| Sažetak | U ovome radu opisani su osnovni procesi nastanka i razvoja tumora te njihovi mehanizmi. Svi opisani procesi su povezani sa duhanskim dimom kao karcinogenom. Iako komponenata duhanskoga dima sa karcinogenim potencijalom ima mnogo (preko 62), većina istraživanja je usmjerena na tri komponente: nikotin, 4-(metilnitrozamino)-1-(3-piridil)-1- butanon (NNK) i policiklički aromatski ugljikovodici (PAH). Nikotin i NNK su specifični za duhanski dim dok su PAH-ovi spojevi koji se mogu naći i u okolišu, a nastaju industrijskim zagađenjem. U radu su opisani genotoksični mehanizmi, ali i vrlo važni ne-genotoksični odnosno epigenetički mehanizmi tumorigeneze. Najčešće epigenetičke promjene odnose se na promjene u metilaciji DNA, modifikacije histona i nekodirajućih RNA molekula, a služe u regulaciji važnih staničnih funkcija Takve modifikacije vode do promjena u ekspresiji proteina bitnih za normalni stanični ciklus. Mehanizmi koji uzrokuju promociju i progresiju tumora su kompleksni i uključuju mnoge molekularne mete kao što su: receptori, regulatori staničnog ciklusa, MAP kinaze, medijatori apoptoze, faktori angiogeneze te medijatori invazije i metastaziranje. Među receptorima, nAChR, β-AR i AhR su najznačajniji posrednici u tumorigenezi uzrokovanoj duhanskim dimom. Pojačana ekspresija ili aktivacija ovih receptora može rezultirati oslobađanjem neurotransmitera i faktora rasta koji sudjeluju u inhibiciji apoptoze, staničnoj proliferaciji, angiogenezi te invaziji i metastaziranju tumorskih stanica. Signalni putovi PI3K/AKT, Stat3, ERK1/2 imaju važnu ulogu u procesima tumorigeneze. To su također zajednički putovi na koje djeluju komponente duhanskog dima (nikotin, NNK i PAH). Signalni putovi poput PKC, AKT, ERK i COX-2 uključeni su u promocijski i progresijski korak tumorigeneze uzrokovane duhanskim dimom. Pretpostavlja se da bi se ove molekule mogle iskoristiti kao potencijalne mete za budući razvoj terapija i lijekova protiv tumora. |
| Sažetak (engleski) | This paper described the basic processes responsible for the emergence and development of tumors (tumorigenesis) and their mechanisms. All the described processes were associated with tobacco smoke as the carcinogen. There are many (over 62) components of tobacco smoke with carcinogenic potential; however, most research has focused on three components: nicotine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons (PAH). Nicotine and NNK are specific to tobacco smoke while the PAH compounds are found in the environment as a result of industrial pollution. In this paper genotoxic mechanisms were described, but the focus was placed on the the very important non-genotoxic i.e. epigenetic mechanisms of tumorigenesis. The most common epigenetic changes are related to the changes in DNA methylation, histone modifications, and noncoding RNA molecule, which serve to regulate important cellular functions. These modifications lead to changes in the expression of proteins essential for normal cell cycle. Mechanisms that cause tumor promotion and progression are complex and involve many molecular targets, such as receptors, cell cycle regulators, mitogen-activated protein kinases, apoptosis mediators, angiogenic factors, and invasion and metastasis mediators. Among the receptors, nAChR, β-AR, and AhR have the closest association with cigarette smoke-induced carcinogenesis. Over expression or activation of these receptors may result in a release of neurotransmitters and growth factors that participate in apoptosis inhibition, cell proliferation, angiogenesis, cancer cell invasion and metastasis. Signaling pathways PI3K/AKT, Stat3, and ERK1/2 play an important role in the carcinogenetic processes. They are also common paths affected by cigarette smoke components, including nicotine, NNK, and PAHs. In addition, PKC, AKT, ERK, and COX-2 signaling pathways are involved in both promotion and progression stages of tumorigenesis caused by cigarette smoke. It is assumed that these molecules could be used as potential targets for future development of therapies and medicines against tumors. |
