**5. ROS and cancer**

The imbalance between cellular generation of ROS and its removal leads to oxidative stress which was associated, among other deleterious effects, with the initiation and progression of cancer.

Regarding the carcinogenesis, it is important to note that reactive oxygen species are consid‐ ered to be regulators of the following major signaling mechanisms: extracellular signalregulated kinases (ERKs), mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinases (PI3Ks) and transcription factors such as hypoxia-inducible factors (HIFs). All of these signaling pathways play key roles in cell proliferation, cell growth and cell survival. It was observed that high levels of ROS can induce irreversible oxidative damage in lipids, proteins and nucleic acids. Furthermore, ROS are active in multistage carcinogenesis from initiation to malignant conversion, by inducing oxidative DNA damage and mutations in protooncogenes and tumor suppressor genes, and subsequent activation of signal transduction pathways [14].

In the first stage of carcinogenesis, cancer cells usually express genetic instability and a significant increase in ROS concentration as a consequence of a "vicious circle": ROS induce genetic mutations (especially in mitochondrial DNA), which lead to metabolic dysfunction and additional ROS generation [14].

ROS cause almost all forms of DNA damage, such as changes of the nucleotide bases, strand breakage and DNA protein cross-links, but the end-products depend on the type of ROS. It was mentioned that the mutations induced by specific ROS are implicated in the genesis of cancer. Another mechanism of action of ROS in carcinogenesis was to induce and keep the oncogenic phenotypes of tumor cells. At present, oxidative stress is widely accepted as a key contributor to cancer development [14,29].

Previous studies have demonstrated that oxidative stress is associated with carcinogenesis and is also related to the incidence of cancer [39,40]. During the carcinogenesis process, the imbalance between ROS production and ROS elimination is represented by the increased concentrations of reactive oxygen species in cancer cells and a reduction of antioxidants levels. The increase of ROS in these cells occurs due to the influence of intrinsic or extrinsic factors, resulting in gene mutations and changes in transcriptional processes as well as changes in signaling pathways and, ultimately, the occurrence of cancer [40]. Other contributory factors for the enhanced production of ROS in cancer cells are: cancer-associated fibroblasts (CAFs), cancer-associated macrophages (CAMs), and hypoxia. Cancer-associated macrophages are able to generate ROS via NADPH oxidase in tumor cells [39].

It was also shown that ROS affects the expression of the p53 suppressor gene which is a key factor in apoptosis. In addition, oxidative injury induced by changes in gene expression, cell proliferation, apoptosis, and angiogenesis plays a significant role in tumor initiation and progression [39].

alterations are features of cellular senescence. Other studies have proposed the hypothesis that

The imbalance between cellular generation of ROS and its removal leads to oxidative stress which was associated, among other deleterious effects, with the initiation and progression of

Regarding the carcinogenesis, it is important to note that reactive oxygen species are consid‐ ered to be regulators of the following major signaling mechanisms: extracellular signalregulated kinases (ERKs), mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinases (PI3Ks) and transcription factors such as hypoxia-inducible factors (HIFs). All of these signaling pathways play key roles in cell proliferation, cell growth and cell survival. It was observed that high levels of ROS can induce irreversible oxidative damage in lipids, proteins and nucleic acids. Furthermore, ROS are active in multistage carcinogenesis from initiation to malignant conversion, by inducing oxidative DNA damage and mutations in protooncogenes and tumor suppressor genes, and subsequent activation of signal transduction pathways [14].

In the first stage of carcinogenesis, cancer cells usually express genetic instability and a significant increase in ROS concentration as a consequence of a "vicious circle": ROS induce genetic mutations (especially in mitochondrial DNA), which lead to metabolic dysfunction

ROS cause almost all forms of DNA damage, such as changes of the nucleotide bases, strand breakage and DNA protein cross-links, but the end-products depend on the type of ROS. It was mentioned that the mutations induced by specific ROS are implicated in the genesis of cancer. Another mechanism of action of ROS in carcinogenesis was to induce and keep the oncogenic phenotypes of tumor cells. At present, oxidative stress is widely accepted as a key

Previous studies have demonstrated that oxidative stress is associated with carcinogenesis and is also related to the incidence of cancer [39,40]. During the carcinogenesis process, the imbalance between ROS production and ROS elimination is represented by the increased concentrations of reactive oxygen species in cancer cells and a reduction of antioxidants levels. The increase of ROS in these cells occurs due to the influence of intrinsic or extrinsic factors, resulting in gene mutations and changes in transcriptional processes as well as changes in signaling pathways and, ultimately, the occurrence of cancer [40]. Other contributory factors for the enhanced production of ROS in cancer cells are: cancer-associated fibroblasts (CAFs), cancer-associated macrophages (CAMs), and hypoxia. Cancer-associated macrophages are

It was also shown that ROS affects the expression of the p53 suppressor gene which is a key factor in apoptosis. In addition, oxidative injury induced by changes in gene expression, cell

ROS is cause and consequence of NF-κB pathway activation during senescence [38].

**5. ROS and cancer**

12 Toxicology Studies - Cells, Drugs and Environment

and additional ROS generation [14].

contributor to cancer development [14,29].

able to generate ROS via NADPH oxidase in tumor cells [39].

cancer.

There are recent studies that sustain the idea that ROS induced by oxidative stress might lead to apoptotic or necrotic cell death of skin cells. Especially, the accumulated ROS plays a critical role in the intrinsic aging and photo-aging of human skin in vivo, what leads to the hypothesis that ROS are responsible for different skin cancers and other cutaneous inflammatory malad‐ ies. Ultraviolet radiation type B (UVB) is considered a complete carcinogen and generates increased levels of ROS, leading to oxidative damage at skin level. According to several studies, exposure of mammalian skin cells to UVB radiation determines alterations of cellular function via oxidation of macromolecules, DNA damage, generation of ROS, and changes in signaling pathways. As major sources of H2O2 were described UVB-induced leukocyte infiltration in the skin, and inflammatory leukocytes and it was stated that H2O2 plays an important role in inflammatory skin diseases and skin cancer [5].

ROS exert key roles in a variety of processes associated with epithelial malignancy such as cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, apoptosis evasion and enhancement of metastatic potential [41].

Free radicals in carcinogenesis, ROS and RNS (reactive nitrogen species) contribute in different ways to carcinogenesis and the malignant progression of tumor cells, enhancing their meta‐ static potential. In fact, they are now considered a distinctive characteristic of cancer. These species lead to genomic damage and genetic instability, and they participate as intermediaries in mitogenic and survival signals via growth factor receptors and adhesion molecules, promoting cell mobility, inducing inflammation/repair and angiogenesis in the tumor microenvironment [16].
