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Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
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Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibit extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells display morphological abnormalities. Deletion of the autophagy regulator, ATG7, fails to elicit similar effects, suggesting additional novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice show E-CADHERIN mislocalisation associated with abnormalities in the endocytic trafficking pathway. This provides a mechanism linking endocytic trafficking mediated by BECLIN1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has important implications for our understanding of intestinal pathophysiology.
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Apoptosis , Células Epiteliales , Ratones , Animales , Beclina-1/genética , Beclina-1/metabolismo , Apoptosis/genética , Células Epiteliales/metabolismo , Autofagia/genética , Homeostasis , MamíferosRESUMEN
Deregulation of the Hippo pathway is a driver for cancer progression and treatment resistance. In the context of gastric cancer, YAP1 is a biomarker for poor patient prognosis. Although genomic tumor profiling provides information of Hippo pathway activation, the present study demonstrates that inhibition of Yap1 activity has anti-tumor effects in gastric tumors driven by oncogenic mutations and inflammatory cytokines. We show that Yap1 is a key regulator of cell metabolism, proliferation, and immune responses in normal and neoplastic gastric epithelium. We propose that the Hippo pathway is targetable across gastric cancer subtypes and its therapeutic benefits are likely to be mediated by both cancer cell-intrinsic and -extrinsic mechanisms.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Microambiente Tumoral , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vía de Señalización Hippo , Factor de Transcripción STAT3/metabolismoRESUMEN
Specific signalling thresholds of the WNT/ß-catenin pathway affect embryogenesis and tissue homeostasis in the adult, with mutations in this pathway frequently occurring in cancer. Excessive WNT/ß-catenin activity inhibits murine anterior development associated with embryonic lethality and accounts for the driver event in 80% of human colorectal cancers. Uncontrolled WNT/ß-catenin signalling arises primarily from impairment mutation in the tumour suppressor gene APC that otherwise prevents prolonged stabilisation of ß-catenin. Surprisingly, no inhibitor compounds for WNT/ß-catenin signalling have reached clinical use in part owing to the lack of specific in vivo assays that discriminate between on-target activities and dose-limiting toxicities. Here, we present a simple in vivo assay with a binary outcome whereby the administration of candidate compounds to pregnant and phenotypically normal Apcflox/flox mice can rescue in utero death of Apcmin/flox mutant conceptus without subsequent post-mortem assessment of WNT/ß-catenin signalling. Indeed, the phenotypic plasticity of born Apcmin/flox conceptus enables future refinement of our assay to potentially enable dosage finding and cross-compound comparisons. Thus, we show for the first time the suitability of endogenous WNT/ß-catenin signalling during embryonic development to provide an unambiguous and sensitive mammalian in vivo model to assess the efficacy and bioavailability of potential WNT/ß-catenin antagonists.
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Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
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Inmunidad Innata , Neoplasias Gástricas , Humanos , Ratones , Animales , Interleucina-13/metabolismo , Neoplasias Gástricas/patología , Linfocitos/metabolismo , Hiperplasia/metabolismo , Metaplasia/metabolismoRESUMEN
Tumour heterogeneity is one of the critical confounding aspects in decoding tumour growth. Malignant cells display variations in their gene transcription profiles and mutation spectra even when originating from a single progenitor cell. Single-cell and spatial transcriptomics sequencing have recently emerged as key technologies for unravelling tumour heterogeneity. Single-cell sequencing promotes individual cell-type identification through transcriptome-wide gene expression measurements of each cell. Spatial transcriptomics facilitates identification of cell-cell interactions and the structural organization of heterogeneous cells within a tumour tissue through associating spatial RNA abundance of cells at distinct spots in the tissue section. However, extracting features and analyzing single-cell and spatial transcriptomics data poses challenges. Single-cell transcriptome data is extremely noisy and its sparse nature and dropouts can lead to misinterpretation of gene expression and the misclassification of cell types. Deep learning predictive power can overcome data challenges, provide high-resolution analysis and enhance precision oncology applications that involve early cancer prognosis, diagnosis, patient survival estimation and anti-cancer therapy planning. In this paper, we provide a background to and review of the recent progress of deep learning frameworks to investigate tumour heterogeneity using both single-cell and spatial transcriptomics data types.
