Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression

Science ◽  
2020 ◽  
Vol 369 (6501) ◽  
pp. eaay1813 ◽  
Author(s):  
Sachiko Taniguchi ◽  
Ajit Elhance ◽  
Avery Van Duzer ◽  
Sushil Kumar ◽  
Justin J. Leitenberger ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Immunoglobulin E ◽  
Transforming Growth Factor Β ◽  
Drug Resistant ◽  
Tumor Initiating Cells ◽  
Interleukin 33 ◽  
High Affinity ◽  
Feedforward Loop ◽  
Close Proximity

Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33–responding FcεRIα+ macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33–TGF-β feedforward loop could potentially be exploited for cancer treatment.

scholarly journals Comment on “Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression”

Science ◽  
2021 ◽  
Vol 372 (6538) ◽  
pp. eabf2022
Author(s):  
Jasper B. J. Kamphuis ◽  
William P. M. Worrall ◽  
Julien Stackowicz ◽  
Aurélie Mougel ◽  
Emilie Mauré ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immunoglobulin E ◽  
Research Articles ◽  
Tumor Initiating Cells ◽  
Tumor Associated Macrophages ◽  
Interleukin 33

Taniguchi et al. (Research Articles, 17 July 2020, p. 269) claim that the cytokine interleukin-33 induces accumulation of tumor-associated macrophages expressing the immunoglobulin E receptor FcεRI. Although these findings hold great therapeutic promise, we provide evidence that the anti-FcεRI antibody used in this study is not specific for FcεRI on macrophages, which raises concerns about the validity of some of the conclusions.

scholarly journals Response to Comment on “Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression”

Science ◽  
2021 ◽  
Vol 372 (6538) ◽  
pp. eabf3316
Author(s):  
Sachiko Taniguchi ◽  
Ajit Elhance ◽  
Avery Van Duzer ◽  
Sushil Kumar ◽  
Justin Leitenberger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cell ◽  
Cancer Progression ◽  
Squamous Cell ◽  
Immunoglobulin E ◽  
Marrow Cell ◽  
Squamous Cell Carcinomas ◽  
Nonspecific Binding ◽  
Tumor Initiating Cells ◽  
High Affinity

Kamphuis et al. argue that macrophages accumulated in the proximity of tumor-initiating cells do not express the high-affinity immunoglobulin E receptor FcεRIα. Although we cannot exclude the possibility of nonspecific binding of anti-FcεRIα antibody (clone MAR-1), we provide evidence that macrophages in squamous cell carcinomas express FcεRIα and that IL-33 induces FcεRIα expression in bone marrow cell–derived macrophages.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Dichotomous roles of TGF-β in human cancer

2016 ◽  
Vol 44 (5) ◽  
pp. 1441-1454 ◽  
Author(s):  
Jennifer J. Huang ◽  
Gerard C. Blobe
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Biological Processes ◽  
Cellular Homeostasis ◽  
Angiogenic Therapy ◽  
Promising Strategy

Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.

The human NUPR1/P8 gene is transcriptionally activated by transforming growth factor β via the SMAD signalling pathway

2012 ◽  
Vol 445 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Roxane M. Pommier ◽  
Johann Gout ◽  
David F. Vincent ◽  
Carla E. Cano ◽  
Bastien Kaniewski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Stress Resistance ◽  
Nuclear Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transcriptional Level ◽  
Smad Proteins ◽  
Activation Cascade ◽  
Tgfβ Superfamily

NUPR1 (nuclear protein 1), also called P8 (molecular mass 8 kDa) or COM1 (candidate of metastasis 1), is involved in the stress response and in cancer progression. In the present study, we investigated whether human NUPR1 expression was regulated by TGFβ (transforming growth factor β), a secreted polypeptide largely involved in tumorigenesis. We demonstrate that the expression of NUPR1 was activated by TGFβ at the transcriptional level. We show that this activation is mediated by the SMAD proteins, which are transcription factors specifically involved in the signalling of TGFβ superfamily members. NUPR1 promoter analysis reveals the presence of a functional TGFβ-response element binding the SMAD proteins located in the genomic DNA region corresponding to the 5′-UTR (5′-untranslated region). Altogether, the molecular results of the present study, which demonstrate the existence of a TGFβ/SMAD/NUPR1 activation cascade, open the way to consider and investigate further a new mechanism enabling TGFβ to promote tumorigenesis by inducing stress resistance.

