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)

We have used a two-transgene tetracycline system to reversibly express oncogenic H-Ras(V12G) in mouse skin and primary keratinocytes culture using the bovine keratin 5 promoter. Induction of H-Ras(V12G) expression in skin at 30 days after birth causes epidermal basal cell hyperplasia, an eruption of keratinous cysts and loss of hair follicles by 3 weeks. Subsequent H-Ras(V12G) de-induction for 3 days results in massive apoptosis in the non-H-Ras(V12G)-expressing stroma as well as in the suprabasal cells of the epidermis. Several procaspases such as CASP3, 1alpha, 5 and 12 disappeared, whereas the pro-apoptotic proteins AIF, Bax and Fas ligand were induced in H-Ras(V12G) de-induction skin. This process is followed by a wave of cell division at 14 days as hair follicles regrew, returning to near normal histology and skin appearance by 30 days. Using Kinetworkstrade mark multi-immunoblotting screens, the phosphorylation status of 37 proteins and expression levels of 75 protein kinases in the skin were determined in three samples: (i) wild-type skin, (ii) hyperplastic H-Ras(V12G)-expressing skin and (iii) skin where H-Ras(V12G) expression was suppressed for 7 days. Following H-Ras(V12G) induction, 16 kinases were increased over 2-fold, and 2 kinases were reduced over 50%. This included increased phosphorylation of both known downstream H-Ras(V12G) targets and unknown H-Ras(V12G) targets. After H-Ras(V12G) suppression, many but not all protein changes were reversed. These results from skin and primary keratinocytes are organized to reflect the molecular events that cause the histological changes observed. These proteomic changes identify markers that may mediate the oncogenic addiction paradigm.
Carcinogenesis 2007 Oct
PMID:Histological and proteomic analysis of reversible H-RasV12G expression in transgenic mouse skin. 1755 Oct 62

Recent advances in genomic analysis have provided a comprehensive view of the genetic and epigenetic changes present in cancer cells. While therapies targeting genes causally linked to carcinogenesis have been successful in a subset of tumor types, the hope for treatments tailored on patient genomic profiles seems, for most cancers, still elusive. Cancer genes belong to two clearly defined groups. The first subset of genes is frequently mutated across samples and tumor types, and includes well-studied oncogenes and tumor suppressor genes, such as members of the RAS, AKT and TP53 families, whose direct targeting has so far been largely disappointing. In the other group, the vast majority of putative cancer genes emerging from sequencing and genomic studies show a low incidence (5% or less). The possibility of finding novel selective drugs against such a high number of gene products seems daunting. However, recent genomic and proteomic findings, as well as novel frameworks arising from systems biology approaches, suggest that this apparent discordance may converge towards a more satisfying model. It seems that genetic lesions in cancer tend to cluster around certain pathways, suggesting that the concept of 'network addiction', rather than 'oncogene addiction', would recapitulate more closely what is happening during tumor development and after exposure to therapeutic agents. This new perspective, arising from genomic and systems biology studies, will likely provide a valuable frame for the design of the cancer drugs of the future.
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PMID:From oncogene to network addiction: the new frontier of cancer genomics and therapeutics. 1868 67

Recent advances and insights into the molecular pathogenesis of cancer provide unprecedented opportunities for discovery and development of molecularly target-therapeutic (MTT) strategies. Cancer is a complex process due to accumulation of multiple mutations and alterations in the genoma. Tumor cells seem to rely heavily on the continued deregulation of one or more signaling pathways. Complete identification on cell signaling deregulations have provided greater understanding on the biology that underlies most cancers. High-throughput technologies in genomics and proteomics can help to detect the response in vitro and in vivo of targeted MTT effects. Cancer MTT are drugs blocking specific oncogenes or oncogenic signaling pathways and can secondary block off the growth and spreading involved in carcinogenesis and tumor progression. In this paper we revised concepts of oncogene addiction, oncogenic pathways signature and commented the high-tech technologies related to their study. Also we revised the favorable clinical results using new MTT strategies for hard-to-treat cancers in the last year, and the limitations and perspectives to achieve more effective targeted cancer therapy results. Identification of a progressive number of molecularly targeted oncogenes and their corresponding blocking agents will give cancer MTT strategies great potential for development in the next years. Novel biologic endpoints and innovative clinical designs are also required to the successful application of the therapies.
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PMID:[Molecular therapeutics in patients with cancer unresponsive to conventional treatments]. 1894 68

