (HIF-1) and VEGF. Similarly, using a nude mouse model, we demonstrated that PTEN decreased expression of HIF-1 and VEGF and suppressed HepG2-induced angiogenesis. This inhibitory effect was not observed in cells expressing a phosphatase-deficient PTEN mutant, suggesting that PTEN inhibits angiogenesis and VEGF through a phosphatase-dependent pathway. Strikingly, reintroducing the C2 domain of PTEN also resulted in a significant decrease in angiogenesis and VEGF expression, although it did not affect Akt phosphorylation or HIF-1 expression. In summary, this study suggests the novel viewpoint that PTEN suppresses angiogenesis and VEGF expression in HCC through both phosphatase-dependent and -independent mechanisms.
Carcinogenesis 2010 Jul
PMID:PTEN regulates angiogenesis and VEGF expression through phosphatase-dependent and -independent mechanisms in HepG2 cells. 2043 Aug 45

The oncogenic ability of aberrant hepatocyte growth factor receptor (Met) signaling is thought to mainly rely on its mitogenic and anti-apoptotic effects. Recently, however, cumulating evidences suggest that genomic instability may be a crucial factor in tumorigenesis. Here, we address whether oncogenic Met receptor is linked to the centrosome abnormality and genomic instability. We showed that expression of the constitutive active Met (CA-Met) induced supernumerary centrosomes probably due to deregulated centrosome duplication, which was accompanied with multipolar spindle formation and aneuploidy. Interestingly, LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly suppressed the appearance of supernumerary centrosomes. Moreover, knockdown of Akt with small interfering RNAs and overexpression of phosphatase and tensin homolog or dominant-negative Akt abrogated supernumerary centrosome formation, evidencing the involvement of PI3K signaling. We further showed that expression of CA-Met significantly increased aneuploidy in p53(-/-) HCT116 cells, but not in p53(+/+) HCT116 cells, indicating that the ability of CA-Met to induce chromosomal instability (CIN) phenotype is related with p53 status. Together, our data demonstrate that aberrant hepatocyte growth factor/Met signaling induces centrosome amplification and CIN via the PI3K-Akt pathway, providing an example that oncogenic growth factor signals prevalent in a wide variety of cancers have cross talks to centrosome abnormality and CIN.
Carcinogenesis 2010 Sep
PMID:The PI3K-Akt mediates oncogenic Met-induced centrosome amplification and chromosome instability. 2058 48

The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) and the androgen receptor (AR) play important roles in tumor development and progression in prostate carcinogenesis. Among many functions, PTEN negatively regulates the cytoplasmic phosphatidylinositol-3-kinase/AKT anti-apoptotic pathway; and nuclear PTEN affects the cell cycle by also negatively regulating the MAPK pathway via cyclin D. Decreased PTEN expression is correlated with prostate cancer progression. Over-expression of AR and upregulation of AR transcriptional activity are often observed in the later stages of prostate cancer. Recent studies indicate that PTEN regulates AR activity and stability. However, the mechanism of how AR regulates PTEN has never been studied. Furthermore, resveratrol, a phytoalexin enriched in red grapes, strawberries and peanuts, has been shown to inhibit AR transcriptional activity in prostate cancer cells. In this study, we use prostate cancer cell lines to test the hypothesis that resveratrol inhibits cellular proliferation in both AR-dependent and -independent mechanisms. We show that resveratrol inhibits AR transcriptional activity in both androgen-dependent and -independent prostate cancer cells. Additionally, resveratrol stimulates PTEN expression through AR inhibition. In contrast, resveratrol directly binds epidermal growth factor receptor (EGFR) rapidly inhibiting EGFR phosphorylation, resulting in decreased AKT phosphorylation, in an AR-independent manner. Thus, resveratrol may act as potential adjunctive treatment for late-stage hormone refractory prostate cancer. More importantly, for the first time, our study demonstrates the mechanism by which AR regulates PTEN expression at the transcription level, indicating the direct link between a nuclear receptor and the PI3K/AKT pathway.
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PMID:Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. 2072 95

Sprouty 2 is a key antagonist regulator of receptor tyrosine kinases, and downstream signaling pathways, like fibroblastic growth factor (FGF) and Ras-mitogen-activated protein kinase (RAS-MAPK). By controlling these pathways, sprouty 2 is involved in regulation of cell proliferation, differentiation, and angiogenesis. Alterations in fibroblastic growth factor receptor (FGFR) and members of the RAS-MAPK pathway are frequent in endometrial carcinoma. The expression of sprouty 2 has been found to be decreased in several types of human cancer, by mechanisms of promoter methylation. In the present study, we have assessed the expression of sprouty 2 in endometrial carcinoma, in correlation with sprouty 2 promoter methylation. Sprouty 2 immunohistochemical expression was assessed using 3 different tissue microarrays: one constructed from paraffin blocks of 80 samples of normal endometrium and 2 tissue microarrays containing samples of 157 endometrial carcinoma (1 tissue microarray constructed with 95 endometrial carcinomas previously studied for microsatellite instability and alterations in phosphatase and tensin homolog (PTEN), k-ras, and b-catenin, and 1 tissue microarray containing 62 endometrial carcinoma, which were also subjected to sprouty 2 promoter methylation analysis). The immunohistochemical expression of sprouty 2 was correlated with cellular proliferation (Ki67) and clinicopathologic data. Sprouty 2 promoter methylation was assessed by methylation-specific polymerase chain reaction, with DNA obtained from fresh-frozen samples of endometrial carcinoma and corresponding normal tissues, and correlated with promoter methylation of RAS association domain family-1A (RASSF1A). A highly significant decrease in sprouty 2 immunoexpression was seen in the proliferative phase of normal endometrium (P < .001). Differences were detected between types I and II endometrial carcinoma, but they were not statistically significant. Reduced immunoexpression of sprouty 2 was seen in 19.85% of endometrial carcinoma and was strongly and inversely associated with increased cell proliferation (Ki67; r = -0.367; P = .001). Sprouty 2 promoter methylation was detected in 31 (53.4%) of 58 endometrial carcinomas. Results from our study show that alterations in sprouty 2 may be involved in endometrial carcinogenesis by controlling cell proliferation.
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PMID:Promoter hypermethylation and expression of sprouty 2 in endometrial carcinoma. 2111 54

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