Abstract:
:Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H2O2 secretion compared with normal fibroblasts (FIBs). These results suggest that extracellular H2O2 acts as a field effect carcinogen. Indeed, H2O2-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H2O2 resulted in the acquisition of an oxidative, CAF-like state. In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H2O2 production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Chan JS,Tan MJ,Sng MK,Teo Z,Phua T,Choo CC,Li L,Zhu P,Tan NSdoi
10.1038/cddis.2016.492subject
Has Abstractpub_date
2017-01-19 00:00:00pages
e2562issue
1issn
2041-4889pii
cddis2016492journal_volume
8pub_type
杂志文章abstract::Protein tyrosine kinase 7 (PTK7) and cancer-associated fibroblasts (CAFs) play important roles in cancer stemness, respectively. However, little is known about interaction between CAFs and PTK7 in cancers. In this study, we showed that PTK7 was significantly correlated with the Wnt/β-Catenin pathway and aggressive cli...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1116-6
更新日期:2018-10-22 00:00:00
abstract::Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and huma...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.398
更新日期:2017-08-24 00:00:00
abstract::We have previously shown that the combination of statins and taxanes was a powerful trigger of HGT-1 human gastric cancer cells' apoptosis1. Importantly, several genes involved in the "Central carbon metabolism pathway in cancer", as reported in the Kyoto Encyclopedia of Genes and Genomes, were either up- (ACLY, ERBB2...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0761-0
更新日期:2018-07-03 00:00:00
abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-019-2189-6
更新日期:2020-01-06 00:00:00
abstract::STAT1, which carries tumor suppressor functions in several models, consists of two isoforms, namely STAT1α and STAT1β. The biological function and significance of STAT1β has never been examined in human cancer. We examined STAT1β function in esophageal squamous cell carcinoma (ESCC) by transfecting a STAT1β gene into ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.481
更新日期:2017-10-05 00:00:00
abstract::Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p21-mediated PLK1 re...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.527
更新日期:2014-01-09 00:00:00
abstract::The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT a...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03235-w
更新日期:2020-12-11 00:00:00
abstract::Senescence is an antiproliferative mechanism that can suppress tumor development and can be induced by oncogenes such as genes of the Ras family. Although studies have implicated bioactive sphingolipids (SL) in senescence, the specific mechanisms remain unclear. Here, using MCF10A mammary epithelial cells, we demonstr...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03281-4
更新日期:2021-01-04 00:00:00
abstract::Altered mitochondrial metabolism acts as an initial cause for cardiovascular diseases and metabolic intermediate succinate emerges as a mediator of mitochondrial dysfunction. This work aims to investigate whether or not extracellular succinate accumulation and its targeted G protein-coupled receptor-91 (GPR91) activat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0708-5
更新日期:2018-06-04 00:00:00
abstract::In Slavic folklore, Koschei the Immortal was bony, thin and lean. Was his condition caused by severe calorie restriction (CR)? CR deactivates the target of rapamycin pathway and slows down aging. But the life-extending effect of severe CR is limited by starvation. What if Koschei's anti-aging formula included rapamyci...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/cddis.2014.520
更新日期:2014-12-04 00:00:00
abstract::Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-02845-8
更新日期:2020-08-13 00:00:00
abstract::The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX wo...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.108
更新日期:2017-03-16 00:00:00
abstract::miRNAs have emerged as a pivotal component of gene regulatory networks, mediating cytokines secretion, cell cycle, and differentiation regulation. However, how miRNAs collaborate with transcription factors and downstream effector proteins that determine the fate of ovarian cancer cells remains to be understood, especi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2501-5
更新日期:2020-05-11 00:00:00
abstract::Despite successful antiretroviral drug therapy, a subset of human immunodeficiency virus-1 (HIV)-positive individuals still display synaptodendritic simplifications and functional cognitive impairments referred to as HIV-associated neurocognitive disorders (HANDs). The neurological damage observed in HAND subjects can...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1920-7
更新日期:2019-09-12 00:00:00
abstract::Upregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. The...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.103
更新日期:2017-03-16 00:00:00