The head and neck squamous cell carcinoma (HNSCC) accounts for about 30-40% of all cancer types in India and the subcontinent in general. HNSCCs are primarily not hereditary, but rather a disease of older and middle aged adults. Many etiological factors like tobacco, alcohol and HPV infection are known to play important roles. Eastern India, particularly Kolkata, has a population heavily exposed to various types of smoked and smokeless tobacco, with only limited exposure to alcoholic beverages. Since there have been no previous epidemiological studies on tobacco as the main risk factor for head and neck carcinogenesis in Kolkata, we here carried out a hospital based case control study in the city and its adjoin regions. Data from 110 patients diagnosed with HNSCC and a similar number of matched control samples were analyzed using the chi-square test. Survival status of the patients was also analyzed using the Kaplan-Meier method. A tobacco habit was significantly correlated with the incidence of HNSCC and persons with current addiction had a 2.17 fold increased risk of cancer development. Dose-response relationships were seen for the frequency (p=0.01) and duration (p=0.02) of tobacco exposure with the risk. No significant difference in impact was found with smoked as opposed to smokeless tobacco in the development of the disease. Among HNSCC patients, significant poor survival in cases with tobacco habit than in those with no addiction and in cases with >10 years of addiction than in those with 10 years of addiction. Our data suggest that tobacco in both smoked and smokeless forms is the most important risk factor for both development and prognosis of HNSCCs and may be a major source of field cancerization on the head and neck epithelium in the eastern Indian population.
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PMID:Role of tobacco in the development of head and neck squamous cell carcinoma in an eastern Indian population. 1899 6

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single-nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently, observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1250 cases (562 adenocarcinoma, 391 squamous cell carcinoma and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5-3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without; however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.
Carcinogenesis 2009 Jan
PMID:Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese. 1900 85

Twenty years were passed between the discovery of oncogene HER2, the description of its implication in mammary carcinogenesis, and the development of specific targeted therapies. To date, trastuzumab and lapatinib are the two anti-HER2 targeted therapies commonly used, demonstrating therapeutic effects. Although their clinical efficacy seems to be exclusively related to the amplification of the HER2 gene or to the overexpression of the protein, these factors are not sufficient since tumors can develop resistance. Because of a better knowledge in those mechanisms of resistance, novel therapeutic agents could help to bypass them. How should these be used with respect to current anti-HER2 targeted therapies? Recent notions such as oncogene addiction, tumor cell dormancy and residual disease led us to propose a new entity that we named the "sedimentation strategy", in which distinct targeted approaches are summed during the treatment of metastatic breast cancer patients.
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PMID:Resistance to HER2 inhibitors: is addition better than substitution? Rationale for the hypothetical concept of drug sedimentation. 2068 84

MicroRNAs (miRNAs) belong to a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. miRNAs have crucial functions in the development and establishment of cell identity, and aberrant metabolism or expression of miRNAs has been linked to human diseases, including cancer. Components of the miRNA machinery and miRNAs themselves are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. Some miRNAs, referred to as oncomiRs, show differential expression levels in cancer and are able to affect cellular transformation, carcinogenesis and metastasis, acting either as oncogenes or tumour suppressors. The phenomenon of 'oncogene addiction' reveals that despite the multistep nature of tumorigenesis, targeting of certain single oncogenes can have therapeutic value, and the possibility of oncomiR addiction has been proposed but never demonstrated. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Despite great interest in miR-21, most of the data implicating it in cancer have been obtained through miRNA profiling and limited in vitro functional assays. To explore the role of miR-21 in cancer in vivo, we used Cre and Tet-off technologies to generate mice conditionally expressing miR-21. Here we show that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene. When miR-21 was inactivated, the tumours regressed completely in a few days, partly as a result of apoptosis. These results demonstrate that tumours can become addicted to oncomiRs and support efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR-21.
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PMID:OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. 2069 87

