Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using reverse transcription and the polymerase chain reaction, we have cloned estrogen receptor complementary DNAs from normal human uterine tissue. Restriction endonuclease analysis identified a polymorphic PvuII recognition site within half of the receptor cDNAs. Sequence analysis revealed a number of differences with the sequence previously reported for the ER cDNA isolated from MCF7 cells and confirmed that the codon for amino acid 400 was erroneously assigned as valine (GTG) rather than glycine (GGG). Sequencing also defined the nature of the PvuII polymorphism, with allele A coding for Glu22 and allele B (with an additional PvuII site) coding for Gln22. We demonstrate that both alleles of this receptor activate transcription of an estrogen-responsive gene to the same extent. This selective cloning method should have wide application in the investigation of naturally occurring cDNA variants from diseased tissues, such as breast cancer cell lines and primary tumor specimens.
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PMID:Characterization of estrogen receptor cDNAs from human uterus: identification of a novel PvuII polymorphism. 939 42

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been identified, the Raf protein kinases which are upstream regulators of the mitogen-activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic effectors. Constitutive upregulation of this pathway by oncogenic ras is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2 were not detectable under conditions of exponential growth or serum-starvation. Depending upon the cell line, the block in Erk signaling was observed to occur at either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack of Erk activation observed in both cell lines and primary tumor tissue suggests that constitutive Erk activation may not be required for tumor maintenance or progression in K-ras transformed pancreatic cells. We hypothesize that other Ras-dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have important implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.
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PMID:Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. 1040 37

We performed dual (two-color) fluorescence in situ hybridization (FISH) using direct fluorescent labeling probes for p53 and chromosome 17 in six gastrointestinal (3 stomach and 3 colon) cancers. In three of these (1 stomach and 2 colon) the interphase cell nuclei showed an imbalance of signals for the p53 and chromosome 17; that is, the p53 signal count was lower than the chromosome 17 signal count, indicating deletion of the p53 gene. Moreover, metaphase FISH analysis demonstrated that those nuclei actually had a chromosome 17 with deletion of the p53 gene. Interestingly, these three cases had an abnormal chromosome 17 copy number, that is, chromosome 17 aneusomy. Furthermore, to investigate the possibility of p53 mutation in tumors with an imbalance of signals for chromosome 17 and p53 per nucleus, we performed a GeneChip p53 assay which has recently been developed. GeneChip p53 assay demonstrated that a primary tumor sample from one colon cancer case had a heterozygous point mutation of CGT (Arg) to CAT (His) at codon 273 in exon 8. In addition, a sample of metastatic tumor in the liver from the same case revealed two heterozygous point mutations. One of them was the same mutation as that is the primary tumor; the other was GTG (Val) to GGG (Gly) at codon 217 in exon 6. In conclusion, we found that the combination of dual-color FISH and GeneChip p53 assay offered reliable results and important information concerning not only deletion of the p53 gene and chromosome 17 aneusomy but also p53 mutations. Using these techniques, we demonstrated that an imbalance of signals for chromosome 17 and p53 per nucleus, chromosome 17 aneusomy, and accumulation of p53 mutations had occurred during carcinogenesis and development of gastrointestinal cancers.
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PMID:Detection of aberrations of 17p and p53 gene in gastrointestinal cancers by dual (two-color) fluorescence in situ hybridization and GeneChip p53 assay. 1095 39

Development of effective chemopreventive agents against prostate cancer (CaP) for humans requires conclusive evidence of their efficacy in animal models that closely emulates human disease. The autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops metastatic CaP, is one such model that mimics progressive forms of human disease. Employing male TRAMP mice, we show that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. In two separate experiments, the cumulative incidence of palpable tumors at 32 weeks of age in 20 untreated mice was 100% (20 of 20). In these mice, 95% (19 of 20), 65% (13 of 20), 40% (8 of 20), and 25% (5 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, liver, and bone, respectively. However, 0.1% GTP (wt/vol) provided as the sole source of drinking fluid to TRAMP mice from 8 to 32 weeks of age resulted in (i) significant delay in primary tumor incidence and tumor burden as assessed sequentially by MRI, (ii) significant decrease in prostate (64%) and genitourinary (GU) (72%) weight, (iii) significant inhibition in serum insulin-like growth factor-I and restoration of insulin-like growth factor binding protein-3 levels, and (iv) marked reduction in the protein expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with water-fed TRAMP mice. The striking observation of this study was that GTP infusion resulted in almost complete inhibition of distant site metastases. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of prostate cancer development, progression, and metastasis of CaP to distant organ sites.
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PMID:Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. 1150 10

SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTP-bound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and - with their collapse - to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell.
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PMID:Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. 1265 73

