RESUMEN
BACKGROUND: The major cause of death in prostate cancer (PCa) cases is due to distant metastatic lesions, with the bone being the most prevalent site for secondary colonization. Utilization of small molecule inhibitors to treat bone metastatic PCa have had limited success either as monotherapies or in combination with other chemotherapeutics due to intolerable toxicities. In the current study, we developed a clinically relevant in vivo intraosseous tumor model overexpressing the platelet-derived growth factor D (PDGF D) to test the efficacy of a newly characterized vascular endothelial growth factor receptor (VEGFR)/PDGFR inhibitor, cediranib (also called AZD2171). METHODS: An intratibial-injection model was established utilizing DU145 cells with or without increased PDGF D expression. Tumor-bearing mice were treated by daily gavage administration of cediranib and/or weekly i.p. injection of docetaxel for 7 weeks. Tibiae were monitored by in vivo/ex vivo X-rays and histomorphometry analysis was performed to estimate tumor volume and tumor-associated trabecular bone growth. RESULTS: Cediranib reduced intraosseous growth of prostate tumors as well as tumor-associated bone responses. When compared to the standard chemotherapeutic agent docetaxel, cediranib exhibited a stronger inhibition of tumor-associated bone response. The efficacy of cediranib was further enhanced when the drug was co-administered with docetaxel. Importantly, the therapeutic benefits of cediranib and docetaxel are more prominent in intraosseous prostate tumors overexpressing PDGF D. CONCLUSION: These novel findings support the utilization of cediranib, either alone or in combination with docetaxel, to treat bone metastatic PCa exhibiting PDGF D expression.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Inhibidores de Crecimiento/uso terapéutico , Linfocinas/biosíntesis , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Quinazolinas/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Línea Celular Tumoral , Transformación Celular Neoplásica/metabolismo , Humanos , Linfocinas/antagonistas & inhibidores , Masculino , Ratones , Ratones SCID , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Neoplasias de la Próstata/metabolismo , Distribución Aleatoria , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
PURPOSE: The aim of this study is to determine the ability of intratumorally delivered docetaxel to enhance the antitumor activity of adenovirus-mediated delivery of p53 (Ad-p53) in murine head and neck cancer xenograft model. MATERIALS AND METHODS: A xenograft head and neck squamous cell carcinoma mouse model was used. Mice were randomized into 4 groups of 6 mice receiving 6 weeks of biweekly intratumoral injection of (a) diluent, (b) Ad-p53 (1 x 10(10) viral particles per injection), (c) docetaxel (1 mg/kg per injection), and (d) combination of Ad-p53 (1 x 10(10) viral particles per injection) and docetaxel (1 mg/kg per injection). Tumor size, weight, toxicity, and overall and disease-free survival rates were determined. RESULTS: Intratumoral treatments with either docetaxel alone or Ad-p53 alone resulted in statistically significant antitumor activity and improved survival compared with control group. Furthermore, combined delivery of Ad-p53 and docetaxel resulted in a statistically significant reduction in tumor weight when compared to treatment with either Ad-p53 or docetaxel alone. CONCLUSION: Intratumoral delivery of docetaxel enhanced the antitumor effect of Ad-p53 in murine head and neck cancer xenograft model. The result of this preclinical in vivo study is promising and supports further clinical testing to evaluate efficacy of combined intratumoral docetaxel and Ad-p53 in treatment of head and neck cancer.
Asunto(s)
Adenoviridae/genética , Antineoplásicos/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Taxoides/administración & dosificación , Proteína p53 Supresora de Tumor/administración & dosificación , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Docetaxel , Inyecciones Intralesiones , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The range of the mosquito Aedes aegypti continues to expand, putting more than two billion people at risk of arboviral infection. The sterile insect technique (SIT) has been used to successfully combat agricultural pests at large scale, but not mosquitoes, mainly because of challenges with consistent production and distribution of high-quality male mosquitoes. We describe automated processes to rear and release millions of competitive, sterile male Wolbachia-infected mosquitoes, and use of these males in a large-scale suppression trial in Fresno County, California. In 2018, we released 14.4 million males across three replicate neighborhoods encompassing 293 hectares. At peak mosquito season, the number of female mosquitoes was 95.5% lower (95% CI, 93.6-96.9) in release areas compared to non-release areas, with the most geographically isolated neighborhood reaching a 99% reduction. This work demonstrates the high efficacy of mosquito SIT in an area ninefold larger than in previous similar trials, supporting the potential of this approach in public health and nuisance-mosquito eradication programs.
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Aedes/microbiología , Aedes/fisiología , Control de Mosquitos/métodos , Mosquitos Vectores/microbiología , Mosquitos Vectores/fisiología , Wolbachia/fisiología , Aedes/crecimiento & desarrollo , Migración Animal , Animales , California , Femenino , Larva/crecimiento & desarrollo , Larva/microbiología , Larva/fisiología , Masculino , Control de Mosquitos/estadística & datos numéricos , Mosquitos Vectores/crecimiento & desarrollo , Dinámica Poblacional , Caracteres SexualesRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
UNLABELLED: Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates intracellular signaling networks for inhibition of apoptosis. Tetraspanin (CD63), a cell surface binding partner for TIMP-1, was previously shown to regulate integrin-mediated survival pathways in the human breast epithelial cell line MCF10A. In the current study, we show that TIMP-1 expression induces phenotypic changes in cell morphology, cell adhesion, cytoskeletal remodeling, and motility, indicative of an epithelial-mesenchymal transition (EMT). This is evidenced by loss of the epithelial cell adhesion molecule E-cadherin with an increase in the mesenchymal markers vimentin, N-cadherin, and fibronectin. Signaling through TIMP-1, but not TIMP-2, induces the expression of TWIST1, an important EMT transcription factor known to suppress E-cadherin transcription, in a CD63-dependent manner. RNAi-mediated knockdown of TWIST1 rescued E-cadherin expression in TIMP-1-overexpressing cells, demonstrating a functional significance of TWIST1 in TIMP-1-mediated EMT. Furthermore, analysis of TIMP-1 structural mutants reveals that TIMP-1 interactions with CD63 that activate cell survival signaling and EMT do not require the matrix metalloproteinase (MMP)-inhibitory domain of TIMP-1. Taken together, these data demonstrate that TIMP-1 binding to CD63 activates intracellular signal transduction pathways, resulting in EMT-like changes in breast epithelial cells, independent of its MMP-inhibitory function. IMPLICATIONS: TIMP-1's function as an endogenous inhibitor of MMP or as a "cytokine-like" signaling molecule may be a critical determinant for tumor cell behavior.
