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| Open AccessSoluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment
IL-33 is a pro-inflammatory cytokine with a role in colorectal cancer. Here, the authors show that circulating tumour-derived sST2, an IL-33 decoy receptor, delayed the growth and progression of colorectal cancer cells by inhibiting Th1/Th2 polarization, macrophage infiltration and angiogenesis.
- Miho Akimoto
- , Riruke Maruyama
- & Keizo Takenaga
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Article
| Open AccessDendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma
Activation and biological function of B cells in cancer are still unclear. Here, the authors show that hepatocarcinoma cells drive the formation of semimature dendritic cells that in turn activate FcγRIIlow/−tumour B cells through the CD95L/CD95 axis, leading to the production of IL-10 and suppression of CD8 T cells.
- Fang-Zhu Ouyang
- , Rui-Qi Wu
- & Dong-Ming Kuang
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Article
| Open AccessCancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers
A reactive tumour stroma is associated with poor prognosis. Here, the authors show that in patients with triple negative breast cancer resident monocytes activate cancer-associated fibroblasts and induce production of CXCL16, which acts as a monocyte chemoattractant, resulting in an amplificatory feedback loop.
- Roni Allaoui
- , Caroline Bergenfelz
- & Karin Leandersson
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Article
| Open AccessObesity-associated NLRC4 inflammasome activation drives breast cancer progression
Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.
- Ryan Kolb
- , Liem Phan
- & Weizhou Zhang
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Article
| Open AccessATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion
Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homeostasis of the tumour microenvironment. Here the authors show that all-trans retinoic acid reduces retinoic acid receptor beta dependent-actomyosin contractility and restores mechanical quiescence in PSCs.
- Antonios Chronopoulos
- , Benjamin Robinson
- & Armando del Río Hernández
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Article
| Open AccessDiscontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism
Anti-VEGF therapy often produces limited beneficial effects in cancer patients. Here, the authors show that discontinuation of anti-VEGF cancer therapy in xenografts-bearing mice increases cancer cells extravasation and intravasation in liver through the host-derived VEGF.
- Yunlong Yang
- , Yin Zhang
- & Yihai Cao
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Article
| Open AccessStromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth
The Hedgehog signalling pathway can drive tumorigenesis. Here, the authors show that in a colitis-associated colon cancer model downstream Hedgehog signalling is restricted to the stroma and its over-activation can inhibit tumorigenesis, associated with activation of BMP signaling.
- Marco Gerling
- , Nikè V. J. A. Büller
- & Rune Toftgård
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Article
| Open AccessEphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance
Ephrins are transmembrane proteins involved in cell-cell communication, and implicated in cancer cell growth and progression. Here, the authors show that EphrinB2 expression is reduced in glioma cells both by genetic and epigenetic alterations and under hypoxia, through a HIF1α-mediated direct regulation of ZEB2, which enhances invasion and anti-angiogenic resistance.
- C. Depner
- , H. zum Buttel
- & A. Acker-Palmer
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Article
| Open AccessStromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.
- Megan K. Ruhland
- , Andrew J. Loza
- & Sheila A. Stewart
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Article
| Open AccessCXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment
Adipose stromal cells (ASC) have been shown to migrate to tumours and promote tumour growth. Using animal models and human tissue samples, the authors show here that ASC recruitment to prostate cancers is mediated by the chemokine CXCL1, which is secreted from tumour cells, and acts on CXCR1 on ASCs.
- Tao Zhang
- , Chieh Tseng
- & Mikhail G. Kolonin
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Article
| Open AccessHypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells
Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. Here, the authors show that caveolin-1 can down-regulate global membrane protein endocytosis in hypoxic cells with potential implications for targeting the hypoxic 3microenvironment of aggressive tumours.
- E. Bourseau-Guilmain
- , J. A. Menard
- & M. Belting
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Article
| Open AccessAdaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer.
- Shohei Koyama
- , Esra A. Akbay
- & Peter S. Hammerman
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Article
| Open AccessC1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation
C1q is known to initiate the activation of the complement classical pathway. Here, the authors show the C1q is expressed in the tumour microenvironment and can promote cancer cell migration and adhesion in a complement activation-independent manner.
