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

Improved understanding of the molecular signaling pathways that mediate cellular transformation has led to the development of novel strategies for the treatment of cancer. The epidermal growth factor receptor (EGFR), a transmembrane protein with intrinsic tyrosine kinase activity, transduces important signals from the surface of epithelial cells to the intracellular domain. Aberrant signaling through EGFR plays a key role in the carcinogenesis of squamous cell carcinomas of the head and neck (SCCHN). SCCHN tend to express high levels of EGFR, and the degree of expression correlates with poor clinical outcome. Since EGFR is present at much higher levels in cancerous lesions than in normal epithelial tissue, the receptor has been implicated as a highly specific therapeutic target for the treatment of SCCHN. EGFR can be abrogated at the extracellular level using either monoclonal antibodies or toxin conjugates that compete with the natural ligand at the binding site of the receptor, and targeting of the EGFR intracellular domain has been achieved by specific inhibitors of tyrosine kinase activity. Antisense strategies use synthesized DNA or RNA oligonucleotides to block the translation of the mRNA sequences that code for the production of the EGFR or other proteins with a role in EGFR-mediated cell signaling. Clinical evaluation of EGFR-specific monoclonal antibodies and tyrosine kinase inhibitors has demonstrated limited toxicity in SCCHN patients, and concurrent administration with standard cytotoxic therapies has produced additive or synergistic antitumor effects.
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PMID:The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. 1559 51

Recently it has been reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene occur in a subset of patients with lung cancer showing a dramatic response to EGFR tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung carcinogenesis, we sequenced exons 18-21 of the tyrosine kinase domain using total RNA extracted from unselected 277 patients with lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around codons 746-750 in exon 19, 54 were point mutations including 49 at codon 858 in exon 21 and 4 at codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001), adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.
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PMID:Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. 1560 53

This study represents an attempt of showing own author's example of using basic research data as an inspiration for the clinical studies. The project evaluates the role of gastrin in colorectal carcinogenesis as well as the differences of its action in proximal and distal colon. Colonocytes were isolated from Fischer-344 rats and incubated for 2 minutes with gastrin (10(-8)M). This treatment resulted with 60-70% rise in tyrosine kinase (Tyr-k) and 150-200% - in phospholipase C activity as regards to basal levels. In vivo infusion of gastrin for 5 days to Fischer-344 rats resulted with 90-150% increase in distal but not proximal colonic mucosal proliferative activity as well as tyrosine phosphorylation of several colonic mucosal proteins. In clinical study, the mean fasting gastrin level in the control group was significantly lower (p<0.01) than in patients with colorectal cancer before surgery. Mean plasma gastrin level in patients with distal tumor yielded 105,31 +/- 12,5 microU/l and was significantly higher than in patients with the proximal tumor site (42, 2 +/- 3,1 microU/l) (p<0,001). We conclude, that Tyr-k is involved in the mechanism of the trophic action of gastrin, particularly in distal colon. The differences in gastrin concentration in patients with distal and proximal tumors may probably contribute to the distinct pathogenesis and biological properties of those cancers.
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PMID:Experimental studies as an inspiration for clinical investigation. 1560 68

Lung cancer remains a major cause of mortality worldwide, despite advances in surgery, radiotherapy and chemotherapy. Most patients present with advanced disease, and early detection approaches are still experimental. Chemoprevention strategies are therefore essential. Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent progression to invasive cancer. The present review will provide an update on lung cancer clinical chemoprevention trials as well as the molecular basis of lung carcinogenesis. A better knowledge of lung carcinogenesis is obviously fundamental to improve chemoprevention strategies. Identification of molecular defects involved in premalignant lesions and/or invasive cancer could lead to clinical studies with new molecular-targeted agents (mainly tyrosine kinase inhibitors, farnesyl-transferase inhibitors and/or antiangiogenic molecules) and the development of surrogate biomarkers. Such biomarkers would be essential to detect high-risk patients, select adequate chemoprevention strategies and monitor drug efficacy. New chemoprevention trials are planned with collaborative efforts of researchers involved in fundamental or clinical studies.
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PMID:Chemoprevention of lung cancer. 1564 89

