title: The redox biology network in cancer pathophysiology and therapeutics.
abstract: The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1) and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic), greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular heterogeneity and the hypoxia map in the tumor niche, along with the adjoining and systemic effects of oxidative stress-based therapies.
authors.affiliation: Cellular and Molecular Medicine Department, Radiobiology Laboratory, "Victor Babes" National Institute of Pathology, Bucharest, Romania. Electronic address: gina.manda@gmail.com.
authors.forename: Gina
authors.initials: G
authors.lastname: Manda
authors.affiliation: Cellular and Molecular Medicine Department, Radiobiology Laboratory, "Victor Babes" National Institute of Pathology, Bucharest, Romania.
authors.forename: Gheorghita
authors.initials: G
authors.lastname: Isvoranu
authors.affiliation: Cellular and Molecular Medicine Department, Radiobiology Laboratory, "Victor Babes" National Institute of Pathology, Bucharest, Romania.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Comanescu
authors.affiliation: Cellular and Molecular Pharmacology Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
authors.forename: Adrian
authors.initials: A
authors.lastname: Manea
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Ege University, Izmir, Turkey.
authors.forename: Bilge
authors.initials: B
authors.lastname: Debelec Butuner
authors.affiliation: Department of Bioengineering, Cancer Biology Laboratory, Ege University, İzmir, Turkey.
authors.forename: Kemal Sami
authors.initials: KS
authors.lastname: Korkmaz
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D017319:Photosensitizing Agents / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases
keywords: Bystander and abscopal effects; Cancer; Photodynamic therapy; Radiotherapy; Redox signaling; Tumor niche