Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increasing interest in fish species as sentinels of environmental pollution and in carcinogenesis research has led to the identification of diagnostically challenging neoplasms of uncertain cellular origin and the need for additional diagnostic methods. To determine the potential of using commercially available antibodies to intermediate filament proteins on paraffin-embedded fish tissues for immunocytochemistry in tumor diagnosis, the application of three antikeratin antibodies to normal adult tissues from two fish species was assessed. Multiple tissues from 12-14-in. striped bass (Morone saxatilis) and 6-month-old medaka (Oryzias latipes) of both sexes were fixed in Bouin's or formalin fixatives. Formalin-fixed neoplasms from several mammalian species, including cat, dog, hedgehog (Atelerix albiventris, Erinaceus europaeus), rhesus macaque (Macaca mulatta), and sloth bear (Melursus ursinus), were also used as positive controls. Using a strepavidin horseradish peroxidase method on paraffin-embedded tissues, the broad spectrum antibodies AE1/AE3 (Boehringer Mannheim, Indianapolis, IN) and MAK-6 (Triton Biosciences, Alameda, CA), which recognize most of the 19 human cytokeratins, and CAM 5.2 (Becton Dickinson, Mountain View, CA), which recognizes cytokeratins present in human liver, were used as primary antibodies. Epithelia from skin, gills, cornea, bile ducts, renal tubules, gastrointestinal tract, and thymus were strongly positive with AE1/AE3 and MAK-6 in striped bass, but nonepithelial tissues such as bone and muscle were negative. Skin, gills, cornea, and portions of the gastrointestinal tract were strongly positive in medaka with the same antibodies, whereas bile duct, renal, and intestinal epithelia were less so. Tissue digestion improved the intensity of staining, and fixation with Bouin's fixative improved results somewhat compared with formalin fixation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The immunocytochemistry of cytokeratin in fish tissues. 750 8

Many genes originally identified because of their role in embryonic development are also important in control of cell growth and differentiation postnatally. Mutations in some of these genes have been shown to contribute to carcinogenesis. The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin as well as widespread developmental defects. The gene for this disorder, NBCCS, maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary basal cell carcinomas suggests that it functions as a tumor suppressor. NBCCS was positionally cloned and shown to be the human homologue of the Drosophila gene, patched. Drosophila patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. That mutations in human patched result in dysregulation of several genes known to play a role in both organogenesis and carcinogenesis may explain both the birth defects and the cancer predisposition seen in the nevoid basal cell carcinoma syndrome.
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PMID:Molecular basis of the nevoid basal cell carcinoma syndrome. 942 97

Basal-cell carcinomas (BCCs) are the most common cancer in Caucasians. It has been reported that the patched gene is inactivated in 30-40% sporadic BCCs and 20% sporadic medulloblastomas via loss of heterozygosity and nonsense mutations. Recently, two activating smoothened mutations have been found in the sporadic basal cell carcinomas. One, at base pair 1604 (G-to-T transversion) of exon 9, changes codon 535 from tryptophan to leucine, and the other, at base pair 1685 (G-to-A transition) of exon 10, changes codon 562 from arginine to glutamine (Xie et al., 1998). In our study, 1604G-->T was found in 20 out of 97 (20.6%) sporadic BCCs. The high prevalence indicates that 1604G is the mutation hot spot in our tumor samples. This mutation was detected in all three histological subtypes of BCCs, suggesting that smoothened mutation is an early event during the development of the tumor. Our finding of a high smoothened mutation rate, together with high frequent patched gene mutations reported recently, indicates that activation of the hedgehog signal transduction pathway is the most common and early event in the development of sporadic BCCs. Additionally, to determine whether smoothened, like patched, is also involved in the carcinogenesis of medulloblastomas, we screened medulloblastoma samples for these two mutations by restriction analysis. We have found the 1604G-->T mutation in 1 out of 21 medulloblastomas. This result confirmed smoothened gene involvement in the carcinogenesis of medulloblastoma.
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PMID:A frequent activated smoothened mutation in sporadic basal cell carcinomas. 998 36

Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.
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PMID:Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. 1262 53

The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.
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PMID:UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis. 1452 Dec 17

Stem cells possess two basic characteristics: they are able to renew themselves and to develop into different cell types. The link between normal stem cells and tumor cells could be examined in three aspects: what are the differences and similarities in the control of self-renewal capacity between stem cells and tumor cells; whether tumor cells arise from stem cells; do tumorous stem cells exist? Since tumor cells also exhibit self-renewal capacity, it seems plausible that their regulation is similar to that of the stem cells. The infinite self-renewal ability (immortalization) is assured by several, so far only partly known, mechanisms. One of these is telomerase activity, another important regulatory step for survival is the inhibition of apoptosis. Other signal transduction pathways in stem cell regulation may also play certain roles in carcinogenesis: e.g. Notch, Sonic hedgehog (SHH), and Wnt signals. Existence of tumor stem cells was suggested since it is simpler to retain the self-renewal capacity than to reactivate the immortality program in an already differentiated cell. Moreover, stem cells live much longer than the differentiated ones, and so they are exposed for a long period of time to impairments, collecting gene errors leading to the breakdown of the regulation. However, it is still an open question whether all cells in the tumor possess the capacity that produces this tissue or not, that is: are there tumor stem cells or there are not. If tumor stem cells exist, they would be the main target for therapy: only these must be killed since the other tumor cells possess limited proliferative capacity, therefore limited life span. The only problem is that during tumor progression stem-like cells can develop continuously and the identification but mainly the prevention of their formation is still a great challenge.
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PMID:Tumor stem cells. 1518 21

