Harnessing cytokines and chemokines for cancer therapy

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 19(4), P. 237 - 253

Published: Jan. 7, 2022

Language: Английский

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Targeting TGF-β signal transduction for fibrosis and cancer therapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: April 23, 2022

Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, adult homeostasis. The role of TGF-β fibrosis cancer is complex sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage disease. Under pathological conditions, overexpressed causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, cancer. Given critical downstream molecules progression cancers, therapeutics targeting signaling appears be a promising strategy. However, due potential systemic cytotoxicity, lagged. In this review, we summarized biological process TGF-β, dual tumorigenesis, clinical application TGF-β-targeting therapies.

Language: Английский

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Dynamic EMT: a multi‐tool for tumor progression

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(18)

Published: Aug. 30, 2021

Review30 August 2021Open Access Dynamic EMT: a multi-tool for tumor progression Simone Brabletz Corresponding Author [email protected] orcid.org/0000-0003-0936-1526 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center Molecular Medicine, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany Search more papers by this author Harald Schuhwerk orcid.org/0000-0001-6971-3760 Thomas orcid.org/0000-0003-2983-9048 Marc P. Stemmler orcid.org/0000-0002-7866-3686 Information *,1, Schuhwerk1, Brabletz1 and *,1 1Department *Corresponding author. Tel: +49 9131 85 29101; E-mail: The EMBO Journal (2021)40:e108647https://doi.org/10.15252/embj.2021108647 This article is part the Cancer Reviews 2021 series. PDFDownload PDF text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract process epithelial–mesenchymal transition (EMT) fundamental embryonic morphogenesis. Cells undergoing it lose epithelial characteristics integrity, acquire mesenchymal features, become motile. In cancer, program hijacked confer essential changes in morphology motility that fuel invasion. addition, EMT increasingly understood orchestrate large variety complementary cancer such as cell stemness, tumorigenicity, resistance therapy adaptation microenvironment. review, we summarize recent findings related these various classical non-classical functions, introduce true tumorigenic multi-tool, involved many aspects cancer. We suggest therapeutic targeting will—if acknowledging complexities—be possibility concurrently interfere with on levels. Introduction Epithelial-to-mesenchymal describes transdifferentiation stationary cells mesenchymal, motile phenotype was initially observed early development (Hay, 1995). Here, contributes embryonal processes like gastrulation, neural crest formation, or heart (Thiery et al, 2009; Nieto 2016). also crucial physiological wound healing (Arnoux 2008) tissue homeostasis (Ahmed 2006). Importantly, pathological reactivation plays role diseases organ fibrosis metastasis (Fig 1A), which focus review. Figure 1. Classical functions (A) frequently occurs at invasive front tumors, destroys well-defined structures, allows migrate, invade tissue, intravasate blood lymphatic vessels. Tumor their way through body can travel single cells, clusters exhibiting partial headed leader cell. At secondary site, extravasate colonize distant organ, where MET outgrowth macrometastases. (B) induced mainly set transcription factors (EMT-TFs) ZEB1, ZEB2, SNAIL, SLUG TWIST differ protein structure, size, individual functions. All them are repressors E-cadherin activate markers Vimentin, Fibronectin N-cadherin. Epithelial displaying apical–basal polarity held together tight junctions, adherens desmosomes anchored underlying basement membrane hemidesmosomes. They express three different complexes junctional molecules maintain polarity. EMT, expression EMT-TFs leads inhibition major components structures concomitantly activates genes associated state. gain front–rear polarity, display actin stress fibers, capacities. Notably, very rarely switch completely phenotype, but fluently convert between intermediate states certain features keeping sets characteristics. Further, reversible process. Mesenchymal revert state MET. An important execution played microRNAs miR-200 mir-34 families regulated double-negative feedback loops ZEB1/2 respectively, serve reinforce either Download figure PowerPoint an extremely complex diverse disease not only varying entities, within same entity, subtypes, even subtypes. tumors spatial temporal heterogeneity be elicited, e.g., via occurrence consecutive mutations clonal evolution (McGranahan Swanton, 2017). However, plasticity, allowing continuous adaption ever-changing conditions, mediated genetically fixed, depending accumulating mutations, epigenetically orchestrated signals from microenvironment, rendering whole (by activating mesenchymal–epithelial transition; MET) highly dynamic (see overview Fig 2). 