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)

Genistein, a component of soy, has been reported to protect against spontaneously developing prostate tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. This is consistent with reports showing that Asians eating a diet high in soy have reduced incidence of clinically manifested prostate cancer. In order to understand the mechanism of action of genistein, we have investigated the expression of androgen and estrogen receptors, four growth factor receptors that signal via tyrosine protein kinases, and specific growth factor proteins in the dorsolateral prostates of TRAMP mice fed 250 mg genistein/kg diet, starting at 5 weeks of age. These analyses were carried out at 12 weeks, prior to the development of solid tumors, allowing us to readily investigate cell proliferation and biomarkers in premalignant tissue. Cell proliferation, AR, ER-alpha, EGFR, ErbB2, EGF, IGF-1R, IGF-1, VEGFR2, ERKs-1 and 2 proteins and TGF-alpha mRNA, but not ER-beta and VEGF, were significantly increased in prostates of TRAMP compared to C57BL/6 mice. Genistein in the diet significantly down-regulated cell proliferation, EGFR, IGF-1R, ERK-1 and ERK-2, but not AR, ER-alpha, ER-beta, ErbB2, EGF, TGF-alpha, IGF-1, VEGF and VEGFR in prostates of TRAMP mice. Serum testosterone and dihydrotestosterone concentrations were not significantly different in C57BL/6 or TRAMP male mice fed control or genistein-containing diets. The up-regulation of sex steroid receptors and multiple growth signaling pathways in TRAMP mice supports the concept of multiple dysregulation contributing to carcinogenesis. Down-regulation of the tyrosine kinase regulated proteins, EGFR and IGF-1R, and of the downstream mitogen-activated protein kinases, ERK-1 and 2, with genistein in the diet provides a possible mechanism for prostate cancer chemoprevention.
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PMID:Genistein alters growth factor signaling in transgenic prostate model (TRAMP). 1514 38

Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer in the past decade. However, the development of agents targeting specific signaling pathways that drive carcinogenesis has heralded a major paradigm shift in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC), many researchers have focused on the epidermal growth factor receptor (EGFR) because this protein is present on a relatively high proportion of non-small cell lung cancers and its intracellular tyrosine kinase activates a signaling cascade that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients with previously treated advanced NSCLC demonstrated anti-tumor activity with objective response rates of 10-19% with acceptable toxicities and an associated improvement in lung cancer symptomatology. Gefitinib is now an FDA approved treatment for advanced NSCLC previously treated with platinum and docetaxel-based therapies. However, phase III trials of gefitinib and erlotinib in combination with chemotherapy doublets have failed to demonstrate a survival advantage when compared with chemotherapy alone. It remains unclear why these drugs work so effectively in certain patients and so poorly in combination with chemotherapy. The goal of ongoing and future investigation is to identify which patients may benefit from this new therapeutic approach.
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PMID:Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go. 1518 24

Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of beta-carotene, alpha-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor beta (RAR-beta), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
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PMID:Molecularly targeted approaches to the chemoprevention of lung cancer. 1521 68

Cancer is the second leading cause of death in the western world. Despite advances in diagnosis and treatment, overall survival of patients remains poor. Scientific advances in recent years have enhanced our understanding of the biology of cancer. Human protein tyrosine kinases (PTKs) play a central role in human carcinogenesis and have emerged as the promising new targets. Several approaches to inhibit tyrosine kinase have been developed. These agents have shown impressive anticancer effects in preclinical studies and are emerging as promising agents in the clinic. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (STI571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Innovative approaches are needed to fully evaluate the potential of these agents, and a concerted international effort will hopefully help to integrate these inhibitors in cancer therapy in the near future.
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PMID:Tyrosine kinase inhibitors in cancer therapy. 1523 43