Using comparative genomic hybridization (CGH), we present a genome-wide screening of a mixed mesenchymal-epithelial hepatoblastoma, its recurrence and 2 novel hepatoblastoma cell lines raised from the ascites, 18 (HepU1) and 23 (HepU2) months after diagnosis of a hepatoblastoma in a 35-month-old boy. Both cell lines were also characterized by GTG-banding, multicolor-fluorescence in situ hybridization (M-FISH) and multicolor banding (M-Band). On the basis of CGH, we compared the cytogenetics of histologically different tumor areas of the parental tumor and its recurrence with the hepatoblastoma cell lines. We found different CGH profiles in the parental tumor rev ish enh(1q31-q32,8p,12,17,20,X), dim(4q34-q35,18q23)[cp] and its recurrence rev ish enh(8q24,17,Xq26-q28), dim(7q11.2-q21,13q34)[cp]. Although both epithelial cell lines were obtained at different times and the clonal ancestor of HepU2 had been exposed to a higher cumulative dose of chemotherapy, HepU1 and HepU2 have an identical karyotype: 48-56,XY,+Y,dup(2)(q32-q34),t(3;4)(q21;q34),+8,+12,+13, +17,+t(18;19)(q21;q?),+20[cp] and identical CGH profiles: rev ish enh(2q24-q33,8,12,13q,17,20), dim(4q34-q35,18q22-q23). In common with previously described hepatoblastoma cell lines, HepU1 and HepU2 demonstrate a gain of chromosome 20. The in situ aberrations most closely resembling that of HepU1 and HepU2 were found in areas of fetal-embryonal differentiation of the primary tumor. Interestingly, both cell lines mimic this histology in their three-dimensional growth pattern in vitro. HepU1 and HepU2 are thus cytogenetically and phenotypically highly characteristic of fetal-embryonal hepatoblastoma.
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PMID:Two novel in vitro human hepatoblastoma models, HepU1 and HepU2, are highly characteristic of fetal-embryonal differentiation in hepatoblastoma. 1270 68

Recurrence and metastasis are commonly associated with poor prognosis of hepatocellular carcinoma (HCC). Therefore, a better understanding of molecular mechanisms involved in HCC metastasis may lead to more effective treatment for HCC patients. Rac plays important roles in cytoskeletal reorganization leading to cell motility in renal and breast carcinomas. However, the role of Rac is controversial in tumors and has not been studied in HCC. The aim of this study was to investigate the importance of the Rac signaling pathway in HCC cell motility and the anti-metastatic potential of FTY720. Recently a pair of HCC cell lines from a primary tumor (H2P) and its matched metastasis (H2M) was established. These two cell lines provide a useful tool for the study of HCC metastasis. The results show that the Rac signaling pathway is activated in the metastatic HCC cell line (H2M) compared with the primary HCC cell line (H2P). FTY720 specifically suppressed H2M cell motility by down-regulation of the Rac-GTP level through inhibition of phosphoinositide 3-kinase activity. To conclude, this study is the first to demonstrate an essential role of Rac signaling pathway activation in HCC metastasis and suppression of cell motility by FTY720 through blocking of the Rac pathway.
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PMID:Significance of the Rac signaling pathway in HCC cell motility: implications for a new therapeutic target. 1560 94

Tyrosine kinase receptors have an essential role in various aspects of tumor progression. In particular, epidermal growth factor receptor (EGFR) and its ligands have been implicated in the growth and dissemination of a wide array of human carcinomas. Here, we describe an EGFR-mediated signaling pathway that regulates human pancreatic carcinoma cell invasion and metastasis, yet does not influence the growth of primary tumors. In fact, ligation/activation of EGFR induces Src-dependent phosphorylation of two critical tyrosine residues of p130CAS, leading to the assembly of a Crk-associated substrate (CAS)/Nck1 complex that promotes Ras-associated protein-1 (Rap1) signaling. Importantly, GTP loading of Rap1 is specifically required for pancreatic carcinoma cell migration on vitronectin but not on collagen. Furthermore, Rap1 activation is required for EGFR-mediated metastasis in vivo without impacting primary tumor growth. These findings identify a molecular pathway that promotes the invasive/metastatic properties of human pancreatic carcinomas driven by EGFR.
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PMID:EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. 2196 50

Septins are a large family of GTP-binding proteins abnormally expressed in many solid tumors. Septin 9 (SEPT9) in particular has been found overexpressed in diverse human tumors including breast, head and neck, ovarian, endometrial, kidney, and pancreatic cancer. Although we previously reported SEPT9 amplification in breast cancer, we now show specifically that high-grade breast carcinomas, the subtype with worst clinical outcome, exhibit a significant increase in SEPT9 copy number when compared with other tumor grades. We also present, for the first time, a sensitive and quantitative measure of seven (SEPT9_v1 through SEPT9_v7) isoform variant mRNA levels in mammary epithelial cells. SEPT9_v1, SEPT9_v3, SEPT9_v6, and SEPT9_v7 isoforms were expressed at the highest levels followed by SEPT9_v2 and SEPT9_v5, whereas SEPT9_v4 was almost undetectable. Although most of the isoforms were upregulated in primary tumor tissues relative to the patient-matched peritumoral tissues, SEPT9_v4 remained the lowest expressing isoform. This comprehensive analysis of SEPT9 provides substantial evidence for increased SEPT9 expression as a consequence of genomic amplification and is the first study to profile SEPT9_v1 through SEPT9_v7 isoform-specific mRNA expression in tumor and nontumor tissues from patients with breast cancer.
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PMID:Septin 9 amplification and isoform-specific expression in peritumoral and tumor breast tissue. 2412 42

Members of the ADP-ribosylation factor (Arf) family of small GTP-binding (G) proteins regulate several aspects of membrane trafficking, such as vesicle budding, tethering and cytoskeleton organization. Arf family members, including Arf-like (Arl) proteins have been implicated in several essential cellular functions, like cell spreading and migration. These functions are used by cancer cells to disseminate and invade the tissues surrounding the primary tumor, leading to the formation of metastases. Indeed, Arf and Arl proteins, as well as their guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) have been found to be abnormally expressed in different cancer cell types and human cancers. Here, we review the current evidence supporting the involvement of Arf family proteins and their GEFs and GAPs in cancer progression, focusing on 3 different mechanisms: cell-cell adhesion, integrin internalization and recycling, and actin cytoskeleton remodeling.
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PMID:Arf proteins in cancer cell migration. 2758 48


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