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)

Significant advances have been made in understanding the mechanisms that contribute to carcinogenesis in OCSCC. This progress has led to the development of therapeutic strategies that target dysregulated processes in the tumor microenvironment (Fig. 11) [72]. The introduction of angiogenesis inhibitors, growth factor receptor tyrosine kinase inhibitors, and cell cycle regulators into clinical trials for the management of OCSCC has resulted from the great strides made in the understanding of tumor biology. It is important for those caring for patients who have OCSCC to have a firm background in tumor biology, because many future therapies will be based on this complex panorama of cellular physiology.
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PMID:Molecular biology of oral cavity squamous cell carcinoma. 1658 Sep 9

The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.
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PMID:Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. 1664 58

EphA2 receptor tyrosine kinase is frequently overexpressed in different human cancers, suggesting that it may promote tumor development and progression. However, evidence also exists that EphA2 may possess antitumorigenic properties, raising a critical question on the role of EphA2 kinase in tumorigenesis in vivo. We report here that deletion of EphA2 in mouse led to markedly enhanced susceptibility to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis. EphA2-null mice developed skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grew faster and were twice as likely to show invasive malignant progression. Haploinsufficiency of EphA2 caused an intermediate phenotype in tumor development but had little effects on invasive progression. EphA2 and ephrin-A1 exhibited compartmentalized expression pattern in mouse skin that localized EphA2/ephrin-A1 interactions to the basal layer of epidermis, which was disrupted in tumors. Loss of EphA2 increased tumor cell proliferation, whereas apoptosis was not affected. In vitro, treatment of primary keratinocytes from wild-type mice with ephrin-A1 suppressed cell proliferation and inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) activities. Both effects were abolished in EphA2-null keratinocytes, suggesting that loss of ERK inhibition by EphA2 may be one of the contributing mechanisms for increased tumor susceptibility. Interestingly, despite its tumor suppressive function, EphA2 was overexpressed in skin tumors compared with surrounding normal skin in wild-type mice, similar to the observations in human cancers. EphA2 overexpression may represent a compensatory feedback mechanism during tumorigenesis. Together, these results show that EphA2 is a novel tumor suppressor gene in mammalian skin.
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PMID:Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. 1684 50

The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1alpha and HIF-1beta. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1alpha levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1alpha/HIF-1beta transcriptional activities. HIF-1alpha has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1alpha a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1alpha in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1alpha is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1alpha levels. In prostate cancer, androgens upregulate HIF-1alpha through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1alpha in endocrine oncology and present new data on HIF-1alpha signaling and the potential for targeted therapies, including combinatory hormonal therapies.
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PMID:Hypoxia-inducible factor-1 in human breast and prostate cancer. 1695 28

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in signal transduction pathways that are initiated at sites of integrin-mediated cell adhesions and by growth factor receptors. FAK is a key regulator of survival, proliferation, migration and invasion: processes that are all involved in the development and progression of cancer. FAK is also linked to oncogenes at both a biochemical and functional level. Moreover, overexpression and/or increased activity of FAK is common in a wide variety of human cancers, implicating a role for FAK in carcinogenesis. Given the important role of FAK in a large number of processes involved in tumorigenesis, metastasis and survival signalling FAK should be regarded as a potential target in the development of anti-cancer drugs. Therefore, selective inhibitors of FAK need to be developed. Combination of these selective FAK inhibitors with cytotoxic agents could be a very promising anti-cancer therapy.
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PMID:Focal adhesion kinase: a potential target in cancer therapy. 1699 83

The neurotrophic receptor tyrosine kinase TrkB, while binding its high affinity ligand brain-derived neurotrophic factor (BDNF), will play an essential role for nervous system development, neuronal survival, differentiation, and maintenance. However, accumulating evidences implies that TrkB signal pathway may also be involved in a variety of human cancers, in which TrkB is likely to play a role in initiation and metastasis of carcinomas. Overexpression of TrkB is often correlated with the tumorigenesis, angiogenesis and drug resistance in these malignancies, contributing significantly to the metastasis and aggressive phenotype of these poor prognosis tumors. The evidences to show the significant contribution of TrkB to malignancy not only came from solid tumors such as neoblastoma, pancreas cancer, Wilm's tumor and hepatocarcinoma, but also came from haematological malignancies such as Hodgkin lymphoma and multiple myeloma. In summary, besides its role in development and function of nervous system, TrkB is likely to also play a role in initiation and metastasis of carcinoma although it still remains to be further investigated and confirmed. Emerging data have suggested that TrkB may be a mediator as well as a marker of carcinogenesis and metastasis, therefore TrkB may be used as a valuable target for cancer therapy especially for the metastatic tumors with poor prognosis.
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PMID:Neurotrophic receptor TrkB: Is it a predictor of poor prognosis for carcinoma patients? 1700 23

