Smoking and lung cancer.

Department of Chest Diseases, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.
Tuberkuloz ve toraks 02/2005; 53(2):200-9.
Source: PubMed

ABSTRACT Nowadays, around one-third of adults are known to be smokers, and smoking rates are increasing among the female population. It is estimated that deaths attributable to tobacco use will rise to 10 million by 2025, and one-third of all adult deaths are expected to be related to cigarette smoking. The association between cigarettes and lung cancer has been proven by large cohort studies. Tobacco use has been reported to be the main cause of 90% of male and 79% of female lung cancers. 90% of deaths from lung cancer are estimated to be due to smoking. The risk of lung cancer development is 20-40 times higher in lifelong smokers compared to non-smokers. Environmental cigarette smoke exposure and different types of smoking have been shown to cause pulmonary carcinoma. DNA adducts, the metabolites of smoke carcinogens bound covalently with DNA, are regarded as an indicator of cancer risk in smokers. In recent decades, there has been a shift from squamous and small cell lung cancer types to adenocarcinoma, due to increasing rates of smoking among female population and rising light cigarette usage. After smoking cessation, the cumulative death risk from lung cancer decreases. Patients who continue smoking experience greater difficulties during cancer treatment. Stopping smoking may prolong survival in cancer patients, and also decreases the risk of recurrent pulmonary carcinoma. In order to save lives and prevent smoking related hazards, physicians should advise both healthy individuals and those with cancer of the benefits of stopping smoking.

