Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison

Abstract

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.

Figure 1

ROS play multiple roles in the hallmarks of cancers. Contribution of oxidants is indicated for each point (see text for details). (1) Self-sufficiency in proliferation signals: most normal cells wait for an external message before dividing. Conversely, cancer cells often counterfeit their individual proliferative messages. ROS a play role in ligand-independent RTK transactivation, decreased RTK activation threshold [11, 12]. (2) Insensitivity to antiproliferation signals: as the tumor enlarges, it squeezes adjacent tissues and therefore receives messages that would normally stop cell division. Malignant cells ignore these command. ROS are involved in p53 activation, loss of contact inhibition, and loss of anchorage dependence [–14]. (3) Invasion and metastasis: cancers usually lead to death only after they overcome their confines to the particular organ in which they arose. Cancer cells need to escape the primary tumour, invade matrix of different organs, find a suitable metastatic niche, and then grow in this secondary site. ROS play a role in Met overexpression, matrix metalloproteinase secretion, invadopodia formation, and plasticity in cell motility, EMT [, –18]. (4) Limitless replication: healthy cells can divide no more than 70 times, but malignant cells need more than 70 cycles to make tumours. Hence tumours need to enforce the reproductive limit of cells. ROS are involved in expression of telomerase [12, 19]. (5) Continuous angiogenesis: tumour is characterized by a chronically activated angiogenesis due to an unbalanced mix of pro-angiogenic signals thus sustaining cancer “feeding.” ROS play role in: endothelial progenitor activation, signalling of VEGF and angiopoietin, recruitment of perivascular cells, release of VEGF [–22]. (6) Escaping apoptosis: in healthy cells, several conditions (including genetic damage or lack of ECM adhesion) activate a suicide program, but tumour cells bypass these mechanisms, thereby surviving to death messages. ROS are involved in PTEN inactivation, Src activation, Anoikis resistance, NF-κB activation, and CREB activation [, , –25]. (7) Change of cell metabolism tumours have the capability to modify or reprogram cellular metabolism to successfully carry on the neoplastic progression. ROS are involved in Warburg effect, upregulation of glucose transporter, activation of oncogene (Ras, Myc) and mutation of tumour suppressor (p53), and increase of HIF-1 [, –28]. (8) Escaping immune destruction tumours acquire the capability to evade natural immunological destruction by T and B lymphocytes, macrophages, and natural killer cells [29]. Furthermore, there are two additional characteristics facilitating the acquisition of aggressive features called “enabling characteristics.” (9) Genome instability and mutation genomic alteration due to epigenetic mechanisms, the increase rate of mutation, or enhanced sensitivity to mutagenic agents can drive tumour progression. ROS are involved in increasing the rates of mutation, increasing sensibility to mutagenic agents, and compromising the surveillance systems [12, 29, 30]. (10) Tumor promoting inflammation innate immune cells, which are designed to fight infections and heal wounds, inadequately support the acquisition of hallmark capabilities with this leading to tumor expansion. ROS are involved in acquisition of mutation by neoplastic cells, thus accelerating their evolution towards heightened malignancy [29, 31].

Figure 2

Oxidative stress in tumor microenvironment. Within microenvironment, oxidative stress can have intrinsic or extrinsic origin. Some stromal components can directly produce ROS. CAMs generate ROS through NOX2 activation and RNS through iNOS, while hypoxia produces oxidant species by deregulation of the complex III of mitochondrial electron transport or by NADPH oxidase activity [, –46]. In response to extrinsic or intrinsic oxidative stress, CAFs became activated thus producing cytokines and proteases that affect tumour progression [41, 47, 48]. In addition, microenvironment or ageing-induced oxidative stress leads to secretion of “Senescent Activated Secretory Pathway” (SASP) by senescent fibroblasts affecting both stroma and cancer cells to promote cancer progression [49, 50]. Finally, cancer cells exacerbate oxidant environment by intrinsic production of oxidative stress through down-regulation of Jun D or enhanced of NOX-4, LOX-5 and COX-2 activity [, , –53].