Conversely to normal cells, where deregulated oxidative stress drives the activation of death pathways, malignant cells exploit oxidative milieu for its advantage. Cancer cells are located in a very complex microenvironment together with stromal components that participate to enhance oxidative stress to promote tumor progression. Indeed, convincing experimental and clinical evidence underline the key role of oxidative stress in several tumor aspects thus affecting several characteristics of cancer cells. Oxidants influence the DNA mutational potential, intracellular signaling pathways controlling cell proliferation and survival and cell motility and invasiveness as well as control the reactivity of stromal components that is fundamental for cancer development and dissemination, inflammation, tissue repair, and de novo angiogenesis. This paper is focused on the role of oxidant species in the acquisition of two mandatory features for aggressive neoplastic cells, recently defined by Hanahan and Weinberg as new “hallmarks of cancer”: tumor microenvironment and metabolic reprogramming of cancer cells. 1. Introduction With over 3 million novel cases each year in Europe, cancer is a main public health hitch with a vital need for new therapies. Hanahan and Weinberg defined in the 2000s the so-called hallmarks of cancers, mandatory characteristics of virtually all neoplastic cells, enabling them to grow in a foreign and hostile environment and allowing escaping endogenous protective systems [1]. These hallmarks are listed in our reinterpretation of the Hanahan and Weinberg picture (Figure 1). Firstly, we mention self-sufficiency in growth signals, that is, the ability of several cancer cells to produce in autocrine manner growth factors and cytokines, as well as the development of compensatory mechanisms enhancing growth factor receptor. activation [2, 3]. The insensitivity to natural growth arrest signals, as the abolishment of cell contact inhibition, and the ability to evade apoptosis are two other intimately correlated cues of neoplastic cells [2–4]. Cancer cells evade apoptotic death due to lack of cell adhesion, a process called anoikis, as well as death induced by several chemotherapeutic drugs, thereby leading to chemoresistance, at present the main obstacle to fight cancer dissemination [3–8]. Beside evasion from apoptotic death, cancer cells also escape senescence and the limiting in lifespan, overcoming immortalization. Last, they achieve two further features, which strongly facilitate dissemination of metastatic colonies and repopulation tumors
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