scholarly journals Adipose Tissue-Derived Mesenchymal Stem Cell Modulates the Immune Response of Allergic Rhinitis in a Rat Model

2019 ◽  
Vol 20 (4) ◽  
pp. 873 ◽  
Author(s):  
Nesrine Ebrahim ◽  
Yasser Mandour ◽  
Ayman Farid ◽  
Ebtesam Nafie ◽  
Amira Mohamed ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Adipose Tissue ◽  
Rat Model ◽  
Transforming Growth Factor ◽  
Immunoglobulin E ◽  
Physiological Saline ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Albino Rats ◽  
Microscopical Examination

This study was designed to investigate the potential effects and underlying mechanism of adipose tissue-derived mesenchymal stem cells (MSCs) on allergic inflammation compared to Montelukast as an antileukotriene drug in a rat model of allergic rhinitis (AR). The effect of MSCs was evaluated in albino rats that were randomly divided into four (control, AR, AR + Montelukast, and AR + MSCs) groups. Rats of AR group were sensitized by ovalbumin (OVA) and then challenged with daily nasal drops of OVA diluted in sterile physiological saline (50 μL/nostril, 100 mg/mL, 10% OVA) from day 15 to day 21 of treatment with/without Montelukast (1 h before each challenge) or MSCs I/P injection (1 × 106 MCSs; weekly for three constitutive weeks). Both Montelukast and MSCs treatment started from day 15 of the experiment. At the end of the 5th week, blood samples were collected from all rats for immunological assays, histological, and molecular biology examinations. Both oral Montelukast and intraperitoneal injection of MSCs significantly reduced allergic symptoms and OVA-specific immunoglobulin E (IgE), IgG1, IgG2a and histamine as well as increasing prostaglandin E2 (PGE2). Further analysis revealed that induction of nasal innate cytokines, such as interleukin (IL)-4 and TNF-α; and chemokines, such as CCL11 and vascular cell adhesion molecule-1 (VCAM-1), were suppressed; and transforming growth factor-β (TGF-β) was up-regulated in Montelukast and MSCs-treated groups with superior effect to MSCs, which explained their underlying mechanism. In addition, the adipose tissue-derived MSCs-treated group had more restoring effects on nasal mucosa structure demonstrated by electron microscopical examination.

scholarly journals Alteration in transforming growth factor-β receptor expression in gallbladder disease: implications of chronic cholelithiasis and chronic Salmonella typhi infection

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Yogesh D. Walawalkar ◽  
Yatindra Vaidya ◽  
Vijayashree Nayak
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Receptor Gene ◽  
Gallbladder Disease ◽  
Fold Increase ◽  
Transforming Growth Factor Β ◽  
Salmonella Typhi ◽  
Receptor Expression ◽  
Β Receptor

Gallbladder cancer prevalence is ever increasing with <em>Salmonella typhi</em> chronic infection being one of the predisposing factors. Altered ratios or expression of transforming growth factor-β (TGF-β) receptors and changes in its function are associated with loss in anti-proliferative effects of TGF-β and cancer progression. Using reverse transcriptase polymerase chain reaction we monitor any changes in TGF-β receptor gene expression. We simultaneously screen for <em>S. typhi</em> within the samples. From 73 patients undergoing cholecystectomy 39-50% had significant expression (P&lt;0.05) of TGF-β receptor (TβR)- I and TβR-II during chronic cholelithiasis as compared to the remaining 19-23% with acute chronic cholelithiasis. There was no significant increase in TβR-III receptor expression. Patient’s positive for <em>S. typhi</em> (7/73) did not show any significant changes in expression of these receptors, thus indicating no direct relation in regulating the host TGFβ-signaling pathway. Further analysis on expression of downstream Smad components revealed that patients with up-regulated TGFβ receptor expression show &gt;2-fold increase in the RSmads and Co-Smads with a &gt;2-fold decrease in I-Smads. Thus gain of TβR-I and II expression in epithelial cells of the gallbladder was associated with chronic inflammatory stages of the gallbladder disease.

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