Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
Oncol Rep ; 49(2)2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36633146

RESUMEN

Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro­ and anti­tumorigenic functions in a cell type­dependent manner. Therefore, designing strategies that block pro­tumorigenic signaling, without impeding anti­tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which ß3­integrin­mediated binding to a secreted RGDKGE­containing collagen fragment stimulates an autocrine­like signaling pathway that differentially governs the activity of both YAP and (protein kinase­A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD­L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine­like signaling pathway that may provide tumor cells with the ability to regulate PD­L1, but our findings may also help in the development of more effective strategies to control pro­tumorigenic ß3­integrin signaling without disrupting its tumor suppressive functions in other cellular compartments.


Asunto(s)
Antígeno B7-H1 , Colágeno , Integrinas , Neoplasias , Fragmentos de Péptidos , Complejo de la Endopetidasa Proteasomal , Humanos , Antígeno B7-H1/metabolismo , Colágeno/química , Colágeno/metabolismo , Integrinas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo
2.
Am J Pathol ; 191(3): 527-544, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33307038

RESUMEN

The growth and spread of malignant tumors, such as ovarian carcinomas, are governed in part by complex interconnected signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. Herein, we provide evidence that blocking cellular interactions with an RGDKGE-containing collagen peptide that selectively binds integrin ß3 on ovarian tumor cells enhances the phosphorylation of the hippo effector kinase large tumor suppressor kinase-1 and reduces nuclear accumulation of yes-associated protein and its target gene c-Myc. Selectively targeting this RGDKGE-containing collagen fragment inhibited ovarian tumor growth and the development of ascites fluid in vivo. These findings suggest that this bioactive collagen fragment may represent a previously unknown regulator of the hippo effector kinase large tumor suppressor kinase-1 and regulate ovarian tumor growth by a yes-associated protein-dependent mechanism. Taken together, these data not only provide new mechanistic insight into how a unique collagen fragment may regulate ovarian cancer, but in addition may help provide a useful new alternative strategy to control ovarian tumor progression based on selectively disrupting a previously unappreciated signaling cascade.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Colágeno/metabolismo , Neoplasias Ováricas/patología , Fragmentos de Péptidos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-yes/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos C57BL , Ratones Desnudos , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-yes/genética , Transducción de Señal , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Cell Physiol ; 235(12): 9005-9020, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32400053

RESUMEN

Structural remodeling of the extracellular matrix is a well-established process associated with tumor growth and metastasis. Tumor and stromal cells that compose the tumor mass function cooperatively to promote the malignant phenotype in part by physically interacting with intact and structurally altered matrix proteins. To this end, collagen represents the most abundant component of the extracellular matrix and is known to control the behavior of histologically distinct tumor types as well as a diversity of stromal cells. Although a significant molecular understanding has been established concerning how cellular interactions with intact collagen govern signaling pathways that control tumor progression, considerably less is known concerning how interactions with cryptic or hidden regions within remodeled collagen may selectively alter signaling cascades, or whether inhibition of these cryptic signaling pathways may represent clinically effective therapeutic strategies. Here, we review the emerging evidence concerning the possible mechanisms for the selective generation of cryptic or hidden elements within collagen and their potential cell surface receptors that may facilitate signal transduction. We discuss the concept that cellular communication links between cell surface receptors and these cryptic collagen elements may serve as functional signaling hubs that coordinate multiple signaling pathways operating within both tumor and stromal cells. Finally, we provide examples to help illustrate the possibility that direct targeting of these unique cryptic signaling hubs may lead to the development of more effective therapeutic strategies to control tumor growth and metastasis.


Asunto(s)
Colágeno/metabolismo , Metástasis de la Neoplasia/patología , Neoplasias/metabolismo , Neovascularización Patológica/patología , Animales , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Humanos
4.
Am J Pathol ; 188(10): 2356-2368, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30118657

RESUMEN

Stromal components not only help form the structure of neoplasms such as melanomas, but they also functionally contribute to their malignant phenotype. Thus, uncovering signaling pathways that integrate the behavior of both tumor and stromal cells may provide unique opportunities for the development of more effective strategies to control tumor progression. In this regard, extracellular matrix-mediated signaling plays a role in coordinating the behavior of both tumor and stromal cells. Here, evidence is provided that targeting a cryptic region of the extracellular matrix protein collagen (HU177 epitope) inhibits melanoma tumor growth and metastasis and reduces angiogenesis and the accumulation of α-SMA-expressing stromal cell in these tumors. The current study suggests that the ability of the HU177 epitope to control melanoma cell migration and metastasis depends on the transcriptional coactivator Yes-associated protein (YAP). Melanoma cell interactions with the HU177 epitope promoted nuclear accumulation of YAP by a cyclin-dependent kinase-5-associated mechanism. These findings provide new insights into the mechanism by which the anti-HU177 antibody inhibits metastasis, and uncovers an unknown signaling pathway by which the HU177 epitope selectively reprograms melanoma cells by regulating nuclear localization of YAP. This study helps to define a potential new therapeutic strategy to control melanoma tumor growth and metastasis that might be used alone or in combination with other therapeutics.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Colágeno/fisiología , Epítopos/fisiología , Melanoma/fisiopatología , Neoplasias Cutáneas/fisiopatología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Inhibidores de la Angiogénesis/farmacología , Anticuerpos Antiidiotipos/farmacología , Anticuerpos Antiidiotipos/fisiología , Proliferación Celular/fisiología , Colágeno/inmunología , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 5 Dependiente de la Ciclina/metabolismo , Humanos , Melanoma/patología , Metástasis de la Neoplasia , Neovascularización Patológica/inmunología , Fosfoproteínas/metabolismo , Fosforilación/fisiología , Neoplasias Cutáneas/patología , Células del Estroma/fisiología , Talina/metabolismo , Factores de Transcripción , Células Tumorales Cultivadas , Proteínas Señalizadoras YAP
5.
Am J Pathol ; 186(6): 1649-61, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27216148

