Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review DOI Creative Commons
Hannah R. Bolland, Stephen T. Tiffany, Syafiq Ramlee

et al.

Biochemical Society Transactions, Journal Year: 2021, Volume and Issue: 49(3), P. 1251 - 1263

Published: May 18, 2021

Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant radiation. The biological response one few physiologically relevant stresses that activates both the unfolded protein DNA damage responses (UPR DDR). Links between these pathways have been identified in studies carried out normoxia. Based part on previous recent work from our laboratory, we hypothesised likely includes overlap DDR UPR. While inhibition recognised strategy improving radiation response, possibility achieving this through targeting UPR has not realised. We systematic review identify links UPR, human cell lines exposed <2% O2. Following PRISMA guidance, literature January 2010 October 2020 were retrieved via Ovid MEDLINE evaluated. A total 202 included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 SP1 highlighted as potential hypoxic Overall, very which demonstrate molecular link hypoxia, however, it clear many molecules warrant further investigation under may include novel therapeutic targets improve radiotherapy response.

Language: Английский

ATR/CHK1 inhibitors and cancer therapy DOI
Zhaojun Qiu,

Nancy L. Oleinick,

Junran Zhang

et al.

Radiotherapy and Oncology, Journal Year: 2017, Volume and Issue: 126(3), P. 450 - 464

Published: Oct. 19, 2017

Language: Английский

Citations

270
DNA damage kinase signaling: checkpoint and repair at 30 years DOI Open Access
Michael C. Lanz, Diego Dibitetto, Marcus B. Smolka

et al.

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(18)

Published: Aug. 8, 2019

Language: Английский

Citations

243
Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids DOI Creative Commons

Stephen Riffle,

Rashmi S. Hegde

Journal of Experimental & Clinical Cancer Research, Journal Year: 2017, Volume and Issue: 36(1)

Published: Aug. 3, 2017

Under hypoxic conditions, tumor cells undergo a series of adaptations that promote evolution more aggressive phenotype including the activation DNA damage repair proteins, altered metabolism, and decreased proliferation. Together these changes mitigate negative impact oxygen deprivation allow preservation genomic integrity proliferative capacity, thus contributing to growth metastasis. As result presence microenvironment is considered clinical feature many solid tumors. Hypoxic niches in tumors also represent therapeutically privileged environment which chemo- radiation therapy less effective. Although hypoxia has been well established, precise effect on cell behavior, molecular signals survive vivo are poorly understood. Multicellular spheroids (MCTS) have used as an vitro model for avascular niche, capable accurately recreating profiles predicting therapeutic response. However, relatively few studies MCTS study mechanisms driving within environment. Here we will review what known about proliferation, repair, metabolic pathways modeled comparison observations made A definition populations present 3D models could better inform our understanding heterogeneity provide representative platform testing strategies.

Language: Английский

Citations

182
Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter DOI Open Access
Tord Hompland,

Christina S. Fjeldbo,

Heidi Lyng

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(3), P. 499 - 499

Published: Jan. 28, 2021

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier cancer treatment. The distribution of hypoxia levels highly heterogeneous, ranging from mild, almost non-hypoxic, to severe anoxic levels. individual induce variety biological responses that impair the treatment effect. A stronger focus on rather than absence or presence our investigations will help development improved strategies treat patients hypoxic tumors. Current knowledge how are sensed by cells mediate cellular promote resistance comprehensive. Recently, it has become evident also an important, more unexplored role interaction between cells, stroma immune influencing composition structure microenvironment. Establishment such processes depend level requires advanced models methodology. In this review, we describe promising model systems tools for We further present current emerging research levels, discuss their impact novel therapeutic approaches overcome barrier.

Language: Английский

Citations

134
Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages DOI Creative Commons
Charlotte K.Y. Ng, Eva Dazert,

Tuyana Boldanova

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 4, 2022

Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional translational control, signaling transduction, metabolism are dysregulated differentially regulated the genomic, transcriptomic, proteomic phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, Wnt-β-catenin, AKT/mTOR Notch pathways, cycle DNA damage regulation. The targetable aurora kinase A CDKs upregulated. CTNNB1 TP53 mutations associated with altered protein phosphorylation actin filament organization lipid metabolism, respectively. Integrative clusters show that HCC constitutes heterogeneous subgroups distinct regulation biological processes, metabolic reprogramming activation. Our study provides a comprehensive overview phophoproteomic landscapes HCCs, revealing major pathways (phospho)proteome.