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    ABSTRACT: BACKGROUND: This review summarizes peer-reviewed studies examining cancer risks among police officers. It provides an overview of existing research limitations and uncertainties and the plausible etiologic risk factors associated with cancer in this understudied occupation. METHODS: Previous cancer studies among police officers were obtained via a systematic review of the MEDLINE, CABDirect, and Web of Science bibliographic databases. RESULTS: Quality observational studies of cancer among police officers are sparse and subject to limitations in exposure assessment and other methods. Results from three studies suggested possible increased mortality risks for all cancers, and cancers of the colon, kidney, digestive system, esophagus, male breast, and testis, as well as Hodgkin's disease. Few incidence studies have been performed, and results have been mixed, although some associations with police work have been observed for thyroid, skin, and male breast cancer. CONCLUSIONS: Police are exposed to a mix of known or suspected agents or activities that increase cancer risk. Epidemiologic evidence to date is sparse and inconsistent. There is a critical need for more research to understand the biological and social processes underlying exposures and the suggested disproportionate risks and to identify effective prevention strategies. Am. J. Ind. Med. © 2012 Wiley Periodicals, Inc.
    American Journal of Industrial Medicine 12/2012; · 1.97 Impact Factor
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    ABSTRACT: The transcription factor nuclear factor kappa-B (NFkB) plays a pivotal role in the immune response but is also involved in cancer development and progression. In unstimulated cells NFkB is kept inactive in the cytoplasm by inhibitor of NFkB (IkB) proteins. Dysregulation of the pathway or activation of NFkB by chemotherapeutic agents may lead to cancer progression or drug resistance. The NFkB activation status was investigated in human lung cancer, pancreatic cancer, and hematopoietic cancer cell lines. Non-small cell lung cancer (NSCLC) cells possess a functional NFkB pathway exhibiting basal NFkB activity in unstimulated cells and a strong increase upon stimulation. NFkB in small cell lung cancer (SCLC) cells could not be activated by tumor necrosis factor alpha (TNF-a) due to absence of the TNF-receptor 1 (TNF-R1). Other components of the pathway such as the inhibitor of NFkB kinase (IKK) complex or IkB-a were functional in SCLC, as topoisomerase poisons could activate the NFkB pathway in these cells. Pancreatic cancer cells exhibited increased NFkB activity in unstimulated cells, possibly due to upstream activating signals. On the one hand, NFkB activity could be decreased by proteasome inhibition, yet on the other hand it could be further enhanced by TNF-a treatment. Investigation of hematopoietic cancer cells demonstrated that Hodgkin’s lymphoma, many B-cell lymphoma or multiple myeloma cell lines showed strong NFkB activity in untreated cells. There, cells acquired constitutive NFkB activity possibly due to mutations in the IkB-a protein or activation of upstream signals. Treatment with IKK inhibitors in above mentioned cell lines caused cellular toxicity, but EC50 was similar in all cell lines checked, independent of their kB activation status. In lung cancer cells, activation of NFkB by cytotoxic drugs was confined to topoisomerase poisons such as etoposide or camptothecin, but could not be detected in cells incubated with DNA crosslinkers such as cisplatin or alkylating agents such as mafosfamide. Additionally, activation of NFkB by the topoisomerase poisons was cell line dependent. Furthermore, the influence of histone deacetylase inhibitors (HDIs) on the NFkB pathway in human NSCLC cell lines was investigated. Incubation of NSCLC cells with HDIs reduced the responsiveness of NFkB to TNF-a. It was shown that this reduction was due to drastic downregulation of TNF-R1 by HDIs. After 24 hours of HDI treatment, mRNA levels of TNF-R1 were lowered to approx. 10%, protein levels and cell surface expression were decreased as well. Substantially, the consequence of this reduced TNF-R1 level was an almost abolished activation of the NFkB pathway by TNF-a through limited phosphorylation of the kinases IKK-a and IKK-b, yielding delayed and weakened phosphorylation and degradation of the inhibitor IkB-a. This resulted in reduced NFkB translocation and DNA binding, and strongly diminished target gene expression upon stimulation. Downregulation of TNF-R1 by HDIs could also be shown for other tumor entities and normal cell lines. In contrast, TRAIL-R2 expression was increased in response to HDIs. The results clearly demonstrate that HDIs do not directly affect NFkB or downstream signaling, but affect receptors at the cell surface due to a reprogramming of gene expression. Der Transkriptionsfaktor NFkB (nuclear factor kappa-B) ist ein zentraler Mediator des Immunsystems. NFkB ist aber auch in der Krebsentstehung und im Fortschreiten der Krebserkrankung involviert. In unstimulierten Zellen liegt NFkB, an seinen Inhibitor IkB gebunden, im Zytoplasma vor. Seine fehlerhafte Regulation sowie die Aktivierung durch Zytostatika kann zur Entstehung von Krebs sowie Resistenzen gegenüber diesen Medikamenten führen. Eine zentrale Aufgabenstellung in der vorliegenden Arbeit war die Bestimmung des NFkB Aktivierungsstatus in menschlichen Krebszelllinien aus folgenden Geweben: Lunge, Pankreas sowie hämatopoetischen Zellen. Experimente zeigten einen funktionalen NFkB Signalweg im nicht-kleinzelligen Lungenkarzinom (NSCLC), d.h. in der unstimulierten Zelle liegt NFkB inaktiv im Zytoplasma vor und kann durch Stimulation mit TNF-a aktiviert werden und in den Zellkern gelangen. NFkB im kleinzelligen Lungenkarzinom (SCLC) hingegen konnte nicht mit TNF-a aktiviert werden. Als Ursache wurde die fehlende Expression des TNF-R1 nachgewiesen. Andere Proteine im Signalweg wie der IKK-Komplex oder der Inhibitor IkB-a sind in SCLC funktionell, da die Behandlung dieser Zellen mit Topoisomerase Inhibitoren den NFkB Signalweg anschaltete. Pankreaskrebszelllinien zeigten eine erhöhte NFkB Aktivität im unstimulierten Zustand. Das ist möglicherweise auf NFkB vorgeschaltete aktivierende Signale zurückzuführen. Es wurde gezeigt, dass die verstärkte NFkB Aktivität durch Proteasominhibition reduziert, aber mit TNF-a weiter stimuliert wird. Blutkrebszelllinien abgeleitet von Hodgkin’s Lymphom, verschiedene B-Zell Lymphome sowie im Multiplem Myelom zeigten eine starke NFkB Aktivität im Zellkern auch im nicht stimulierten Zustand. Dies ist vermutlich auf Mutationen im Inhibitor IkB-a oder durch Aktivierung von vorgeschalteten Signalen zurückzuführen. Die Toxizität von IKK Inhibitoren zeigte sich in allen Zelllinien, jedoch lag der EC50 unabhängig vom NFkB Aktivierungszustandes im gleichen Bereich. Eine Aktivierung von NFkB im Lungenkarzinom durch Zytostatika konnte mit Topoisomerase Inhibitoren wie Etoposid und Camptothecin, aber nicht mit DNA vernetzenden Medikamenten wie Cisplatin oder alkylierenden Substanzen wie Mafosfamid detektiert werden. Der beobachtete NFkB aktivierende Effekt war zudem Zelltyp abhängig. Der letzte Teil dieser Arbeit bestand in der Analyse von Histondeacetylase Inhibitoren (HDI) und deren Einfluss auf die NFkB Aktivität in menschlichen NSCLC Zelllinien. Es konnte gezeigt werden, dass HDI die NFkB Aktivität nach TNF-a Stimulation drastisch reduzierten. Als Ursache wurde eine Reduktion des TNF-R1 auf RNA Ebene auf etwa 10 % innerhalb von 24 Stunden Behandlung der Zellen mit HDI nachgewiesen. Die Proteinexpression sowie die Expression des Rezeptors an der Zelloberfläche wurden ebenfalls stark herabgesetzt. Dies hatte ein verringertes Ansprechen von NFkB auf TNF-a zur Folge, das sich äußerte in: verringerte Phosphorylierung der aktivierenden Kinasen IKK-a und IKK-b, Reduktion der Inhibitor Phosphorylierung sowie des Abbaus, verringerte Translokation von NFkB in den Zellkern verbunden mit einer Reduktion der DNA-Bindung und verminderte Expression NFkB abhängiger Gene. Diese Herabregulation des TNF-R1 konnte nicht nur im NSCLC nachgewiesen werden, sondern auch in anderen Tumor- und Normalzelllinien. Die Reduktion der TNF-R1 Expression wurde von einer Aktivierung der TRAIL-R2 Expression begleitet. Diese Ergebnisse belegen, dass HDI in den NFkB Signalweg nicht direkt eingreifen, sondern durch eine Veränderung der Genexpression Zelloberflächenrezeptoren beeinflussen.
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