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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basal cell carcinoma (basalioma, BCC) is undoubtedly the most common malignant skin cancer and the most common human malignancy in general, with the continuous increase in its incidence. BCC is generally a disorder of white individuals, especially those with fair skin. UV radiation is the most important risk factor in the development of BCC. Short-wavelength UVB radiation (290-320 nm, sunburn rays) is believed to play a greater role in BCC formation than long-wavelength UVA radiation (320-400 nm, tanning rays). A latency period of 20-50 years is typical between the time of UV damage and the clinical onset of BCC. Therefore, in most cases BCC develops on chronically sun-exposed skin in elderly people, most commonly in the area of head and neck. UVB radiation damages DNA and its repair system and alters the immune system resulting in a progressive genetic alterations and formation of neoplasm. UV-induced mutations in the TP53 tumor-suppressor gene have been found in about 50% of BCC cases. The mutations that activate the Hedgehog intercellular signaling pathway genes, including PTCH, Sonic hedgehog (Shh) and Smoothened (Smo) play a significant role in cutaneous carcinogenesis. Epidemiologic studies demonstrate the higher incidence of the BCC in more equatorial latitudes than in polar latitudes. Other risk factors for the development of BCC include sun bed use, family history of skin cancers, skin type 1 and 2, immunosuppression, previous radiotherapy, and chronic exposure to toxic substances such as inorganic arsenic. Although rarely metastatic, its malignant nature is sometimes emphasized by the local tissue destruction, disfigurement, and even death if left untreated. Due to extremely high incidence of BCC medical professionals should be aware of the importance of the public education on the etiology of this tumor and the importance of the UV protection.
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PMID:The role of UV radiation in the development of basal cell carcinoma. 1913 22

The hedgehog and Wnt signaling pathways play important roles in human cancers with possible interaction. This study aimed at analysis and correlation of the expression of Gli1, a transcriptional factor and target gene of hedgehog signaling pathway, with clinicopathological parameters and expression of beta-catenin, an important member of the Wnt pathway, in normal, hyperplastic and malignant endometrium. Immunohistochemical study on 15 normal endometrium, 14 simple and complex hyperplasia without atypia, 37 atypical complex hyperplasia and 80 endometrial cancers showed significant Gli1 overexpression and beta-catenin nuclear immunoreactivity in endometrial cancers and atypical endometrial hyperplasia when compared with normal endometrium (P<0.05). Overexpression of Gli1 in endometrial cancers correlated with well-differentiated histological grade (P<0.001), non-myometrial invasion (P=0.004) and superficial myometrial invasion (P=0.041). beta-Catenin nuclear immunoreactivity was also associated with well-differentiated histology (P=0.013). Gli1 overexpression positively correlated with beta-catenin nuclear immunoreactivity in atypical complex hyperplasia (P=0.013) and endometrial carcinoma (P=0.017). Similar Gli1 and beta-catenin protein expression pattern was observed in normal and endometrial cancer cell lines by western blotting. We further showed a complex formation between Gli1 and beta-catenin protein in endometrial cancer cell lines in an immunoprecipitation study. Ectopic overexpression of Gli1 into endometrial cancer cells led to reduced expression of beta-catenin in cell cytoplasm and increased expression of beta-catenin in the nuclei. In summary, overexpression of Gli1 was an early event in endometrial carcinogenesis. Aberrant activation of hedgehog pathway may play important roles in endometrial cancer through beta-catenin nuclear accumulation.
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PMID:Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through beta-catenin. 1932 35

Esophageal atresia (EA) is a rather common neonatal anomaly frequently associated with other congenital anomalies such as cardiac, genitourinary, and anorectal malformations and chromosomal disorders. It is suggested that the abnormal pattern of expression of the gene Sonic hedgehog is associated with failure of tracheoesophageal separation resulting in EA in an animal model. EA with distal tracheoesophageal fistula (TEF) is the most common type of EA and is usually treated successfully with division of the TEF and primary anastomosis. However, the optimal surgical treatment for long-gap EA remains controversial. Even though the results of delayed anastomosis with the Lividitis method or Collis-Nissen method are mainly reported to be satisfactory, long-term results show a high incidence of gastroesophageal reflux (GER) and esophageal dysmotility. Replacement with the gastric tube, stomach, colon, or jejunum has been performed when the gap is too long to use the native esophagus. Anastomotic stricture, obstruction due to redundancy, and adhesion of substitutes were reported in long-term follow-up studies. Moreover, the risk of carcinogenesis in Barrett's metaplasia, which is associated with GER, must be taken into consideration. Thus, long-term follow-up into adulthood is warranted in patients with EA.
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PMID:[Long-term complications of esophageal atresia]. 1966 31

