Article

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: 5.33). 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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    • "Many of the environmental cancer risk factors can initially induce chronic inflammation that subsequently leads to pancreatic cancer. Recurrent pancreatic injury from alcohol abuse, smoking, high-fat diet, diabetes, and genetic predisposition, induces a pro-inflammatory environment consisting of various types of immune cells, cytokines, chemokines, and growth factors that, when dysregulated and persistent, can ultimately lead to the development and progression of cancer (Lowenfels et al., 2001; Shoelson et al., 2007; Pannala et al., 2009; Momi et al., 2012). "
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