Environmental Determinants of Ferroptosis in Cancer
Author:
Setayeshpour Yasaman12ORCID, Lee Yunji3, Chi Jen-Tsan124ORCID
Affiliation:
1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA 2. Department of Cell and Molecular Biology, Duke University Medical Center, Durham, NC 27708, USA 3. Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan 215316, China 4. Center for Advanced Genomic Technology, Duke University, Durham, NC 27708, USA
Abstract
Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many “cancer-friendly,” non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells’ susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.
Funder
Ovarian Cancer Research Alliance National Institutes of Health U.S. Department of Defense
Subject
Cancer Research,Oncology
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