Ligand-dependent activation of the Hedgehog (Hh) pathway in colorectal cancers (CRCs) is controversial, and the regulation mechanism of Hh ligands expression remains to be determined. In the present study, the mRNA expressions of Sonic hedgehog (SHH), Indian hedgehog (IHH), Patched, Smoothened, and Gli1 were examined in four cultured colon cancer cell lines by reverse transcription-PCR. Moreover, ligands mRNA expression (SHH and IHH) were examined by reverse transcription-PCR, and SHH protein expression by immunohistochemistry in 25 primary CRCs. The methylation status of SHH and IHH was also investigated by bisulfate sequencing or methylation specific PCR. IHH mRNA was completely absent in cell lines studied, and expressed at a very low level or not expressed at all in primary CRCs. Methylation analysis revealed that IHH promoter was hypermethylated in colon cancer cell lines. Absence of SHH mRNA expression and hypermethylation of its promoter was also observed in colon cancer cell lines. However, high level expression of SHH and hypomethylation of its promoter was detected in primary CRCs. In conclusion, ligand dependent activity of Hh pathway is inactive in cultured colon cancer cells correlating to ligands hypermethylation. In contrast, SHH overexpression, possible consequence of promoter hypomethylation, could play a role in the carcinogenesis of primary CRCs.
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PMID:Distinct expression patterns of hedgehog ligands between cultured and primary colorectal cancers are associated with aberrant methylation of their promoters. 1985 79

The hedgehog pathway, initially discovered by two Nobel laureates Drs E Wieschaus and C Nusslein-Volhard in Drosophila, is a major regulator for cell differentiation, tissue polarity and cell proliferation. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last 2 years in our understanding of hedgehog signaling activation in human cancer, interactions between hedgehog signaling and other pathways in carcinogenesis, potential antagonists for hedgehog signaling inhibition and their clinical implications for human cancer treatment.
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PMID:Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. 1993 12

This perspective places the article by Tang et al. in this issue of the journal (beginning on page 25) in the context of recent work defining the hedgehog signaling pathway as a central etiologic factor and as a therapeutic target in basal cell cancer. Tang et al. show that inhibition of cyclooxygenase activity, either genetically (in a relevant mouse model) or pharmacologically (in the mouse and in patients highly predisposed to develop basal cell skin cancers), may suppress basal cell carcinogenesis. This new study of cyclooxygenase inhibition, together with recent data on the efficacy of hedgehog pathway inhibition, offers new hope for patients at a high risk for basal cell cancer.
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PMID:Beyond the scalpel: targeting hedgehog in skin cancer prevention. 2005 70

Basal cell carcinoma is the most common human malignancy in populations of European origin, and Australia has the highest incidence of basal cell carcinoma in the world. Great advances in the understanding of the genetics of this cancer have occurred in recent years. Mutations of the patched 1 gene (PTCH1) lead to basal cell carcinoma predisposition in Gorlin syndrome. PTCH1 is part of the hedgehog signalling pathway, and derangements within this pathway are now known to be important in the carcinogenesis of many different cancers including sporadic basal cell carcinoma. The molecular biology of the hedgehog pathway is discussed, and mouse models of basal cell carcinoma based on this pathway are explored. New developments in non-surgical treatment of basal cell carcinoma are based on this knowledge. Other genes of importance to basal cell carcinoma development include the tumour suppressor gene P53 and the melanocortin-1 receptor gene. In addition, we discuss molecules of possible importance such as the glutathione-S-transferases, DNA repair genes, cyclin-dependent kinase inhibitor 2A, Brahma and connexins. Evidence of familial aggregation of this cancer is explored and supports the possibility of genetic predisposition to this common malignancy.
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PMID:Genetics of basal cell carcinoma. 2054 11