Sonic hedgehog (Shh) signaling plays a critical role during development and carcinogenesis. While Gli family members govern the transcriptional output of Shh signaling, little is known how Gli-mediated transcriptional activity is regulated. Here we identify the actin-binding protein Missing in Metastasis (MIM) as a new Shh-responsive gene. Together, Gli1 and MIM recapitulate Shh-mediated epidermal proliferation and invasion in regenerated human skin. MIM is part of a Gli/Suppressor of Fused complex and potentiates Gli-dependent transcription using domains distinct from those used for monomeric actin binding. These data define MIM as both a Shh-responsive gene and a new member of the pathway that modulates Gli responses during growth and tumorigenesis.
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PMID:MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. 1554 30

Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) are Hedgehog family ligands, which play key roles in embryogenesis and carcinogenesis, especially in pancreatic cancer and gastric cancer. Drosophila Costal-2 (Cos2) is a Hedgehog signaling regulator, interacting with Smoothened (Smo), Cubitus interruptus (Ci), Fused (Fu) and microtubule. KIF27 is one of the mammalian orthologs for Drosophila Cos2. KIF7 gene is the paralog of KIF27 gene; however, complete coding sequence (CDS) of KIF7 remains elusive. Here we characterized human KIF7 gene by using bioinformatics. Human LOC374654 cDNA (NM_198525.1) was a 5'-truncated partial KIF7 cDNA, corresponding to the nucleotide position 1418-4538 of KIF7 complete CDS. KIF7 gene, consisting of 19 exons, was found to encode a 1343-amino-acid KIF7 protein. Human KIF7 showed 43.6% total-amino-acid identity with human KIF27. Kinesin motor catalytic (KISc) domain (codon 15-347 of KIF7) and novel KIF7-KIF27 homologous (KIF727H) domain (codon 699-1196 of KIF7) were well conserved between KIF7 and KIF27. Three coiled-coil regions were located within the KIF727H domain. KIF7 and KIF27 were N-type Kinesins with the KIF727H domain. KIF7 mRNA was expressed in embryonic stem (ES) cells, melanotic melanoma and Jurkat T cells, while KIF27 mRNA was expressed in testis, pancreatic islet, germ cell tumors and Jurkat T cells. This is the first report on the characterization of the KIF7 gene as well as on the identification of KIF727H domain.
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PMID:Characterization of KIF7 gene in silico. 1554 30

Epithelial cells of the gastrointestine undergo a rapid cell-renewal and originate from stem cells throughout the life of the organisms. Previous studies have provided a solid body of evidence to show that the epithelial cell-renewal is under the strict control of cell-cell and cell-extracellular matrix (ECM) interactions between the epithelium and the connective tissue. Especially, the microenvironment around the stem cells called "niche" is thought to play important roles in this control, and its disruption leads to diseases or disorders such as cancer in the human gastrointestine. Although understanding how the niche affects the stem cells is clinically important, its mechanisms still remain mostly unknown at the molecular level, possibly due to difficulties in the identification of the stem cells in the gastrointestine. Recent progress in cell and molecular biology is gradually beginning to shed light on some of the key signaling pathways in the cell-renewal of the intestinal epithelium, such as Wnt/T-cell factor (TCF)/beta-catenin, Notch, Sonic hedgehog (Shh)/bone morphogenetic protein (BMP) signaling pathways, which are also involved in embryonic organogenesis and/or adult carcinogenesis. At present, only fragmentary information is available on their precise functions in the intestine. Nevertheless, there is a growing body of evidence that such signaling pathways have conservative functions in the intestine throughout terrestrial vertebrates, suggesting the usefulness of experimental animals to clarify molecular mechanisms regulating epithelial cell-renewal. In this article, I review some recent findings in this field, with particular focus on our studies using the Xenopus laevis intestine, where the stem cells form the mammalian-type intestinal epithelium under the control of connective tissue during metamorphosis. This Xenopus experimental system will certainly serve as a useful model for the study of the intestinal niche, whose clarification is urgently needed in regenerative medicine.
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PMID:Epithelial-connective tissue cross-talk is essential for regeneration of intestinal epithelium. 1583 3

The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Overexpression of Gli1 under the control of the cytomegalovirus (CMV) promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.
Carcinogenesis 2005 Oct
PMID:Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. 1590


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