2. Overview summarizing multiple oncogenic course progression. allow invade, intra- sites, enables traits support initiation well metastatic colonization. Throughout progression, they help cope changing conditions metabolic reprogramming, enhanced survival altered DNA repair prevention death, immune evasion improved chemo- radiotherapy. supporting handle environmental extracellular from, CAFs microenvironment approaches. executed core EMT-activating including SNAIL (also SNAI1) SNAI2), basic helix–loop–helix TWIST1 (TWIST) TWIST2 zinc finger E-Box binding homeobox ZEB1 ZEB2. share ability repress encoding gene CDH1 motifs cognate promoter regions (Nieto 2016) shown (Batlle 2000; Cano 2000), (Yang 2004), (Eger 2005), ZEB2 (Comijn 2001). parallel, directly indirectly VIM (Vimentin), FN1 (Fibronectin), CDH2 (N-cadherin) 2016; Dongre Weinberg, 2019) 1B). shared, distinct EMT-TFs, patterns size structure (Stemmler 2019). Beyond "classical" traits, motility, capacities, widespread importance biology indicated additional pleiotropic (Brabletz 2018). have been stemness properties increase linking concept stem (CSCs). Additionally, repair, escape senescence apoptosis, resistance, resulting pro-survival providing advantage under types conditions. Altogether, non-redundant context-dependent dynamically (TME) permanently adapt (Puisieux 2014). Consequently, intervention EMT/plasticity will provide opportunity fight blow. all highlight clinical implications. Classical/core Migration invasion normal form protective sheets structural integrity. connection junction junction, desmosomes, junctions seal located apical constitute barrier solutes water. apical-basal function, has defined "asymmetry" tissues. Polarity complexes, Par, Crumbs, Scribble ensure proper organization versus basolateral domains (Huang 2012). Of note, some control regulate spindle orientation division mode (Martin-Belmonte Perez-Moreno, 2011) Elicited TME, activation toward malignancy, accompanied substantial cellular Cell–cell contacts deconstructed repression CDH1, cadherin (E-cadherin), constituent coding other molecules. As consequence disintegration direct transcriptional several members Crumbs lost (Aigner 2007; Moreno-Bueno 2008; Spaderna Lamouille 2014) coincides profound cytoskeletal reorganization constriction, formation conversion cuboidal columnar shapes spindle-like elongated forms (Moreno-Bueno 2008). Newly formed actin-rich protrusions lamellipodia filopodia movement. To surrounding tissues, induce invadopodia, specialized proteolytic function (Yilmaz Christofori, Eckert 2011; Ridley, Sundararajan 2015). supported induction matrix metalloproteases degradation adjacent tissues (Miyoshi 2004; Miyoshi 2005; Huang 2009) inducers prevent synthesis repressing its (Spaderna events cause loss integrity dissemination thus execute first step cascade 1A). MET: colonization 1990, Fearon Vogelstein proposed meanwhile genetic model colorectal tumorigenesis. described deterioration greater malignancy driven stepwise accumulation hypothesized perpetuates during last established malignant carcinoma metastases, implying metastases most degenerated (Fearon Vogelstein, 1990). efforts identify specific metastasis-associated remained unsuccessful. Rather, already twenty years ago, compared de-differentiated nature primary tumor, exhibit re-differentiated morphology, similar center These led hypothesis de-differentiation transient condition opposing re-differentiation needs initiated advantageous macrometastases (Figs 1A But why do re-differentiate? Invasive, were growth arrested, whereas proliferation detected metastasis, suggesting must reversed order fact inhibit 3). There publications confirming relevance (Chaffer 2006; Korpal Ocana 2012; Tsai perfect accordance failure EMT-causing attributed epigenetic regulation 3. Cellular plasticity governed provided window phenotypes cells. Drug sensitivity, proliferation, response apoptosis highest states, drug efflux, invasion, states. A hybrid provides maximal capacity, changes. Note extreme initiation, lost. Whereas investigated great detail below), less known about trigger reverse Is just lack EMT-inducing stimuli coupled reduced EMT-TFs? Several studies could show knockdown EMT-TF sufficient elicit vitro lines entities depletion Zeb1 mouse pancreatic fixes (Krebs Once ZEB-family (ZEB1 ZEB2) declines, reduction reinforced