Accumulating lines of experimental evidence have revealed that the malignant transformation of multipotent tissue-resident adult stem/progenitor cells into cancer stem/progenitor cells endowed with a high self-renewal capacity and aberrant multilineage differentiation potential may be at origin of the most types of human aggressive and recurrent cancers. Based on new cancer stem/progenitor cell concepts of carcinogenesis, it is suggested that a small subpopulation of highly tumorigenic and migrating cancer stem/progenitor cells, also designated as cancer- and metastasis-initiating cells, can provide critical roles for primary tumor growth, metastases at distant tissues and organs, treatment resistance and disease relapse. Particularly, cancer initiation and progression to locally invasive and metastatic stages is often associated with a persistent activation of distinct developmental signaling pathways in these immature cells during epithelial-mesenchymal transition program. The signaling cascades that are often deregulated in cancer stem/progenitor cells include hedgehog, epidermal growth factor receptor (EGFR), Wnt/beta-catenin, NOTCH, polycomb gene product BMI-1 and/or stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4). Importantly, the results from recent investigations have also indicated that different cancer subtypes may harbor distinct subsets and/or number of cancer-initiating cells during cancer progression as well as before or after therapy initiation and disease recurrence. Therefore, the identification of the molecular transforming events that frequently occur in cancer- and metastasis-initiating cells versus their differentiated progenies is of immense interest to develop new targeting approach for improving current therapies against aggressive, metastatic, recurrent and lethal cancers.
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PMID:New advances on critical implications of tumor- and metastasis-initiating cells in cancer progression, treatment resistance and disease recurrence. 2055 55

The hedgehog (Hh) signaling pathway has been reported to be crucial in human carcinogenesis and tumor progression. Glioma-associated oncogenes (Gli), are zinc finger transcription factors which mediate the transcriptional response to Hh signaling. To explore the role of Gli in the development and progression of hepatocellular carcinoma (HCC), we investigated the expression of Gli2 and FoxM1 (forkhead-box transcription factor M1) which is one of the Gli downstream target genes modulating cell cycle progression in 91 specimens of human HCCs with immunohistochemistry. These immunostaining results were compared with various clinicopathologic parameters. Immunoreactivity of Gli2 and FoxM1 was observed respectively in 84.6% (77/91) and 80.2% (73/91) cases of HCC tumor tissues, and this was considerably higher than expression in the peritumoral tissues. Distribution of Gli2 and FoxM1 proteins in tumor cells was nuclear with or without cytoplasmic staining, or cytoplasmic alone. Statistically, increased nuclear immunopositivity of Gli2 protein correlated significantly with poorer tumor differentiation (P<0.05), as well as with portal vein tumor thrombosis (P<0.05). In addition, overexpression of FoxM1 protein was significantly associated with increased tumor grade (P<0.01) and advanced tumor stage (P<0.05). Moreover, there was a significant association between the expressions of Gli2 and FoxM1 proteins in HCC (r=0.464, P=0.000). This is consistent with the concept that in human HCC, the Hh signaling pathway is involved in the differentiation and proliferation of tumor cells, in part through inducing nuclear accumulation of Gli2 protein and subsequent upregulation of FoxM1 protein.
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PMID:Nuclear accumulation of glioma-associated oncogene 2 protein and enhanced expression of forkhead-box transcription factor M1 protein in human hepatocellular carcinoma. 2071 11

This perspective places the report by Villani et al. that appears in this issue of the journal (beginning on page 1222) in the context of recent work showing an intersection between two important developmental pathways implicated in oncogenesis: the hedgehog and insulin-like growth factor (IGF) pathways. Villani et al. define a key role for the IGF regulatory protein Igfbp2 in a genetic model of basal cell carcinogenesis driven by targeted constitutive activation of hedgehog signaling. Placed in the framework of other recently published work, the observations of Villani et al. both raise questions about the cell of origin for basal cell cancers and define additional putative therapeutic and preventive targets for this disease.
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PMID:Skin deep and deeper: multiple pathways in basal cell carcinogenesis. 2085 61


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