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Aprendizaje Profundo , Neoplasias , Humanos , Transcriptoma/genética , Medicina de Precisión , Perfilación de la Expresión GénicaRESUMEN
Doublecortin-like kinase 1 (DCLK1) is a functional serine/threonine (S/T)-kinase and a member of the doublecortin family of proteins which are characterized by their ability to bind to microtubules (MTs). DCLK1 is a proposed cancer driver gene, and its upregulation is associated with poor overall survival in several solid cancer types. However, how DCLK1 associates with MTs and how its kinase function contributes to pro-tumorigenic processes is poorly understood. This review builds on structural models to propose not only the specific functions of the domains but also attempts to predict the impact of individual somatic missense mutations on DCLK1 functions. Somatic missense mutations in DCLK1 are most frequently located within the N-terminal MT binding region and likely impact on the ability of DCLK1 to bind to αß-tubulin and to polymerize and stabilize MTs. Moreover, the MT binding affinity of DCLK1 is negatively regulated by its auto-phosphorylation, and therefore mutations that affect kinase activity are predicted to indirectly alter MT dynamics. The emerging picture portrays DCLK1 as an MT-associated protein whose interactions with tubulin heterodimers and MTs are tightly controlled processes which, when disrupted, may confer pro-tumorigenic properties.
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The gut epithelium not only provides a physical barrier to separate a noxious outside from a sterile inside but also allows for highly regulated interactions between bacteria and their products, and components of the immune system. Homeostatic maintenance of an intact epithelial barrier is paramount to health, requiring an intricately regulated and highly adaptive response of various cells of the immune system. Prolonged homeostatic imbalance can result in chronic inflammation, tumorigenesis and inefficient antitumor immune control. Here we provide an update on the role of innate lymphoid cells, macrophages and dendritic cells, which collectively play a critical role in epithelial barrier maintenance and provide an important linkage between the classical innate and adaptive arm of the immune system. These interactions modify the capacity of the gut epithelium to undergo continuous renewal, safeguard against tumor formation and provide feedback to the gut microbiome, which acts as a seminal contributor to cellular homeostasis of the gut.
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Inmunidad Innata , Mucosa Intestinal , Epitelio , Homeostasis , Linfocitos , MacrófagosRESUMEN
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity.
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Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas. Apc min/+ and doublecortin-like kinase 1 (Dclk1)Cre/+ ;Apc fl/fl mice were exposed to dextran sulphate sodium (DSS) in their drinking water to promote the formation of colon adenomas. Mice were then treated with either a Wnt-signaling antagonist pyrvinium pamoate (PP), an anti-inflammatory agent sulindac or proapoptotic compound ABT263 or a combination of PP+ABT263, or PP+sulindac. Colon adenoma frequency, size, and T-cell abundance were measured. DSS treatment resulted in significant increases in colon adenoma number (P < 0.001, n > 5) and burden in Apc min/+ (P < 0.01, n > 5) and Dclk1 Cre/+ ;Apc fl/fl (P < 0.02, n > 5) mice. There was no effect on adenomas following treatment with PP in combination with ABT263. Adenoma number and burden were reduced with PP+sulindac treatment in Dclk1 Cre/+;Apc fl/fl mice (P < 0.01, n > 17) and in Apc min/+ mice (P < 0.001, n > 7) treated with sulindac or PP+sulindac with no detectable toxicity. PP treatment of Apc min/+ mice increased the frequency of CD3+ cells in the adenomas. The combination of Wnt pathway inhibition with sulindac was more effective in Dclk1 Cre/+;Apc fl/fl mice and provides an opportunity for killing Apc-mutant colon adenoma cells, indicating a strategy for both colorectal cancer prevention and potential new treatments for patients with advanced colorectal cancer. Outcomes from the results of this study may be translatable to the clinic for management of FAP and other patients with a high risk of developing colorectal cancer. Significance: Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing Apc-mutant colon adenoma cells and suggests a strategy for colorectal cancer prevention and new treatments for patients with advanced colorectal cancer.
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Adenoma , Poliposis Adenomatosa del Colon , Neoplasias del Colon , Neoplasias Colorrectales , Animales , Ratones , Adenoma/tratamiento farmacológico , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Sulindac/farmacologíaRESUMEN
Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.