loop family microRNAs. During ZEB transcriptionally members. Vice versa, post-transcriptional level Thus, bidirectional transitions potentiated ZEB/miR-200 circuit (Bracken Burk Wellner 2009). branch inducible tumor-suppressor p53, miR-200s (Kim 2011). Upregulation consequences. It exerts both invasion- migration-inhibiting, tumor-suppressing (Peter, 2009), promotes (Korpal controversial, EMT-MET adapting respective Similar negative loop, miR-34 regulatory (Siemens Diaz-Lopez target themselves, BMI1, CD44, CD133, JAG1, MYC tumor-relevant "non-classical" discussed below Brabletz, 2010; Since slow multistep take requires different, sometimes apparently spatiotemporal manner, valid investigation remains challenging rely models. Recently, focusing EMT/MET using elegant 2012, al (2012) demonstrated induction, case TWIST, supports skin subsequent Twist1 downregulation necessary (Tsai 2012) Another study necessity MMTV-PyMT breast disseminate lung. EMT-state niche local fibroblasts turn (MET) (del Pozo Martin Esposito colleagues found E-selectin adhesion bone vascular elicits (Esposito summary, reports significance detailed still need further investigation. Partial long viewed binary separate populations. past, narrow perspective challenged means metastasis. One example analysis Fischer Fsp1-Cre lineage tracing Based finding lung consist had never switched full Fsp1+ authors concluded (Fischer nowadays accepted that, although reactivated types, fully end-stage Vimentin often expressed. rather gradual incomplete, termed Pastushenko Blanpain, 2019; Yang 2020) Over years, report vivo detection carrying combination markers. Already 1990s, analyses reported observations (Mareel 1992; Birchmeier Behrens, 1994). Later, circulating (CTCs) simultaneous (Yu 2013). Similarly, identified co-expression (EpCAM+) (Vim+) marker autochthonous murine prostate (Ruscetti linked single-cell transcriptomics head neck (Puram group occurring introduced term "hybrid" (Pastushenko 2018; 2021) Moreover, Bornes used (2015) incapable detecting majority disseminating partial/hybrid 2015; does mean important. evidence traps profoundly suppresses mammary (Ye oncogene-induced model, Xu (2017) required small subset (Xu Interestingly, modes involve levels observed. groups forming clusters. Indeed, type "collective migration" might common than dissemination, approaches clustered circulation (Friedl Aceto 2014; Cheung Nevertheless, despite appearance, characteristic detectable migrating (Aiello 2018), follow "leader" pave "follower" (Matise Chen Non-classical Besides drive phenotypes, regulating tumorigenesis Regulation Normal dependent source replenish dying committed terminally differentiated tissue. observation maintained after transplantations into mice, prompted (Reya Simplified, measured capability fractions mice. Strikingly, capacity increasing Shibue 2017; Wilson Overexpression SNAI1, TWIST1, CD44+/CD24lo pool, increased sphere vitro, elevated tumorigenicity (Mani Morel determines healthy gland converts luminal settings (Guo results obtained key determinant reciprocal ZEB1/miR-200 controlling BMI1 SOX2 (Shimono Krebs squamous (SCC) cooperatively CDKN2A (p16INK4A) promote capacities 2010). protocadherin FAT1 one player stemness. inactivated SCC involving CAMK2, SRC activities nuclear translocation YAP1 2021). another promoting factor, PRRX1, thereby uncoupling EMT/migration (Ocana PRRX1 isoform switching driving force (Takano Mechanistically, realm correlate gradually efficiencies seeding line idea addition (Shibue 2013; 2020), transformation. upregulation RAS transformed bronchial unleash favoring aggressive undifferentiated (Morel Liu 2014b; Larsen KRAS dependency (KRAS addiction) thresholds KRAS-dependent (Singh 2014b). effects evident ectopic Zeb2 intestinal epithelium transgenic Elevation generates absence cooperating defects (Slowicka 2020). Therapy Loss durable efficacy relapse initial successful treatment obstacles battle against Conventional favorably eliminating non-stem cell-like fails deplete properties. Settleman, Santamaria Dudas signatures acquisition strongly correlated, standard targeted EGFR PI3K inhibitors (Creighton Farmer Byers For example, gemcitabine-resistant Panc1 sensitized upon (Wellner routes include efflux evading anoikis former ATP-binding cassette (ABC) transporter family, FOXC1 (Aller Singh Saxena contribute therapy-induced interfering p53 PTEN, BCL-XL (Vega Escriva Kurrey Wu Cao Experimentally HMLER 10-fold IC50 doses chemotherapeutics (Gupta Tulchinsky experiments, GFP-labeled PyMT high cyclophosphamide non-small-cell (NSCLC), AXL receptor tyrosine kinase inhibition, sustained activity Sequist Zhang Furthermore, HDAC class I demethylation resensitizes osteosarcoma chemotherapy (Meidhof