Recreational indoor tanning with ultraviolet (UV) radiation has become popular in recent decades, particularly among teenagers and young adults. The consequences for public health have become an important area of concern. The link between this form of UV exposure and both melanoma and non-melanoma skin cancers has been clarified through multiple lines of evidence from epidemiology and laboratory science reflected in recent reports by multiple prestigious bodies. Some have suggested that this form of indoor tanning has a role in vitamin D generation, but a review of existing evidence suggests that indoor tanning is neither a reliable nor advisable source. In addition, laboratory data suggest that tanning promotes a common molecular intermediate in skin carcinogenesis, DNA damage, which thus precludes the concept of a "safe tan." Finally, emerging evidence links UV signaling in skin to dependency/addiction, thus having implications for the organic (rather than cosmetic) impact of the process. This article presents the epidemiologic and mechanistic data relevant to the safety considerations for indoor tanning.
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PMID:Indoor ultraviolet tanning: what the data do and do not show regarding risk of melanoma and keratinocyte malignancies. 2087 Jun 32

The relative risk of clonal evolution to either myelodysplasia (MDS) or acute myelogenous leukemia (AML) is high in patients with chronic bone marrow failure. From 10 to 20% of acquired aplastic anemia survivors will develop clonal evolution within the decade following their diagnosis as will 40% of patients with some of the inherited bone marrow failure syndromes. Studies on bone marrow failure states have provided some perspective on molecular pathogenesis of marrow failure and have also provided insights on the adaptive nature of clonal evolution. We review the scientific evidence validating this model, emphasize the importance of the fitness landscape in the stem cell pool, outline the clinical and investigative implications of the model, suggest that the lack of fitness in the starting pool accounts for the phenomenon of oncogene addiction, promote the value of the model for the evaluation of prevention strategies, and argue that experiments focusing attention on the relative phenotypes of neoplastic stem cell clones and pools of unfit stem cells from which they evolved will provide a useful paradigm of carcinogenesis in general.
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PMID:The stem cell fitness landscape and pathways of molecular leukemogenesis. 2119 92

Smoking is one of the leading preventable causes of disease, disability, and death in the USA and leads to more than 400,000 preventable deaths per year. Nicotine is the major alkaloid present in tobacco smoke, and many of the negative effects of smoking are attributed to nicotine. Nicotine is not only the addictive component of tobacco smoke, but also highly associated with carcinogenesis and induces oxidative stress. Furthermore, the administration of nicotine via subcutaneous mini-osmotic pumps or by injection is an established method in preclinical studies for this area of research. Thus, preclinical research on the negative effects of tobacco smoke and tobacco addiction has focused primarily on the effects of nicotine. However, there are over 4,500 components found in tobacco smoke, many of which are highly toxic. Other components may also contribute to the addictive properties of tobacco smoke. Furthermore, the negative effects of tobacco smoke are not isolated to the smoker but can have negative effects to those exposed to the secondhand smoke (SHS) stream. SHS exposure is the third leading cause of preventable death. Approximately 38,000 deaths per year are attributed to SHS exposure in the USA. SHS exposure increases the risk of heart disease by approximately 30% and is associated with increased risk of stroke, cancer, type II diabetes, as well as pulmonary disease. Thus, methods of administering tobacco smoke in a controlled environment will further our understanding of tobacco addiction and the role tobacco smoke in other disease states. Moreover, combining smoke exposure with proteomics can lead to the discovery of biomarkers that can be potentially useful tools in screening, early diagnosis, prevention, and treatment of diseases caused by SHS.
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PMID:Methods in tobacco abuse: proteomic changes following second-hand smoke exposure. 2223 25


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