Platelet-derived growth factors (PDGFs) comprise a family of growth factors strongly implicated in human oncogenesis. A number of human tumors overexpress PDGF family members or have translocations activating PDGF receptors. Whereas the epidemiologic evidence implicating PDGF in human tumors is strong, malignant transformation of human cells by overexpression of PDGF has not been demonstrated. We have previously developed a human cell line by the sequential introduction of large T cells and telomerase, and we have demonstrated that these cells express functionally active PDGF receptor (PDGFR) beta. In order to determine whether growth factor-mediated transformation of human cells could occur, these cells were transduced with a retrovirus encoding PDGF-BB. Constitutive expression of PDGF-BB led to malignant transformation in nude mice. This is the first demonstration of constitutive signaling causing malignant transformation of human cells. Some of the changes that occur because of constitutive growth factor expression can be reversed by the clinically approved tyrosine kinase inhibitor Glivec, whereas other changes are not reversible by tyrosine kinase inhibitors. Our model allows the assessment of epigenetic changes that occur during human carcinogenesis. In addition, these studies provide insight into the clinical failure of tyrosine kinase inhibitors as monotherapy for advanced malignancy.
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PMID:Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB. 1569 19

A specific treatment for gastrointestinal stromal tumors (GIST) has been found through improved understanding of the molecular mechanism of carcinogenesis. GIST are radio and chemo-resistant (less than 10 objective responses). Stromal tumors originate from the multiplication of the cells of Cajal, which intervene in intestinal motility and express the c-Kit gene, also called CD117, on their surface. CD117 is a protein with tyrosine kinase activity, and can be demonstrated through immunohistochemical staining techniques. Treatment with Imatinib mesylate (Glivec), a recently discovered selective inhibitor of tyrosine kinases already used in chronic myeloid leukemia (in which an overexpression of tyrosine kinase is observed) was associated with tumor regression of more than 50% in the initial series of patients with GIST treated in 2001. Since then, approximately 2,000 patients have been included in therapeutic trials, with an objective response rate between 60% and 70% 12 to 18 months after inclusion. The clinical benefit has been estimated at 80% to 90% in patients whose chance of survival until now has been less than 30% at one year (median survival 18 months). Nonetheless, imatinib mesylate has not shown any activity in CD117-negative sarcoma (10% of sarcoma). The therapeutic importance of this drug in the treatment of solid GI tumors deemed inoperable is considerable.
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PMID:Treatment of gastrointestinal stromal tumors with imatinib mesylate: a major breakthrough in the understanding of tumor-specific molecular characteristics. 1570 44

Epithelial growth factor receptor (EGFR) appears as a key element in carcinogenesis. It displays high levels of expression in some tumor types. Its activation induces cell proliferation, angiogenesis, cell mobility and inhibition of apoptosis. EGFR inhibitors such as monoclonal antibodies or small molecules tyrosine kinase inhibitors have been developed. For EGFR, the diversity of the activation means (amplification, mutation, enhanced transcription, ligands...) leads to technical caveats. Immunohistochemistry appears to be the most appropriate test for clinical use, but standardized assays and scoring systems are mandatory. Pathologists are involved in the selection of patients for a monoclonal antibody based targeted treatment, Erbitux, and numerous standardization efforts are provided. No consensus has been reached, to date, for a scoring system. Whether the EGFR status has to be tested for the selection of patients is a non answered question. The selection of the "right patient for the right treatment" might be through the evaluation of other putative markers involved in resistance. EGFR testing may be required before targeted treatment. An exciting endpoint might be the functional and dynamic evaluation of EGFR and downstream proteins, for patients, before and during treatment. The exact role of the pathologist still have to be accurately determined.
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PMID:[The pathologist and EGFR in 2004: I like you, nor do it]. 1573 67