Language: Английский

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Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: July 29, 2022

Abstract Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which called abscopal effect. The view RT as a simple treatment has dramatically changed in recent years, it now widely accepted that provoke immune response gives strong rationale the combination immunotherapy (iRT). Nevertheless, several points remain to be addressed such interaction system, identification best schedules with (IO), expansion mechanism amplify iRT. To answer these crucial questions, we roundly summarize underlying showing whole landscape clinical trials attempt identify In consideration rarity effect, propose occurrence induced by radiation promoted 100% molecular genetic level. Furthermore, “radscopal effect” refers using low-dose reprogram microenvironment may overcome resistance Taken together, could regarded trigger antitumor response, help IO used radical added into current standard regimen patients metastatic cancer.

Language: Английский

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Tumor microenvironment: barrier or opportunity towards effective cancer therapy

Journal of Biomedical Science, Journal Year: 2022, Volume and Issue: 29(1)

Published: Oct. 17, 2022

Abstract Tumor microenvironment (TME) is a specialized ecosystem of host components, designed by tumor cells for successful development and metastasis tumor. With the advent 3D culture advanced bioinformatic methodologies, it now possible to study TME’s individual components their interplay at higher resolution. Deeper understanding immune cell’s diversity, stromal constituents, repertoire profiling, neoantigen prediction TMEs has provided opportunity explore spatial temporal regulation therapeutic interventions. The variation TME composition among patients plays an important role in determining responders non-responders towards cancer immunotherapy. Therefore, there could be possibility reprogramming overcome widely prevailing issue immunotherapeutic resistance. focus present review understand complexity comprehending future perspective its as potential targets. later part describes sophisticated models emerging valuable means extensive account tools profile predict neoantigens. Overall, this provides comprehensive current knowledge available target TME.

Language: Английский

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TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 5, 2023

Abstract Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express total 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They class ion found in numerous tissues cell types permeable to wide range cations such as Ca 2+ , Mg Na + K others. responsible various sensory responses including heat, cold, pain, stress, vision taste activated by number stimuli. Their predominantly location the surface, their interaction with physiological signaling pathways, unique crystal structure make TRPs attractive drug targets implicate them treatment diseases. Here, we review history discovery, summarize structures functions family, highlight current understanding role pathogenesis human disease. Most importantly, describe channel-related therapeutic interventions diseases limitations targeting clinical applications.

Language: Английский

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Transforming growth factor-β in myocardial disease

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(7), P. 435 - 455

Published: Jan. 4, 2022

Language: Английский

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Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: March 1, 2021

Cancer is a disease which frequently has poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments impedes the clinical outcomes. Besides active driven by genetic epigenetic alterations in tumor cells, microenvironment (TME) also reported be crucial regulator tumorigenesis, progression, resistance. Here, we propose that adaptive mechanisms of are closely connected with TME rather than depending on non-cell-autonomous changes response treatment. comprehensive understanding need further investigation fully elucidate resistance, many targeting successful. In this review, report recent advances concerning molecular events important factors involved TME, particularly focusing contributions provide insights into potential methods or translational medicine overcome therapy

Language: Английский

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Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 2, 2023

Abstract Despite centuries since the discovery and study of cancer, cancer is still a lethal intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as pivotal component tumor microenvironment. The versatility sophisticated mechanisms CAFs in facilitating progression been elucidated extensively, including promoting angiogenesis metastasis, inducing drug resistance, reshaping extracellular matrix, developing an immunosuppressive Owing to their robust tumor-promoting function, are considered promising target for oncotherapy. However, highly heterogeneous group cells. Some subpopulations exert inhibitory role growth, which implies that CAF-targeting approaches must be more precise individualized. This review comprehensively summarize origin, phenotypical, functional heterogeneity CAFs. More importantly, we underscore advances strategies clinical trials CAF various cancers, also progressions immunotherapy.

Language: Английский

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TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer

Gastroenterology, Journal Year: 2021, Volume and Issue: 161(2), P. 434 - 452.e15

Published: April 30, 2021

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator tissue renewal, TGF-β downstream SMAD-dependent transcriptional events play complex roles transition from noncancerous disease state to cancer tract, liver, pancreas. Furthermore, this pathway also regulates stromal cells immune system, which may contribute evasion tumors immune-mediated elimination. Here, we review involvement mediated by regulators SMADs progression digestive The integrates human genomic studies with animal models that provide clues toward understanding managing complexity cancer.

Language: Английский

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