- Roberta Bulla
- , Claudio Tripodo
- & Francesco Tedesco
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Article
| Open AccessEpigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts
Carcinoma-associated fibroblasts are key components of solid tumours and associated with poor clinical outcome. Here the authors show that the cytokine LIF initiates an epigenetic switch which results in the sustained invasive activity of the tumour cells.
- Jean Albrengues
- , Thomas Bertero
- & Cedric Gaggioli
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Article
| Open AccessChronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane
The protein LAMP2 functions to protect lysosomal membranes from acid proteolysis. In this study, the authors show that malignant cells adapt to the acidic tumour microenvironment by redirecting LAMP2 from lysosomes to the plasma membrane.
- Mehdi Damaghi
- , Narges K. Tafreshi
- & Robert J Gillies
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Article
| Open AccessSystematic pan-cancer analysis of tumour purity
The importance of the tumour microenvironment has now been realised, however the presence of non-tumour cells in cancer samples can complicate genomic analyses. Here, the authors estimate tumour purity in 10,000 samples from the TCGA dataset and can detect a signature of T cell activation.
- Dvir Aran
- , Marina Sirota
- & Atul J. Butte
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Article
| Open AccessSTAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody
Cixutumumab is an anti-IGF-1R monoclonal antibody and is used to treat cancer; however, tumours can develop resistance to the therapy. Here, the authors show that the resistance is mediated by activation of STAT3 that results in an IGF2/IGF-2R signalling loop and recruitment of macrophages.
- Ji-Sun Lee
- , Ju-Hee Kang
- & Ho-Young Lee
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Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo
As hypoxia is a hallmark of tumour microenvironment, hypoxia-sensing probes are used for tumour imaging. Here, the authors report a hypoxia probe with increased sensitivity, water solubility and functional pH range, allowing in vivodetection of early metastases as small as a few thousand cells.
- Xianchuang Zheng
- , Xin Wang
- & Xiqun Jiang
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Resolving cancer–stroma interfacial signalling and interventions with micropatterned tumour–stromal assays
Gene expression changes at the tumour–stroma interface are associated with epithelial cancer progression. Here, the authors describe a new in vitrosystem based on cell micropatterning and laser microdissection for examining the tumour–stromal interaction.
- Keyue Shen
- , Samantha Luk
- & Biju Parekkadan
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Article
| Open AccessLoss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR
Little is known on how solid tumours overcome growth inhibitory signals within its hypoxic microenvironment. Here Henze et al.show that oxygen sensor PHD3 is frequently lost in gliomas, and that this loss hyperactivates EGFR signaling to sustain tumour cell proliferation and survival in hypoxia.
- Anne-Theres Henze
- , Boyan K. Garvalov
- & Till Acker
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Article
| Open AccessPHD3 regulates EGFR internalization and signalling in tumours
PHD3 is a hypoxia-inducible prolyl hydroxylase that regulates stability of HIF-1. Here Garvalov et al.report a hydroxylase-independent role of PHD3 in gliomas as a scaffolding protein that promotes internalization and limits signalling of EGFR upon ligand binding, thus inhibiting growth in hypoxia.
- Boyan K. Garvalov
- , Franziska Foss
- & Till Acker
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Src activation by β-adrenoreceptors is a key switch for tumour metastasis
The neurotransmitter noradrenaline can regulate cellular processes that contribute to cancer progression, but the underlying mechanisms remain largely unknown. Here the authors identify Src as a key mediator of noradrenaline signalling networks in tumour metastasis.
- Guillermo N. Armaiz-Pena
- , Julie K. Allen
- & Anil K. Sood
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A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
Interactions of cells with extracellular matrix are important in normal physiology and cancer metastasis. Here, an extracellular matrix molecule array is developed and used to show that conserved changes in adhesive properties are associated with metastasis, including binding to fibronectin in combination with galectin-3, galectin-8 or laminin.
- Nathan E. Reticker-Flynn
- , David F. Braga Malta
- & Sangeeta N. Bhatia