Language: Английский

Citations

109
Tumour hypoxia in driving genomic instability and tumour evolution DOI

Alexandru Suvac,

Jack Ashton, Robert G. Bristow

et al.

Nature reviews. Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

Citations

3
Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells DOI Open Access
Ross Carruthers, Shafiq U. Ahmed,

Shaliny Ramachandran

et al.

Cancer Research, Journal Year: 2018, Volume and Issue: 78(17), P. 5060 - 5071

Published: July 5, 2018

Abstract Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable recurrence, both of which are driven subpopulation GBM cancer stem–like cells (GSC) with tumorigenic self-renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants upregulated DNA-damage response (DDR) subsequent radiation in unknown represent significant barrier to developing effective treatments. In this study, we show that constitutive DDR activation high levels DNA replication stress (RS). CD133+ exhibited reduced velocity higher frequency stalled forks than CD133− non-GSC vitro; immunofluorescence studies confirmed these observations panel orthotopic xenografts human specimens. Exposure low-level exogenous RS generated vitro, confirming as novel determinant cells. double-strand breaks, colocalized “replication factories” RNA: hybrids. also demonstrated increased expression long neural genes (>1 Mbp) containing common fragile sites, supporting hypothesis replication/transcription collisions likely cause GSC. Targeting combined inhibition ATR PARP (CAiPi) provided GSC-specific cytotoxicity complete abrogation vitro. These data identify stem cell–specific target clinical potential. Significance: findings shed new light on cell biology reveal therapeutics potential improve outcomes overcoming inherent radioresistance GBM. Cancer Res; 78(17); 5060–71. ©2018 AACR.

Language: Английский

Citations

140
Hypoxia and the phenomenon of immune exclusion DOI Creative Commons
Violena Pietrobon, Francesco M. Marincola

Journal of Translational Medicine, Journal Year: 2021, Volume and Issue: 19(1)

Published: Jan. 6, 2021

Abstract Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, exclusion lymphocytes from tumor nest common phenomenon that limits efficiency in solid tumors. Despite several mechanisms proposed during years to explain immune excluded phenotype, at present, there no integrated understanding about role played by different models human cancers. Hypoxia hallmark most tumors and, being multifaceted complex condition, shapes unique way microenvironment, affecting gene transcription chromatin remodeling. In this review, we speculate an upstream for hypoxia as biological determinant We also discuss current state ex vivo imaging hypoxic determinants relation T cell distribution could discover functional-morphological features support clinical monitoring.

Language: Английский

Citations

84
Hypoxia Mediates Tumor Malignancy and Therapy Resistance DOI
Weibo Luo, Yingfei Wang

Advances in experimental medicine and biology, Journal Year: 2019, Volume and Issue: unknown, P. 1 - 18

Published: Jan. 1, 2019

Language: Английский

Citations

79
Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities DOI Creative Commons
Claire Beckers, Martin Pruschy, Irene Vetrugno

et al.

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 98, P. 19 - 30

Published: Nov. 29, 2023

Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute a reduced sensitivity hypoxic tumor cells ionizing radiation hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation between the individual fractions, nevertheless hypoxia still remains major hurdle for successful outcome. The technological advances achieved image guidance highly conformal dose delivery make it nowadays possible prescribe larger doses as part single high-dose or hypofractionated radiotherapy, while keeping acceptable level normal tissue complication co-irradiated organs at risk. However, we insufficiently understand impact high-doses RT RT. So called FLASH which delivers ultra-high rates (> 40 Gy/sec), has recently emerged breakthrough field reduce toxicity compared irradiation (few Gy/min). Not surprisingly, oxygen consumption also seem play intriguing role Here will discuss general context novel approaches.

Language: Английский

Citations

38