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1.
Bioorg Med Chem Lett ; 42: 128050, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33887439

RESUMEN

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metal-dependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.


Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oligopéptidos/farmacología , Ácidos Fosfínicos/farmacología , Aminopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Antígenos de Histocompatibilidad Menor/metabolismo , Modelos Moleculares , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/química , Relación Estructura-Actividad
2.
Proc Natl Acad Sci U S A ; 107(46): 19903-8, 2010 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-21041641

RESUMEN

In mammalian epidermis, integrin expression is normally confined to the basal proliferative layer that contains stem cells. However, in epidermal hyperproliferative disorders and tumors, integrins are also expressed by suprabasal cells, with concomitant up-regulation of Erk mitogen-activated protein kinase (MAPK) signaling. In transgenic mice, expression of activated MAPK kinase 1 (MEK1) in the suprabasal, nondividing, differentiated cell layers (InvEE transgenics) results in epidermal hyperproliferation and skin inflammation. We now demonstrate that wounding induces benign tumors (papillomas and keratoacanthomas) in InvEE mice. By generating chimeras between InvEE mice and mice that lack the MEK1 transgene, we demonstrate that differentiating, nondividing cells that express MEK1 stimulate adjacent transgene-negative cells to divide and become incorporated into the tumor mass. Dexamethasone treatment inhibits tumor formation, suggesting that inflammation is involved. InvEE skin and tumors express high levels of IL1α; treatment with an IL1 receptor antagonist delays tumor onset and reduces incidence. Depletion of γδ T cells and macrophages also reduces tumor incidence. Because a hallmark of cancer is uncontrolled proliferation, it is widely assumed that tumors arise only from dividing cells. In contrast, our studies show that differentiated epidermal cells can initiate tumor formation without reacquiring the ability to divide and that they do so by triggering an inflammatory infiltrate.


Asunto(s)
División Celular , Epidermis/patología , Inflamación/patología , Neoplasias/patología , Lesiones Precancerosas/patología , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Epidermis/efectos de los fármacos , Interleucina-1alfa/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Papiloma/metabolismo , Papiloma/patología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Transgenes , Cicatrización de Heridas/efectos de los fármacos
3.
Proc Natl Acad Sci U S A ; 106(23): 9286-91, 2009 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-19478060

RESUMEN

Local tissue stem cells have been described in airways of the lung but their contribution to normal epithelial maintenance is currently unknown. We therefore developed aggregation chimera mice and a whole-lung imaging method to determine the relative contributions of progenitor (Clara) and bronchiolar stem cells to epithelial maintenance and repair. In normal and moderately injured airways chimeric patches were small in size and not associated with previously described stem cell niches. This finding suggested that single, randomly distributed progenitor cells maintain normal epithelial homeostasis. In contrast we found that repair following severe lung injury resulted in the generation of rare, large clonal cell patches that were associated with stem cell niches. This study provides evidence that epithelial stem cells are dispensable for normal airway homeostasis. We also demonstrate that stem cell activation and robust clonal cellular expansion occur only during repair from severe lung injury.


Asunto(s)
Bronquiolos/citología , Pulmón/citología , Células Madre/citología , Animales , Células Epiteliales/citología , Femenino , Homeostasis , Pulmón/fisiología , Masculino , Ratones , Células Madre/fisiología
4.
5.
Nat Cell Biol ; 22(7): 758-766, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32483388

RESUMEN

Cancer-associated fibroblasts (CAFs) perform diverse roles and can modulate therapy responses1. The inflammatory environment within tumours also influences responses to many therapies, including the efficacy of oncolytic viruses2; however, the role of CAFs in this context remains unclear. Furthermore, little is known about the cell signalling triggered by heterotypic cancer cell-fibroblast contacts and about what activates fibroblasts to express inflammatory mediators1,3. Here, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts, leading to the activation of STING and IRF3-mediated expression of interferon-ß1 and other cytokines. Interferon-ß1 then drives interferon-stimulated transcriptional programs in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic herpes simplex virus function.