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Frío/efectos adversos , Hipotermia Inducida/efectos adversos , Infarto de la Arteria Cerebral Media/terapia , Accidente Cerebrovascular Isquémico/terapia , Angiografía de Substracción Digital/métodos , Animales , Arteria Carótida Común/diagnóstico por imagen , Arteria Carótida Común/patología , Arteria Carótida Común/cirugía , Cateterismo/métodos , Modelos Animales de Enfermedad , Procedimientos Endovasculares/métodos , Estudios de Factibilidad , Hipotermia Inducida/instrumentación , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/patología , Accidente Cerebrovascular Isquémico/veterinaria , Fármacos Neuroprotectores/farmacología , Evaluación de Resultado en la Atención de Salud , Imagen de Perfusión/métodos , Seguridad , Ovinos , Trombectomía/métodosRESUMEN
Ets homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) family of transcription factors. To investigate its role in development and epithelial homeostasis, we generated a series of novel mouse strains in which the Ets DNA-binding domain of Ehf was deleted in all tissues (Ehf-/-) or specifically in the gut epithelium. Ehf-/- mice were born at the expected Mendelian ratio, but showed reduced body weight gain, and developed a series of pathologies requiring most Ehf-/- mice to reach an ethical endpoint before reaching 1 year of age. These included papillomas in the facial skin, abscesses in the preputial glands (males) or vulvae (females), and corneal ulcers. Ehf-/-mice also displayed increased susceptibility to experimentally induced colitis, which was confirmed in intestinal-specific Ehf knockout mice. Gut-specific Ehf deletion also impaired goblet cell differentiation, induced extensive transcriptional reprogramming in the colonic epithelium and enhanced Apc-initiated adenoma development. The Ets DNA-binding domain of EHF is therefore essential for postnatal homeostasis of the epidermis and colonic epithelium, and its loss promotes colonic tumour development.
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Transformación Celular Neoplásica/genética , Neoplasias del Colon/etiología , Epidermis/metabolismo , Genes APC , Homeostasis , Mucosa Intestinal/metabolismo , Factores de Transcripción/genética , Animales , Reprogramación Celular/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Regulación de la Expresión Génica , Células Caliciformes/metabolismo , Células Caliciformes/patología , Masculino , Ratones , Ratones Noqueados , Factores de Transcripción/metabolismoRESUMEN
Doublecortin-like kinase 1 (DCLK1) is a putative cancer stem cell marker, a promising diagnostic and prognostic maker for malignant tumors and a proposed driver gene for gastric cancer (GC). DCLK1 overexpression in a majority of solid cancers correlates with lymph node metastases, advanced disease and overall poor-prognosis. In cancer cells, DCLK1 expression has been shown to promote epithelial-to-mesenchymal transition (EMT), driving disruption of cell-cell adhesion, cell migration and invasion. Here, we report that DCLK1 influences small extracellular vesicle (sEV/exosome) biogenesis in a kinase-dependent manner. sEVs isolated from DCLK1 overexpressing human GC cell line MKN1 (MKN1OE -sEVs), promote the migration of parental (non-transfected) MKN1 cells (MKN1PAR ). Quantitative proteome analysis of MKN1OE -sEVs revealed enrichment in migratory and adhesion regulators (STRAP, CORO1B, BCAM, COL3A, CCN1) in comparison to MKN1PAR -sEVs. Moreover, using DCLK1-IN-1, a specific small molecule inhibitor of DCLK1, we reversed the increase in sEV size and concentration in contrast to other EV subtypes, as well as kinase-dependent cargo selection of proteins involved in EV biogenesis (KTN1, CHMP1A, MYO1G) and migration and adhesion processes (STRAP, CCN1). Our findings highlight a specific role of DCLK1-kinase dependent cargo selection for sEVs and shed new light on its role as a regulator of signaling in gastric tumorigenesis.
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Vesículas Extracelulares , Neoplasias Gástricas , Línea Celular Tumoral , Quinasas Similares a Doblecortina , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana , Células Madre Neoplásicas , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Neoplasias Gástricas/genética , Proteínas de Transporte VesicularRESUMEN
Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.
