About this Research Topic
Compared with primary tumors, the occurrence of metastases usually imposes a higher lethal threat to cancer patients, representing one of the deadliest events during cancer progression. Ironically, metastasis has been shown to be an inefficient process, as cancer cells experience severe oxidative stress in the circulation and the distant organs prior to colonization. Only a minimal fraction of disseminated cells that can adapt and survive the stressful microenvironment are capable of forming overt metastases. However, our understanding of how cancer cells overcome these lethal obstacles remains limited, and unraveling the key mechanisms is important for developing anti-metastatic therapeutic strategies.
The key role of redox regulation in metastasis can be highlighted by the finding that highly metastatic cells have markedly increased capacity in withstanding oxidative stress. Moreover, antioxidants such as N-acetylcysteine and vitamin E promote distant metastasis in both experimental mouse models and humans in clinical trials. Cancer cells frequently hijack the KEAP1-NRF2 system, a pivotal regulator of oxidative and electrophilic stresses, for stress adaptation during tumorigenesis and metastasis. Both NRF2 and KEAP1 are frequently mutated in various human cancers, such as epithelial ovarian cancer, lung adenocarcinoma, and gallbladder cancer, which eventually funnels high levels of NRF2 for cellular detoxification and thus tumor progression and metastasis. In addition, oncoproteins such as mutant K-Ras and c-Myc increase the expression of NRF2 to alleviate oxidative stress and promote tumor progression. Recently, transcription factor BACH1 has been shown to be a novel regulator of metastasis. Antioxidant supplements enhance metastasis via stabilizing BACH1, which triggers the transcription of various pro-metastatic genes and also stimulates glycolysis-dependent metastasis. Moreover, highly metastatic tumor cells undergo reversible metabolic changes, such as enhancing the NADPH-generating enzymes in the folate pathway, to increase their capacity to tolerate oxidative stress during metastasis.
The aim of this Research Topic is to cover novel insights into how tumor cells acquire high antioxidant capacities to withstand oxidative stress during the multi-step metastatic cascade. We welcome Original Research, Reviews, Mini-Reviews, Opinions, and Perspective articles focusing on, but not limited to:
• How oncogenes and tumor suppressors are involved in the redox regulation during tumor progression
• How oxidative stress and other mechanisms that affect cell behavior that contributes to the metastatic cascade, such as cell migration, invasion, anoikis-resistance
• Pharmacological agents that modulate cellular redox regulation and the metastatic cascade
• Novel regulators of the redox regulation machinery, such as the KEAP1-NRF2 system and glutathione biogenesis pathways
• Potential therapeutic strategies that target the metastatic cascade via redox regulation mechanisms
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