Abstract
Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.
Highlights
Cancer metabolism involves different changes at cellular level, and altered metabolic pathways have been demonstrated to be involved in tumorigenesis and invasiveness.Metabolic changes in the tumor microenvironment play a critical role in cancer, especially in the uncontrolled cell proliferation related to accumulated alterations in the signaling pathways that control cellular metabolism, which in turn sustain enhanced cell proliferation
The purpose of this review is to focus on the role of transforming growth factor β (TGF-β) as a key molecule in cancer and its interplay with oxidative stress produced at a cellular level, considering that both are part of the complex cascade of events involved in cancer cellular metabolism
Cannito et al [77] demonstrated that reactive oxygen species (ROS) are crucial in the early stages of epithelial to mesenchymal transition (EMT), in the crosstalk with hypoxia, in hepatoblastoma, colon, and pancreas cell lines [77]: it has been shown that the EMT induced by hypoxia is related to an increased intracellular ROS production, which in turn leads to GSK-3β phosphorylation and inactivation, and in turn is linked to the SMADmediated TGF-β pathway
Summary
Cancer metabolism involves different changes at cellular level, and altered metabolic pathways have been demonstrated to be involved in tumorigenesis and invasiveness. In particular, TGF-β expression is significantly increased during tumor progression, and this event often is correlated to a poor prognosis [4] It seems that during tumor progression TGF-β acts differently, in correlation to the stage in carcinogenesis, and according to the different reactivity of the tumor cells; this response may be associated with various factors, independently or related to TGF-β and its receptor expression, the availability of downstream signaling components, evasion of the immune response, stimulation of inflammation, and recruitment of cells that promote tumor growth [4]. Cancers 2021, 13, 3093 tokine in cancer cells, enabling these cells to escape the surveillance exerted by the immune system, thereby promoting tumor growth and metastasis [16]
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