A causative role of the membrane-bound tyrosine kinase ErbB-2 in breast tumorigenesis has been well established. MMTV/neu transgenic mice which overexpress ErbB-2 consistently develop mammary carcinomas with a high incidence. In human breast cancer, ErbB-2 is overexpressed in 25-30 of all cases and is representing a clinical marker of a poor prognosis. Besides to gene amplification, ErbB-2 overexpression has been attributed to transcription factors of the AP-2 family which were shown to control the ErbB-2 gene promoter in cell culture studies. Particularly AP-2alpha and gamma are often coexpressed in ErbB-2-positive breast carcinomas. However, LTRgamma transgenic mice which overexpress AP-2gamma in their mammary epithelium display only a very weak upregulation of the erbB-2 gene and do not develop mammary carcinoma. These findings therefore raise the possibility of functional cooperativity between both genes in breast cancer. To experimentally address the impact of AP-2gammaon ErbB-2-induced breast carcinogenesis we crossed MMTV/neu transgenic mice with LTRgamma transgenic mice and monitored tumor development in bitransgenic female progeny. AP-2gamma overexpression negatively influenced tumor incidence, as reflected by a reduced tumor number and a prolonged tumor latency. Histological analysis revealed three major types of tumors corresponding to different stages of tumor progression. Interestingly, an increased proportion of advanced stage carcinomas was observed in bitransgenic mice. Moreover, the AP-2gamma transgene differentially affected proliferation rates between the different progression stages: proliferation was enhanced at early stages but reduced in advanced stages in comparison to control tumors. Therefore, AP-2gamma while reducing the incidence of mammary tumors is promoting tumor progression.
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PMID:Dual role of AP-2gamma in ErbB-2-induced mammary tumorigenesis. 1583 Jan 41

The variety of diseases caused by mutations in RET receptor tyrosine kinase provides a classic example of phenotypic heterogeneity. Gain-of-function mutations of RET are associated with human cancer. Gene rearrangements juxtaposing the tyrosine kinase domain to heterologous gene partners have been found in sporadic papillary carcinomas of the thyroid (PTC). These rearrangements generate chimeric RET/PTC oncogenes. In the germline, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Both MEN 2 mutations and PTC gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, activate the RET downstream targets. Loss-of-function mutations of RET cause Hirschsprung's disease (HSCR) or colonic aganglionosis. A deeper understanding of the molecular signaling of normal versus abnormal RET activity in cancer will enable the development of potential new treatments for patients with sporadic and inherited thyroid cancer or MEN 2 syndrome. We now review the role and mechanisms of RET signaling in development and carcinogenesis.
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PMID:RET tyrosine kinase signaling in development and cancer. 1598 21

Expression of c-kit has been demonstrated in 33% of adult nasopharyngeal carcinomas (NPCs) and in 88% of paediatric NPCs. Patients with tumours expressing c-kit tend to exhibit better survival, but a paracrine/autocrine function for the stem cell factor (SCF)/c-kit system in nasopharyngeal carcinomas has not been reported. This study evaluated the expression of c-kit and SCF by immunohistochemical staining of nasopharyngeal epithelium (NPE) and of primary and metastatic NPCs. In addition, c-kit and SCF expression were studied in HONE-1 NPC cells by immunoprecipitation and western blotting. Expression of c-kit and SCF was detected in 75% and 57% of NPE, respectively, and there was 48% co-expression. In primary NPCs, 86% expressed c-kit, 69% had SCF expression, and there was 67% co-expression. In metastatic NPCs, 76% expressed c-kit, 72% expressed SCF and there was 68% co-expression. Co-expression of c-kit and SCF with tyrosine autophosphorylation of p145(c - kit) was demonstrated in HONE-1 NPC cells. In addition, the expression level of c-kit and its autophosphorylation status was not obviously influenced by the transient co-expression of Epstein-Barr nuclear antigen 1 (EBNA1) and latent membrane protein 1 (LMP1). Co-expression of c-kit and SCF is therefore commonly found in nasopharyngeal epithelium and NPCs, and in HONE-1 NPC cells with autoactivation possibly independent of the co-expression of EBNA1 and LMP1. All of these findings suggest that autoactivation of SCF/c-kit signalling may be a potent regulator of the nasopharyngeal epithelial barrier and of immune function at the nasopharyngeal mucosa surface, and may contribute to the carcinogenesis and progression of NPC. Further molecular analysis is required to evaluate the possibility of treatment with tyrosine kinase inhibitors in NPC, analogous to the treatment of gastrointestinal stromal tumours with STI571.
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PMID:Co-expression of c-kit and stem cell factor in primary and metastatic nasopharyngeal carcinomas and nasopharyngeal epithelium. 1602 77


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