Asunto(s)
Fibroblastos Asociados al Cáncer/inmunología , Inestabilidad Genómica , Factor 3 Regulador del Interferón/metabolismo , Proteínas de la Membrana/metabolismo , Viroterapia Oncolítica , Neoplasias Cutáneas/inmunología , Células del Estroma/inmunología , Adulto , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Células Cultivadas , Citocinas , Interacciones Huésped-Patógeno , Humanos , Factor 3 Regulador del Interferón/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Virus Oncolíticos/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Células del Estroma/metabolismo , Células del Estroma/patología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Cell Rep ; 23(5): 1239-1248, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29719241

RESUMEN

Tumor-associated macrophages (TAMs) are critical for tumor metastasis. Two TAM subsets support cancer cell intravasation: migratory macrophages guide cancer cells toward blood vessels, where sessile perivascular macrophages assist their entry into the blood. However, little is known about the inter-relationship between these functionally distinct TAMs or their possible inter-conversion. We show that motile, streaming TAMs are newly arrived monocytes, recruited via CCR2 signaling, that then differentiate into the sessile perivascular macrophages. This unidirectional process is regulated by CXCL12 and CXCR4. Cancer cells induce TGF-ß-dependent upregulation of CXCR4 in monocytes, while CXCL12 expressed by perivascular fibroblasts attracts these motile TAMs toward the blood vessels, bringing motile cancer cells with them. Once on the blood vessel, the migratory TAMs differentiate into perivascular macrophages, promoting vascular leakiness and intravasation.


Asunto(s)
Movimiento Celular/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Neoplasias Experimentales/inmunología , Animales , Quimiocina CXCL12/inmunología , Femenino , Macrófagos/patología , Ratones , Monocitos/patología , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/patología , Receptores CCR2/inmunología , Receptores CXCR4/inmunología
7.
Cancer Res ; 76(4): 805-817, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26754935

RESUMEN

Macrophages are essential for the progression and maintenance of many cancers, but their role during the earliest stages of tumor formation is unclear. To test this, we used a previously described transgenic mouse model of wound-induced skin tumorigenesis, in which expression of constitutively active MEK1 in differentiating epidermal cells results in chronic inflammation (InvEE mice). Upon wounding, the number of epidermal and dermal monocytes and macrophages increased in wild-type and InvEE skin, but the increase was greater, more rapid, and more sustained in InvEE skin. Macrophage ablation reduced tumor incidence. Furthermore, bioluminescent imaging in live mice to monitor macrophage flux at wound sites revealed that macrophage accumulation was predictive of tumor formation; wounds with the greatest number of macrophages at day 5 went on to develop tumors. Gene expression profiling of flow-sorted monocytes, macrophages, and T cells from InvEE and wild-type skin showed that as wound healing progressed, InvEE macrophages altered their phenotype. Throughout wound healing and after wound closure, InvEE macrophages demonstrated sustained upregulation of several markers implicated in alternative macrophage activation including arginase-1 (ARG1) and mannose receptor (CD206). Notably, inhibition of ARG1 activity significantly reduced tumor formation and epidermal proliferation in vivo, whereas addition of L-arginase to cultured keratinocytes stimulated proliferation. We conclude that macrophages play a key role in early, inflammation-mediated skin tumorigenesis, with mechanistic evidence suggesting that ARG1 secretion drives tumor development by stimulating epidermal cell proliferation. These findings highlight the importance of cancer immunotherapies aiming to polarize tumor-associated macrophages toward an antitumor phenotype.