abstract::Quantitative and kinetic analyses of apoptotic cell death are integral components of exploring cell biology, measuring cellular stress responses, and performing high-throughput genomic/RNAi/drug screens. Here, we present a detailed method that integrates robust kinetic real-time high-content imaging with Annexin V lab...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.332
更新日期:2016-12-01 00:00:00
abstract::Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of N...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.132
更新日期:2017-03-23 00:00:00
abstract::The development of nephrotoxicity largely limits the clinical use of chemotherapy. MiRNAs are able to target various genes and involved in the regulation of diverse cellular processes, including cell apoptosis and death. Our study showed that miR-181a expression was significantly increased after 5-fluorouracil (5-FU) ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0677-8
更新日期:2018-05-23 00:00:00
abstract::HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome represents a life-threatening pregnancy disorder with high fetal and maternal mortality, but its underlying molecular mechanisms remain unknown. Although apoptosis has been implicated in HELLP syndrome, its pathogenic role remains largely unclear. In th...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.408
更新日期:2013-10-24 00:00:00
abstract::Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1711-1
更新日期:2019-06-17 00:00:00
abstract::miRNA let-7e is involved in stem cell differentiation, and metalloproteinases are among its potential target genes. We hypothesized that the inhibitory action of let-7e on regulation of MMP9 expression could represent a crucial mechanism during differentiation of adipose-derived stem cells (ASCs). ASCs were differenti...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.2
更新日期:2014-02-06 00:00:00
abstract::Missense mutations in TP53 comprise >75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug r...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.80
更新日期:2017-03-09 00:00:00
abstract::Pentose phosphate pathway (PPP) is a major glucose metabolism pathway, which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here we demonstrate ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0635-5
更新日期:2018-05-01 00:00:00
abstract::Chemotherapy is a standard treatment for non-small-cell lung cancer (NSCLC). However, the dose-limiting toxicity of drugs and the development of chemoresistance are major clinical challenges to successful management of NSCLC. Asian traditional medicine is gaining global attention as a non-toxic alternative to chemothe...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0277-7
更新日期:2018-02-14 00:00:00
abstract::Glial cell line-derived neurotrophic factor (GDNF) has strong neuroprotective and neurorestorative effects on dopaminergic (DA) neurons in the substantia nigra (SN); however, the underlying molecular mechanisms remain to be fully elucidated. In this study, we found that the expression level of transcription factor Six...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.120
更新日期:2016-05-05 00:00:00
abstract::Mechanisms underlying the generation of induced pluripotent stem cells (iPSC) and keeping iPSC stability remain to be further defined. Accumulated evidences showed that iPSC reprogramming may be controlled by the cell-division-rate-dependent model. Here we reported effects of absence of mouse p27 or p18 on iPSC genera...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1502-8
更新日期:2019-03-20 00:00:00
abstract::Poly(ADP-ribose) polymerase 1 (PARP1) regulates gene transcription in addition to functioning as a DNA repair factor. Forkhead box O1 (FoxO1) is a transcription factor involved in extensive biological processes. Here, we report that PARP1 binds to two separate motifs on the FoxO1 promoter and represses its transcripti...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2265-y
更新日期:2020-01-28 00:00:00
abstract::Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for pat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.391
更新日期:2014-10-02 00:00:00
abstract::Cell death plays a pivotal role in animal development and tissue homeostasis. Dysregulation of this process is associated with a wide variety of human diseases, including developmental and immunological disorders, neurodegenerative diseases and tumors. While the fundamental role of JNK pathway in cell death has been e...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2135-7
更新日期:2019-11-26 00:00:00
abstract::Pyroptosis is a highly inflammatory form of programmed cell death that is caused by infection with intracellular pathogens and activation of canonical or noncanonical inflammasomes. The purinergic receptor P2X7 is activated by the noncanonical inflammasome and contributes essentially to pyroptotic cell death. The Ca2+...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0373-8
更新日期:2018-02-20 00:00:00