title: Growth suppression of human breast carcinoma stem cells by lipid peroxidation product 4-hydroxy-2-nonenal and hydroxyl radical-modified collagen.
abstract: Breast cancer is a leading cause of mortality and morbidity in women, mostly due to high metastatic capacity of mammary carcinoma cells. It has been revealed recently that metastases of breast cancer comprise a fraction of specific stem-like cells, denoted as cancer stem cells (CSCs). Breast CSCs, expressing specific surface markers CD44(+)CD24(-/low)ESA(+) usually disseminate in the bone marrow, being able to spread further and cause late metastases. The fundamental factor influencing the growth of CSCs is the microenvironment, especially the interaction of CSCs with extracellular matrix (ECM). The structure and function of ECM proteins, such as the dominating ECM protein collagen, is influenced not only by cancer cells but also by various cancer treatments. Since surgery, radio and chemotherapy are associated with oxidative stress we analyzed the growth of breast cancer CD44(+)CD24(-/low)ESA(+) cell line SUM159 cultured on collagen matrix in vitro, using either native collagen or the one modified by hydroxyl radical. While native collagen supported the growth of CSCs, oxidatively modified one was not supportive. The SUM159 cell cultures were further exposed to a supraphysiological (35 microM) dose of the major bioactive lipid peroxidation product 4-hydroxynonenal (HNE), a well known as 'second messenger of free radicals', which has a strong affinity to bind to proteins and acts as a cytotoxic or as growth regulating signaling molecule. Native collagen, but not oxidised, abolished cytotoxicity of HNE, while oxidized collagen did not reduce cytotoxicity of HNE at all. These preliminary findings indicate that beside direct cytotoxic effects of anticancer therapies consequential oxidative stress and lipid peroxidation modify the microenvironment of CSCs influencing oxidative homeostasis that could additionally act against cancer.
authors.affiliation: Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Cipak
authors.forename: Lidija
authors.initials: L
authors.lastname: Mrakovcic
authors.forename: Milan
authors.initials: M
authors.lastname: Ciz
authors.forename: Antonin
authors.initials: A
authors.lastname: Lojek
authors.forename: Boryana
authors.initials: B
authors.lastname: Mihaylova
authors.forename: Ivan
authors.initials: I
authors.lastname: Goshev
authors.forename: Morana
authors.initials: M
authors.lastname: Jaganjac
authors.forename: Marina
authors.initials: M
authors.lastname: Cindric
authors.forename: Sanda
authors.initials: S
authors.lastname: Sitic
authors.forename: Marko
authors.initials: M
authors.lastname: Margaritoni
authors.forename: Georg
authors.initials: G
authors.lastname: Waeg
authors.forename: Marija
authors.initials: M
authors.lastname: Balic
authors.forename: Neven
authors.initials: N
authors.lastname: Zarkovic
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D005260:Female; D006801:Humans; D017665:Hydroxyl Radical / Q000737:chemistry*; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D013499:Surface Properties
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D017665:Hydroxyl Radical; D003094:Collagen; C027576:4-hydroxy-2-nonenal