ABSTRACT
The use of nanotechnology in biomedicine involves the engineering of nanomaterials to act as therapeutic carriers, targeting agents and diagnostic imaging devices. The application of nanotechnology in cancer aims to transform early detection, targeted therapeutics and cancer prevention and control. To assist in expediting and validating the use of nanomaterials in biomedicine, the National Cancer Institute (NCI) Center for Biomedical Informatics and Information Technology, in collaboration with the NCI Alliance for Nanotechnology in Cancer (Alliance), has developed a data sharing portal called caNanoLab. caNanoLab provides access to experimental and literature curated data from the NCI Nanotechnology Characterization Laboratory, the Alliance and the greater cancer nanotechnology community.
ABSTRACT
The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT-inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell-like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation.
Subject(s)
Breast Neoplasms , Cell Transformation, Neoplastic , Claudins , Epithelial-Mesenchymal Transition , Mammary Glands, Human/metabolism , Protein Phosphatase 2 , Twist-Related Protein 1/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Differentiation , Cell Line , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Claudins/genetics , Claudins/metabolism , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Genes, ras , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Mammary Glands, Animal/cytology , Mammary Glands, Animal/metabolism , Mammary Glands, Human/cytology , Mice , Mice, Transgenic , Protein Phosphatase 2/antagonists & inhibitors , Protein Phosphatase 2/metabolism , Retinoblastoma Protein/metabolism , Telomerase/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Protein p53/metabolism , Twist-Related Protein 1/metabolism , Zinc Finger E-box-Binding Homeobox 1ABSTRACT
The tumor suppressors p16(INK4a) and p53 have been implicated as contributors to age-associated stem cell decline. Key functions of p53 are the induction of cell cycle arrest, senescence, or apoptosis in response to DNA damage. Here, we examine senescence, apoptosis, and DNA damage responses in a mouse accelerated aging model that exhibits increased p53 activity, the p53(+/m) mouse. Aged tissues of p53(+/m) mice display higher percentages of senescent cells (as determined by senescence-associated beta-galactosidase staining and p16(INK4a) and p21 accumulation) compared to aged tissues from p53(+/+) mice. Surprisingly, despite having enhanced p53 activity, p53(+/m) lymphoid tissues exhibit reduced apoptotic activity in response to ionizing radiation compared to p53(+/+) tissues. Ionizing radiation treatment of p53(+/m) tissues also induces higher and prolonged levels of senescence markers p16(INK4a) and p21, suggesting that in p53(+/m) tissues the p53 stress response is enhanced and is shifted away from apoptosis toward senescence. One potential mechanism for accelerated aging in the p53(+/m) mouse is a failure to remove damaged or dysfunctional cells (including stem and progenitor cells) through apoptosis. The increased accumulation of dysfunctional and senescent cells may contribute to reduced tissue regeneration, tissue atrophy, and some of the accelerated aging phenotypes in p53(+/m) mice.
Subject(s)
Aging/physiology , Apoptosis , DNA Damage/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Biomarkers , Cells, Cultured , Female , Fibroblasts , Male , Mice , Mice, Transgenic , Models, Animal , Mutation/genetics , Stress, Physiological , Tumor Suppressor Protein p53/geneticsABSTRACT
The cytotoxic and antibacterial properties of nC 60, a buckminsterfullerene water suspension, have been attributed to photocatalytically generated reactive oxygen species (ROS). However, in this work, neither ROS production nor ROS-mediated damage is found in nC 60-exposed bacteria. Furthermore, the colorimetric methods used to evaluate ROS production and damage are confounded by interactions between nC 60 and the reagents, yielding false positives. Instead, we propose that nC 60 exerts ROS-independent oxidative stress, thus reconciling conflicting results in the literature.