Receptor tyrosine kinases play a significant role in carcinogenesis and have been successfully targeted with monoclonal antibodies and small-molecule inhibitors. There have been recent developments in the understanding of receptor tyrosine kinase signal transduction which have enabled better drug development. The use of receptor tyrosine kinase inhibitors in clinical practice has expanded the knowledge on cancer biology, in particular the understanding of resistant mutations and strategies to overcome such resistance. This has driven drug development from single kinase inhibitors to multi-kinase inhibitors and high-affinity kinase inhibitors. Finally, as the use of receptor tyrosine kinase inhibitors grows in clinical practice, more is learned about appropriate patient selection for such therapies. This is an exciting time in cancer therapeutics, highlighted by the advent of effective targeted therapy with receptor tyrosine kinase inhibitors.
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PMID:Forthcoming receptor tyrosine kinase inhibitors. 1710 67

Previous work has suggested that arsenic exposure contributes to skin carcinogenesis by preserving the proliferative potential of human epidermal keratinocytes, thereby slowing the exit of putative target stem cells into the differentiation pathway. To find a molecular basis for this action, present work has explored the influence of arsenite on keratinocyte responses to epidermal growth factor (EGF). The ability of cultured keratinocytes to found colonies upon passaging several days after confluence was preserved by arsenite and EGF in an additive fashion, but neither was effective when the receptor tyrosine kinase activity was inhibited. Arsenite prevented the loss of EGF receptor protein and phosphorylation of tyrosine 1173, preserving its capability to signal. The level of nuclear beta-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative beta-catenin suppressed the increase in both colony forming ability and yield of putative stem cells induced by arsenite and EGF. As judged by expression of three genes regulated by beta-catenin, this transcription factor had substantially higher activity in the arsenite/EGF-treated cells. Trivalent antimony exhibited the same effects as arsenite. A novel finding is that insulin in the medium induced the loss of EGF receptor protein, which was largely prevented by arsenite exposure.
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PMID:Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential. 1740 Feb 67

Treatment of pancreatic cancer remains challenging today and mostly palliative. Despite many efforts to understand the underlying mechanisms of this aggressive tumoral phenotype and to develop new therapeutic agents, advances in its management and survival benefit are poor. Although gemcitabine remains the backbone of routine therapy in advanced disease, newer drugs, mainly constituted by (multi)targeted agents, represent promising therapeutic areas. In this setting, anti-EGF receptor, antiangiogenic or both therapies combined appear to have valuable potential, providing their optimal and comprehensive development and use in pancreatic cancer. Multitargeted agents, such as receptor tyrosine kinase inhibitor small molecules, combining different therapeutic interventions, also deserve new preclinical and clinical development, supported and paralleled by a translational approach. Over the next few years, we need to identify new target mechanisms in pancreatic carcinogenesis, to rapidly test selected drugs against these targets and imperatively to understand and determine which patients respond and who will benefit from such therapies. Significant advances should be immediately evaluated in the perioperative setting in order to improve the curative approach of this devastating disease.
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PMID:Emerging drugs for the treatment of pancreatic cancer. 1760 3

Pancreatic cancer is an aggressive disease characterized by rapid growth and early metastasis. The recepteur d'origine nantais (RON) receptor tyrosine kinase is overexpressed and/or constitutively active in several epithelial cancers, but its role in pancreatic cancer is unknown. In this study, we have characterized RON expression in both murine and human pancreatic cancer. Immunoblotting indicates that RON is expressed in pancreatic intraepithelial neoplasia (PanIN), primary, and metastatic cell lines both in the human and mouse. Immunostaining revealed that 93% of high-grade PanIN, 79% of primary, and 83% of metastatic lesions from human pancreatic tissue samples expressed RON, with minimal expression in normal ducts and low-grade PanIN (6% and 18%, respectively). Moreover, we show a dose-dependent effect of hepatocyte growth factor-like protein (HGFL), the RON-specific ligand, on pancreatic cancer cell migration and invasion, which was reversed by RON inhibition. Although stimulation with HGFL had no effect on proliferation, concurrent RON receptor blockade and gemcitabine treatment increased apoptosis of RON-expressing pancreatic cancer cells versus gemcitabine treatment alone. Finally, HGFL stimulation of pancreatic cancer cells resulted in increased expression of phospho-mitogen-activated protein kinase and phospho-Akt. Taken together, these findings suggest that RON receptor signaling may contribute to pancreatic carcinogenesis, and that further investigation is warranted to assess the potential of RON-directed therapies in this deadly disease.
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PMID:The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. 1761 62


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