Recent work from our laboratory has shown that elevated src kinase activity enhances tumor promotion, malignant progression, and metastasis during multistage skin carcinogenesis. In this study, we have generated "gene-switch" src(530) transgenic mice to further analyze the role of this nonreceptor tyrosine kinase in multistage carcinogenesis. Target transgenic mice that have an activated form of the human c-src (src(530)) gene fused with GAL4 binding sites upstream of the thymidine kinase (TK) promoter were generated. Two lines of epidermis-specific transactivator mice were used that targeted the expression of GLVPc or GLp65 transactivators, fusion molecules containing a truncated progesterone receptor with a GAl4-DNA binding domain, with either a mouse loricrin (ML) or human keratin 14 (HK14) promoter, respectively. The transactivator mice (ML.GLVPc or HK14.GLp65) and the target mice (TK.src(530)) were mated to generate bitransgenic mice, and src(530) transgene expression was induced by topical application of RU486 (mifepristone, a progesterone receptor antagonist). In both ML.GLVPc/TK.src(530) and HK14.GLp65/TK.src(530) bitransgenic mice, histological analysis revealed that only the bitransgenic mice had marked epidermal hyperplasia and hyperkeratosis after treatment with RU486. Neither the nontransgenic mice nor the mice hemizygous for either the transactivator transgene or the target transgene alone showed any response to treatment with RU486. In addition, no differences were observed in the skin of the bitransgenic mice versus nontransgenic littermates without treatment of RU486. Interestingly, in HK14.GLp65/TK.src(530) bitransgenic mice, squamous cell carcinomas (SCCs) arose along the periphery of the area of the punch biopsies in 25% of the bitransgenic mice several weeks after taking the biopsy and subsequent to RU486 treatment. Collectively, the data support a role of c-src activation in epidermal hyperproliferation. Furthermore, the data support the conclusion that src activation can substitute for an initiating event in the presence of a tumor promoting stimulus (i.e., wounding). Finally, inducible src(530) transgenic mice provide a new tool for dissecting the role of src activation in multistage carcinogenesis by allowing temporal control of the expression of this oncogene.
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PMID:Development of transgenic mice that inducibly express an active form of c-Src in the epidermis. 1526 11

The epithelial to mesenchymal transition (EMT) is considered to be an important event during malignant tumor progression and metastasis. Although Raf/MEK/ERK signaling causes EMT, the mechanisms, including the signaling pathways, are as yet unclear. In the present study we have examined the effects of signal transduction pathways on oncogenic Raf-1-induced EMT, using an immortalized mouse hepatic cell line. Oncogenic Raf-1-induced EMT is characterized by down-regulation of adherens and tight junctions and the reorganization of actin. An active Raf-1 gene was introduced into a mouse hepatic cell line which was then treated with the MAP kinase inhibitor PD98059, the p38 MAP kinase inhibitor SB203580, the PI3 kinase inhibitor LY294002 or the c-Src tyrosine kinase inhibitor PP2. The expression and localization of the adherens and tight junction proteins E-cadherin, occludin, ZO-1, claudin-1 and claudin-2 were determined by western blotting, RT-PCR and immunocytochemistry. The barrier function of tight junctions was assessed by measurements of transepithelial electric resistance (TER) and permeability in terms of fluxes of [(14)C]mannitol and [(14)C]inulin. In Raf-1-transfected cells expression of occludin and claudin-2 was markedly down-regulated at the protein and mRNA levels and the TER value was decreased, while the permeability was increased. The distribution of ZO-1, pancadherin and F-actin was changed from linear to zipper-like structures at cell borders. In Raf-1-transfected cells treated with PD98059 and SB203580, but not LY294002, expression and localization of claudin-2, but not occludin, recovered, together with barrier function, measured as the TER value. The distributions of ZO-1, pancadherin and F-actin also recovered on treatment with PD98059 and SB203580, but not LY294002. Expression and localization of occludin recovered slightly on treatment with PP2. Thus, oncogenic Raf-1 regulates EMT via distinct MAP kinase, p38 MAP kinase and c-Src tyrosine kinase signal pathways in the mouse hepatic cell line.
Carcinogenesis 2004 Dec
PMID:Oncogenic Raf-1 regulates epithelial to mesenchymal transition via distinct signal transduction pathways in an immortalized mouse hepatic cell line. 1530 85