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Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Transfección , Resultado del TratamientoRESUMEN
The novel coronavirus disease 2019 (COVID-19) is considered to be a significant health challenge worldwide because of its rapid human-to-human transmission, leading to a rise in the number of infected people and deaths. The detection of COVID-19 at the earliest stage is therefore of paramount importance for controlling the pandemic spread and reducing the mortality rate. The real-time reverse transcription-polymerase chain reaction, the primary method of diagnosis for coronavirus infection, has a relatively high false negative rate while detecting early stage disease. Meanwhile, the manifestations of COVID-19, as seen through medical imaging methods such as computed tomography (CT), radiograph (X-ray), and ultrasound imaging, show individual characteristics that differ from those of healthy cases or other types of pneumonia. Machine learning (ML) applications for COVID-19 diagnosis, detection, and the assessment of disease severity based on medical imaging have gained considerable attention. Herein, we review the recent progress of ML in COVID-19 detection with a particular focus on ML models using CT and X-ray images published in high-ranking journals, including a discussion of the predominant features of medical imaging in patients with COVID-19. Deep Learning algorithms, particularly convolutional neural networks, have been utilized widely for image segmentation and classification to identify patients with COVID-19 and many ML modules have achieved remarkable predictive results using datasets with limited sample sizes.
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The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.
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Neoplasias Gastrointestinales/inmunología , Interleucina-33/inmunología , Mastocitos/inmunología , Microambiente Tumoral/inmunología , Animales , HumanosRESUMEN
The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.
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Interleucina-33/inmunología , Macrófagos/inmunología , Mastocitos/inmunología , Neoplasias Gástricas/inmunología , Aminopiridinas/administración & dosificación , Animales , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/inmunología , Cromolin Sódico/administración & dosificación , Modelos Animales de Enfermedad , Epitelio/inmunología , Epitelio/patología , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Ratones , Ratones Transgénicos , Pirroles/administración & dosificación , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Matrices Tisulares , Microambiente Tumoral/inmunologíaRESUMEN
Excessive signaling through gp130, the shared receptor for the interleukin (IL)6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130-dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130Y757F mice, where tumors arise exclusively through excessive gp130/STAT3 signaling in response to the IL6 family cytokine IL11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumor suppressor gene Apc and the associated ß-catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor-promoting activity of IL11-dependent gp130/STAT3 signaling, tumors of bazedoxifene-treated Apc-mutant mice retain excessive nuclear accumulation of ß-catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL11 plays a tumor-promoting role.
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Reposicionamiento de Medicamentos , Neoplasias Gastrointestinales/tratamiento farmacológico , Indoles/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Proliferación Celular/efectos de los fármacos , Receptor gp130 de Citocinas/química , Receptor gp130 de Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Indoles/metabolismo , Indoles/farmacología , Interleucina-11/química , Interleucina-11/metabolismo , Interleucina-11/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Transcripción STAT3/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (â¼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human colorectal cancer xenografts. MACROD2 deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988-1005. ©2018 AACR.See related commentary by Jin and Burkard, p. 921This article is highlighted in the In This Issue feature, p. 899.
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Enzimas Reparadoras del ADN/genética , Inestabilidad Genómica , Haploinsuficiencia , Hidrolasas/genética , Neoplasias Intestinales/patología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Daño del ADN , Enzimas Reparadoras del ADN/química , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Hidrolasas/química , Neoplasias Intestinales/genética , Neoplasias Intestinales/metabolismo , Ratones , Estadificación de Neoplasias , Trasplante de NeoplasiasRESUMEN
Intercellular communication between tumor cells, immune cells and the stroma characterises the tumor microenvironment, which is instrumental for establishing the ecological niche that fosters tumor growth and metastasis. While tumor cell intrinsic STAT3 signaling provides a crucial axis to support cell proliferation and survival, it also regulates many activities of the non-transformed cells that collectively make up the tumor microenvironment. Accordingly, excessive activation of STAT3 is a hallmark of many malignancies, and often occurs in response to cytokines of the IL-6 and IL-10 families. However, tumor extrinsic STAT3 signaling also regulates the effector function of tumor-associated immune and stromal cells, which support the growth of tumors by suppressing the host's anti-tumor immune response. Given that STAT3 mediates tumorigenic effects in many cell types, the molecular players of STAT3 signaling and its upstream JAK kinases provide viable therapeutic targets for the treatment of cancer. Here we provide an update on novel insights into the role of STAT3 in immune suppression and describe current therapeutic strategies that target the JAK/STAT3 signaling axis for the treatment of malignancies.