Transforming Growth Factor-Beta And Oxidative Stress In Cancer: A Crosstalk In Driving Tumor Transformation

Simple Summary Metabolic changes in tumor microenvironment play a critical role in cancer, related to the accumulated alterations in signaling pathways that control cellular metabolism. Cancer metabolic deregulation is related to specific events such as the control of oxidative stress, and in particular the redox imbalance with aberrant oxidant production and/or a deregulation of the efficacy of the antioxidant systems. In cancer cells, different cytokines are involved in the development and/or progression of cancer; among these cytokines, the transforming growth factor beta (TGF-beta) is central to tumorigenesis and cancer progression. In tumor cells, it has been demonstrated that there is a close correlation between oxidative stress and TGF-beta; this crosstalk strongly contributes to tumorigenesis, both in tumor development and in mediating its invasiveness. This review is addressed to better understanding this crosstalk between TGF-beta and oxidative stress in cancer cell metabolism, in an attempt to improve the pharmacological and therapeutic approach against cancer. 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-1 alpha) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor beta (TGF-beta), 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-beta 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-beta and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.