title: Oxystressed tumor microenvironment potentiates epithelial to mesenchymal transition and alters cellular bioenergetics towards cancer progression.
abstract: During tumorigenesis, cancer cells generate complex, unresolved interactions with the surrounding oxystressed cellular milieu called tumor microenvironment (TM) that favors spread of cancer to other body parts. This dissemination of cancer cells from the primary tumor site is the main clinical challenge in cancer treatment. In addition, the significance of enhanced oxidative stress in TM during cancer progression still remains elusive. Thus, the present study was performed to investigate the molecular and cytoskeletal alterations in breast cancer cells associated with oxystressed TM that potentiates metastasis. Our results showed that depending on the extent of oxidative stress in TM, cancer cells exhibited enhanced migration and survival with reduction of chemosensitivity. Corresponding ultrastructural analysis showed radical cytoskeletal modifications that reorganize cell-cell interactions fostering transition of epithelial cells to mesenchymal morphology (EMT) marking metastasis, which was reversed upon antioxidant treatment. Decreased E-cadherin and increased vimentin, Twist1/2 expression corroborated the initiation of EMT in oxystressed TM-influenced cells. Further evaluation of cellular energetics demonstrated significant metabolic reprogramming with inclination towards glucose or external glutamine from TM as energy source depending on the breast cancer cell type. These observations prove the elemental role of oxystressed TM in cancer progression, initiating EMT and metabolic reprogramming. Further cell-type specific metabolomic analysis would unravel the alternate mechanisms in cancer progression for effective therapeutic intervention. Graphical abstract Schematic representation of the study and proposed mechanism of oxystressed TM influenced cancer progression. Cancer cells exhibit a close association with tumor microenvironment (TM), and oxystressed TM enhances cancer cell migration and survival and reduces chemosensitivity. Oxystressed TM induces dynamic cytomorphological variations, alterations in expression patterns of adhesion markers, redox homeostasis, and metabolic reprogramming that supports epithelial to mesenchymal transition and cancer progression.
authors.affiliation: Cancer Genetics and Nanomedicine Laboratory, Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India.
authors.forename: Dhivya
authors.initials: D
authors.lastname: Sridaran
authors.affiliation: Immunopathology Laboratory, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Ramamoorthi
authors.affiliation: Immunopathology Laboratory, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Rasool
authors.initials: R
authors.lastname: MahaboobKhan
authors.affiliation: Cancer Genetics and Nanomedicine Laboratory, Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India. pkumpati@hotmail.com.
authors.forename: Premkumar
authors.initials: P
authors.lastname: Kumpati
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D045022:Lactate Dehydrogenases / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D066244:Proton Magnetic Resonance Spectroscopy; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D045022:Lactate Dehydrogenases
keywords: Cancer progression; EMT; Metabolic reprogramming; Oxidative stress; Tumor microenvironment