RESUMEN

Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of α-smooth muscle actin-expressing stromal cells. Integrin α10ß1 can serve as a receptor for the HU177 epitope in α-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized α10ß1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.


Asunto(s)
Proliferación Celular , Colágeno/metabolismo , Epítopos , Neoplasias Ováricas/patología , Microambiente Tumoral/fisiología , Animales , Western Blotting , Adhesión Celular/fisiología , Proliferación Celular/fisiología , Colágeno/química , Femenino , Xenoinjertos , Humanos , Ratones , Neovascularización Patológica/metabolismo , Neoplasias Ováricas/metabolismo
6.
J Biol Chem ; 291(6): 2731-50, 2016 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-26668310

RESUMEN

Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin αvß3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by αvß3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting αvß3 signaling, this collagen epitope promoted αvß3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates αvß3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control αvß3 signaling by targeting a pro-angiogenic and inflammatory ligand of αvß3 rather than the receptor itself.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Colágeno/farmacología , Células Endoteliales/metabolismo , Epítopos/farmacología , Mecanotransducción Celular/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Fosfoproteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Colágeno/química , Células Endoteliales/citología , Epítopos/química , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Mecanotransducción Celular/genética , Ratones , Fosfoproteínas/genética , Factores de Transcripción , Proteínas Señalizadoras YAP , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Familia-src Quinasas
7.
Angiogenesis ; 18(1): 31-46, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25249331

RESUMEN

A more complete understanding of the mechanisms that regulate the angiogenic switch, which contributes to the conversion of small dormant tumors to actively growing malignancies, is important for the development of more effective anti-angiogenic strategies for cancer therapy. While significant progress has been made in understanding the complex mechanisms by which integrin αvß3 expressed in endothelial cells governs angiogenesis, less is known concerning the ability of αvß3 expressed within the tumor cell compartment to modulate the angiogenic output of a tumor. Here we provide evidence that αvß3 expressed in melanoma cells may contribute to the suppression of IGFBP-4, an important negative regulator of IGF-1 signaling. Given the multiple context-dependent roles for αvß3 in angiogenesis and tumor progression, our novel findings provide additional molecular insight into how αvß3 may govern the angiogenic switch by a mechanism associated with a p38 MAPK and matrix metalloproteinases-dependent regulation of the endogenous angiogenesis inhibitor IGFBP-4.


Asunto(s)
Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Integrina alfaVbeta3/antagonistas & inhibidores , Melanoma/fisiopatología , Western Blotting , Línea Celular Tumoral , Proliferación Celular , Cartilla de ADN/genética , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Melanoma/complicaciones , Neovascularización Patológica/etiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Microtomografía por Rayos X
8.
J Biol Chem ; 287(3): 1779-89, 2012 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-22134921

RESUMEN

An in-depth understanding of the molecular and cellular complexity of angiogenesis continues to advance as new stimulators and inhibitors of blood vessel formation are uncovered. Gaining a more complete understanding of the response of blood vessels to both stimulatory and inhibitory molecules will likely contribute to more effective strategies to control pathological angiogenesis. Here, we provide evidence that endothelial cell interactions with structurally altered collagen type IV may suppress the expression of insulin-like growth factor binding protein-4 (IGFBP-4), a well documented inhibitor of the IGF-1/IGF-1R signaling axis. We report for the first time that IGFBP-4 differentially inhibits angiogenesis induced by distinct growth factor signaling pathways as IGFBP-4 inhibited FGF-2- and IGF-1-stimulated angiogenesis but failed to inhibit VEGF-induced angiogenesis. The resistance of VEGF-stimulated angiogenesis to IGFBP-4 inhibition appears to depend on sustained activation of p38 MAPK as blocking its activity restored the anti-angiogenic effects of IGFBP-4 on VEGF-induced blood vessel growth in vivo. These novel findings provide new insight into how blood vessels respond to endogenous inhibitors during angiogenesis stimulated by distinct growth factor signaling pathways.


Asunto(s)
Inhibidores de la Angiogénesis/metabolismo , Células Endoteliales/metabolismo , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/genética , Animales , Embrión de Pollo , Células Endoteliales/citología , Humanos , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA