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.

Roles of Oxidative Stress in the Development and Progression of Breast Cancer

“…In addition, hypoxia through the impairment of complex III (cytochrome b oxidoreductase) of the mitochondrial respiratory chain and the activity of NADPH oxidase of macrophages play important roles in aggregate ROS and the intrinsic oxidative stress in tumors. Thus, the hypoxia participates in the induction of tumor angiogenesis and promotes cancer (Barrera, 2012;Fiaschi and Chiarugi, 2012;Sosa et al, 2013). Studies have shown that oxidative stress affects several signaling pathways associated with cell proliferation (Soliman et al, 2014).…”

“…Hence, the activity of the JNK pathway plays an important management role in apoptosis. Some studies indicate that the inhibition of JNK also causes changes in the cell aging process and correspondingly increases the production of free radicals in mitochondria and causes oxidative damage to DNA in MCF-7 breast cancer cells (Martindale and Holbrook, 2002;Schramek et al, 2011;Fiaschi and Chiarugi, 2012;Raj et al, 2012). P66sch proteins also persuade ROS production by inducing the expression of prolin oxidase.…”

“…The characteristics of cancer cells include loss of contact inhibition, resistance to apoptosis, and insensitivity to cell growth arrest signals. Angiogenesis is a chief characteristic of cancer cells (Visvader and Lindeman, 2008;Klaunig et al, 2010;Fiaschi and Chiarugi, 2012;Siegel et al, 2013).…”

A microfluidic co-culture system to monitor tumor-stromal interactions on a chip

“…49,50 We measured the change of total area covered by HuH7 using phase contrast images of the co-culture chip, which was processed by ImageJ software (detailed procedure illustrated in Figure S3, supplementary material). 52 It was observed that the coverage of tumor cells increased significantly after day 4 ( Figure 6(a)).…”

Cancer Metabolic and Immune Reprogramming: The Intimate Interaction Between Cancer Cells and Microenvironment

“…The transcription factors HIF-1 and HIF-2 play also a crucial role in the metabolic reprogramming of both CAFs and tumor cells. Although their role remains controversial under hypoxia, clear evidence now exist indicating that ROS stabilize the HIF proteins under normoxic conditions through modulation of PHD enzyme activity [40][41][42][43][44]. Fiaschi and Chiarugi [43] have shown that accumulation of ROS and HIF stabilization in CAFs result also from the downregulation of SIRT3, a mitochondrial NAD-dependent deacetylase.…”