Pancreatic carcinogenesis is driven by multiple genetic and epigenetic changes. The epidermal growth factor receptor (EGFR) and its downstream signaling pathways, Ras-Raf-MEK-ERK axis, play important roles in pancreatic cancer development. The phosphoinositol 3 kinase (PI3 K)/Akt and the nuclear factor kappaB (NF-kappaB) pathways control both proliferation and resistance to apoptosis of pancreatic cancer. The role of cyclooxygenase (COX) and lipoxygenase (LOX) in the development of pancreatic cancer has been made known recently. The elucidation of these molecular events has led to several distinct therapeutic advances, including therapies that target EGFR, the Ras-Raf-MEK-ERK axis, the COX-2 and LOX pathways, and others. Many novel agents have been developed and are undergoing clinical investigation, such as monoclonal antibodies against EGFR, tyrosine kinase inhibitors (TKIs), farnesyl transferase inhibitors (FTIs), Bay43-9006, CI-1040, CCI-779, celecoxib, and LY293111. This review highlights recent advances in the development of these agents.
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PMID:Molecular targeting therapy for pancreatic cancer. 1531 51

Over the past several years many advances have been made in our understanding of critical pathways involved in carcinogenesis and tumor growth. These advances have led to the investigation of small molecule inhibitors of the ErbB family of receptor tyrosine kinases across a broad spectrum of malignancies. In this article we summarize the rationale for targeting members of the ErbB family in breast cancer, and review the preclinical and clinical data for the agents that are furthest in development. In addition, we highlight directions for future research, such as exploration of the potential crosstalk between the ErbB and hormone receptor signal transduction pathways, identification of predictive markers for tumor sensitivity, and development of rational combination regimens that include the tyrosine kinase inhibitors.
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PMID:New targets for therapy in breast cancer: small molecule tyrosine kinase inhibitors. 1531 26

Head and neck squamous cell carcinomas (HNSCCs) are characterized by up-regulation of the epidermal growth factor receptor (EGFR). We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. GRP can induce rapid phosphorylation of EGFR and p42/44 mitogen-activated protein kinase (MAPK) activation in part via extracellular release of transforming growth factor alpha (TGF-alpha) by matrix metalloproteinases (MMPs). It has been reported that Src family kinases are activated by G-protein-coupled receptors (GPCRs), followed by downstream EGFR and MAPK activation. To further elucidate the mechanism of activation of EGFR by GRP in HNSCC, we investigated the role of Src family kinases. Blockade of Src family kinases using an Src-specific tyrosine kinase inhibitor A-419259 decreased GRP-induced EGFR phosphorylation and MAPK activation. GRP also failed to induce MAPK activation in dominant-negative c-Src-transfected HNSCC cells. Invasion and growth assays showed that c-Src was required for GRP-induced proliferation or invasion of HNSCC cells. In addition to TGF-alpha release, GRP induced amphiregulin, but not EGF, secretion into HNSCC cell culture medium, an effect that was blocked by the MMP inhibitor marimastat. TGF-alpha and amphiregulin secretion by GRP stimulation also was inhibited by blockade of Src family kinases. These results suggest that Src family kinases contribute to GRP-mediated EGFR growth and invasion pathways by facilitating cleavage and release of TGF-alpha and amphiregulin in HNSCC.
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PMID:SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. 1534 1

Focal adhesion kinase (FAK) is a tyrosine kinase that is found in cellular structures called focal adhesions. FAK appears to be a key element in signal transduction pathways involved in cell adhesion and locomotion. FAK is overexpressed in various tumors, including tumors derived from regions of the head and neck, colon, breast, prostate, and liver. In this study, we investigated immunohistochemically whether FAK expression was increased in thyroid cancers. FAK staining was not seen in any of the 20 normal thyroid tissues or the 6 nodular hyperplasia specimens. In contrast, FAK staining was observed in all of 17 papillary carcinomas, 9 follicular carcinomas, 8 medullary carcinomas, and 2 anaplastic carcinomas. Nine of 17 follicular adenomas showed FAK immunoreactivity. FAK was not expressed in normal tissue and nodular hyperplasia, but was expressed in some of the follicular adenoma, and all of the follicular, papillary, medullary and anaplastic thyroid carcinoma. This result indicates that the up-regulation of FAK may play a role in the development of thyroid carcinogenesis.
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PMID:Increased expression of focal adhesion kinase in thyroid cancer: immunohistochemical study. 1548 49


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