Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
Carcinogenesis (Impact Factor: 5.27). 05/2012; 33(9):1617-28. DOI: 10.1093/carcin/bgs186
Source: PubMed

ABSTRACT Despite continuous research efforts directed at early diagnosis and treatment of pancreatic cancer (PC), the status of patients affected by this deadly malignancy remains dismal. Its notoriety with regard to lack of early diagnosis and resistance to the current chemotherapeutics is due to accumulating signaling abnormalities. Hoarding experimental and epidemiological evidences have established a direct correlation between cigarette smoking and PC risk. The cancer initiating/promoting nature of cigarette smoke can be attributed to its various constituents including nicotine, which is the major psychoactive component, and several other toxic constituents, such as nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and polycyclic aromatic hydrocarbons. These predominant smoke-constituents initiate a series of oncogenic events facilitating epigenetic alterations, self-sufficiency in growth signals, evasion of apoptosis, sustained angiogenesis, and metastasis. A better understanding of the molecular mechanisms underpinning these events is crucial for the prevention and therapeutic intervention against PC. This review presents various interconnected signal transduction cascades, the smoking-mediated genotoxicity, and genetic polymorphisms influencing the susceptibility for smoking-mediated PC development by modulating pivotal biological aspects such as cell defense/tumor suppression, inflammation, DNA repair, as well as tobacco-carcinogen metabolization. Additionally, it provides a large perspective toward tumor biology and the therapeutic approaches against PC by targeting one or several steps of smoking-mediated signaling cascades.

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    ABSTRACT: Background: Despite recent valuable steps in initiating a cancer registry in Iran, data depicting prevalence, incidence, and clinical picture of pancreatic tumors in the country are exceedinglyly sparse. With the aim of filling this knowledge gap, we reviewed cases in the pathology archive of Shahid Sadoughi hospital (Yazd, Iran), between 2001 and 2011. Materials and Methods: Medical records of 177 patients are reported in the present study. In cases for which paraffin-embedded blocks were available, the specimens were evaluated by two independent pathologists blinded to the primary diagnosis. We extrapolated the frequency of malignant lesions in our study to the population of Yazd province, derived from national census data, to generate cancer incidence rates. Results: Final diagnosis of malignancy was made in 117 cases (66.1%), and the remainder (60 lesions, 33.9%) were classified as benign. Adenecarcinoma and neuroendocrine tumors were the two most common histological types of malignancy identified in 88 (75.2%) and 11 (9.4%) specimens, respectively. Crude annual incidence of pancreatic cancer was 0.55 per 100,000 person in 2001 and increased to 1.68 in 2011. Age standardized incidence rates in 2001 and 2011 were 0.75 and 2.68, respectively. A significant increasing trend in cancer incidence was observed during the 11 years of the study period (r =+0.856, p=0.009). Sex-stratified analysis, confirmed the observed trend in men (r=+0.728, p=0.034), but not women (r=+0.635, p=0.083). Conclusions: Over the past decade, incidence of pancreas malignancies has risen steadily in Yazd, Iran. Nevertheless, these figures are still substantially lower than those prevalent in developed nations.
    Asian Pacific journal of cancer prevention: APJCP 04/2013; 14(4):2631-2635. · 1.50 Impact Factor
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    ABSTRACT: Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor-infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer.
    Frontiers in Physiology 01/2013; 4:416.
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    ABSTRACT: Objective: The vast majority of pancreatic cancers occurs sporadically. The discovery of frequent variations in germline gene copy number can significantly influence the expression levels of genes that predispose to pancreatic adenocarcinoma. We prospectively investigated whether patients with sporadic pancreatic adenocarcinoma share specific gene copy number variations (CNVs) in their germline DNA. Patients and methods: DNA samples were analyzed from peripheral leukocytes from 72 patients with a diagnosis of sporadic pancreatic adenocarcinoma and from 60 controls using Affymetrix 500K array set. Multiplex ligation-dependent probe amplification (MLPA) assay was performed using a set of self-designed MLPA probes specific for seven target sequences. Results: We identified a CNV-containing DNA region associated with pancreatic cancer risk. This region shows a deletion of 1 allele in 36 of the 72 analyzed patients but in none of the controls. This region is of particular interest since it contains the YTHDC2 gene encoding for a putative DNA/RNA helicase, such protein being frequently involved in cancer susceptibility. Interestingly, 82.6% of Sicilian patients showed germline loss of one allele. Conclusions: Our results suggest that the YTHDC2 gene could be a potential candidate for pancreatic cancer susceptibility and a useful marker for early detection as well as for the development of possible new therapeutic strategies.
    Expert Opinion on Therapeutic Targets 05/2014; · 4.90 Impact Factor


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May 31, 2014