Asunto(s)
MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , Macrófagos/metabolismo , Neoplasias Cutáneas/metabolismo , Cicatrización de Heridas , Animales , Carcinogénesis , Diferenciación Celular , Proliferación Celular , Humanos , Ratones
8.
Nat Commun ; 6: 5932, 2015 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-25575023

RESUMEN

The association between tissue damage, chronic inflammation and cancer is well known. However, the underlying mechanisms are unclear. Here we characterize a mouse model in which constitutive epidermal extracellular-signal-regulated kinase-MAP-kinase signalling results in epidermal inflammation, and skin wounding induces tumours. We show that tumour incidence correlates with wound size and inflammatory infiltrate. Ablation of tumour necrosis factor receptor (TNFR)-1/-2, Myeloid Differentiation primary response gene 88 or Toll-like receptor (TLR)-5, the bacterial flagellin receptor, but not other innate immune sensors, in radiosensitive leukocytes protects against tumour formation. Antibiotic treatment inhibits, whereas injection of flagellin induces, tumours in a TLR-5-dependent manner. TLR-5 is also involved in chemical-induced skin carcinogenesis in wild-type mice. Leukocytic TLR-5 signalling mediates upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in wound-induced papillomas. HMGB1 is elevated in tumours of patients with Recessive Dystrophic Epidermolysis Bullosa, a disease characterized by chronic skin damage. We conclude that in our experimental model the combination of bacteria, chronic inflammation and wounding cooperate to trigger skin cancer.


Asunto(s)
Proteína HMGB1/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/microbiología , Animales , Antibacterianos/química , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Femenino , Flagelina/metabolismo , Hematopoyesis , Humanos , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal , Piel/patología , Receptor Toll-Like 5/metabolismo , Heridas y Lesiones/patología
9.
Cancer Discov ; 5(9): 932-43, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26269515

RESUMEN

UNLABELLED: Dissemination of tumor cells is an essential step in metastasis. Direct contact between a macrophage, mammalian-enabled (MENA)-overexpressing tumor cell, and endothelial cell [Tumor MicroEnvironment of Metastasis (TMEM)] correlates with metastasis in breast cancer patients. Here we show, using intravital high-resolution two-photon microscopy, that transient vascular permeability and tumor cell intravasation occur simultaneously and exclusively at TMEM. The hyperpermeable nature of tumor vasculature is described as spatially and temporally heterogeneous. Using real-time imaging, we observed that vascular permeability is transient, restricted to the TMEM, and required for tumor cell dissemination. VEGFA signaling from TIE2(hi) TMEM macrophages causes local loss of vascular junctions, transient vascular permeability, and tumor cell intravasation, demonstrating a role for the TMEM within the primary mammary tumor. These data provide insight into the mechanism of tumor cell intravasation and vascular permeability in breast cancer, explaining the value of TMEM density as a predictor of distant metastatic recurrence in patients. SIGNIFICANCE: Tumor vasculature is abnormal with increased permeability. Here, we show that VEGFA signaling from TIE2(hi) TMEM macrophages results in local, transient vascular permeability and tumor cell intravasation. These data provide evidence for the mechanism underlying the association of TMEM with distant metastatic recurrence, offering a rationale for therapies targeting TMEM.


Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Macrófagos/metabolismo , Imagen Molecular , Receptor TIE-2/metabolismo , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/farmacología , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunofenotipificación , Ratones , Ratones Transgénicos , Modelos Biológicos , Neovascularización Patológica , Fenotipo , Transducción de Señal/efectos de los fármacos , Imagen de Lapso de Tiempo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
10.
Nat Rev Cancer ; 12(3): 170-80, 2012 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-22362215

RESUMEN

It is well established that tissue repair depends on stem cells and that chronic wounds predispose to tumour formation. However, the association between stem cells, wound healing and cancer is poorly understood. Lineage tracing has now shown how stem cells are mobilized to repair skin wounds and how they contribute to skin tumour development. The signalling pathways, including WNT and Hedgehog, that control stem cell behaviour during wound healing are also implicated in tumour formation. Furthermore, tumorigenesis and wound repair both depend on communication between epithelial cells, mesenchymal cells and bone marrow-derived cells. These studies suggest ways to harness stem cells for wound repair while minimizing cancer risk.


Asunto(s)
Células Epiteliales/citología , Neoplasias Cutáneas/fisiopatología , Células Madre/citología , Cicatrización de Heridas , Animales , Humanos
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