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Neoplasias de la Mama/genética , Transición Epitelial-Mesenquimal/genética , Proteínas Nucleares/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Proteína 1 Relacionada con Twist/metabolismo , Apoptosis/genética , Neoplasias de la Mama/patología , Cadherinas/genética , Cadherinas/metabolismo , Proliferación Celular/genética , Supervivencia Celular/genética , Células Epiteliales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Nucleares/genética , Transducción de Señal , Tetraspanina 30 , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Proteína 1 Relacionada con Twist/genéticaRESUMEN
The platelet-derived growth factors (PDGF A, B, C, and D) and their receptors (α-PDGFR and ß-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative ß-PDGFR is overexpressed and activated during prostate cancer progression, but the identification and functional significance of its complementary ligand have not been elucidated. This study examined potential oncogenic functions of ß-PDGFR ligands PDGF B and PDGF D, using nonmalignant prostate epithelial cells engineered to overexpress these ligands. In our models, PDGF D induced cell migration and invasion more effectively than PDGF B in vitro. Importantly, PDGF D supported prostate epithelial cell tumorigenesis in vivo and showed increased tumor angiogenesis compared with PDGF B. Autocrine signaling analysis of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways found PDGF D-specific activation of the c-jun-NH2-kinase (JNK) signaling cascade. Using short hairpin RNA and pharmacologic inhibitors, we showed that PDGFD-mediated phenotypic transformation is ß-PDGFR and JNK dependent. Importantly, we made a novel finding of PDGF D-specific increase in the shedding and activation of the serine protease matriptase in prostate epithelial cells. Our study, for the first time to our knowledge, showed ligand-specific ß-PDGFR signaling as well as PDGF D-specific regulation of matriptase activity and its spatial distribution through shedding. Taken together with our previous finding that matriptase is a proteolytic activator of PDGF D, this study provides a molecular insight into signal amplification of the proteolytic network and PDGF signaling loop during cancer progression.
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Linfocinas , Factor de Crecimiento Derivado de Plaquetas , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-sis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Animales , Becaplermina , Línea Celular Tumoral , Movimiento Celular , Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica , Humanos , Linfocinas/genética , Linfocinas/metabolismo , Masculino , Ratones , Ratones SCID , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Invasividad Neoplásica , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-sis/genética , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES/HYPOTHESIS: XRP6258 is a novel taxoid, which has antitumor activity in preclinical mouse orthotopic and human xenograft cancer models. However, limited XRP6258 studies have been performed in head and neck squamous cell carcinoma cells (HNSCC). The objective of this study is to identify the antitumor activity of XRP6258 in HNSCC cell line models. METHODS: HNSCC cells (HN30 and HN12) were exposed to either XRP6258 or docetaxel. XRP6258-induced growth suppression, cell cycle arrest and apoptosis were measured. Further, XRP6258-induced expression patterns of selected genes were compared to docetaxel-induced expression patterns using Western blot analysis. RESULTS: XRP6258 suppressed proliferation and induced G(2)M arrest and apoptosis in both of the cell lines tested. XRP6258 and docetaxel produced similar alteration in the expression of cell cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and EGFR were decreased in both XRP6258 and docetaxel-treated HNSCC cells. Finally, XRP6258 induced a greater level of bcl2 phosphorylation than docetaxel in HN12 cell line. CONCLUSIONS: XRP6258 appeared to have a similar mechanism of action as docetaxel in the two HNSCC cell lines studied. XRP6258 induced cell cycle arrest, growth suppression, and apoptosis by altering gene expression patterns similar to that induced by docetaxel. These preclinical experiments suggest that XRP6258 may be useful in treating HNSCC, and the aforementioned genes can potentially be used as surrogate endpoint biomarkers.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Taxoides/farmacología , Anexina A5/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Carcinoma de Células Escamosas/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Ciclina A/metabolismo , Ciclina B1/metabolismo , Docetaxel , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Humanos , Fosforilación , Células Tumorales CultivadasRESUMEN
OBJECTIVES: To identify the antitumor activity and wound-healing effect of docetaxel delivered in the surgical tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). DESIGN: Control and experimental series. SETTING: Academic medical center. SUBJECTS: BALB/c and severe combined immunodeficiency mice. INTERVENTION: Intrawound (IW) docetaxel therapy was tested in 3 HNSCC xenograft and 2 taxane-resistant models. Intratumoral (IT) docetaxel therapy was further tested in the 2 taxane-resistant models. MAIN OUTCOME MEASURES: Tumor size, survival, and wound toxic effects were measured. The effect of docetaxel on various factors involved in wound healing and tumor growth within the surgical tumor microenvironment was also analyzed. RESULTS: In a pilot study using BALB/c mice, IW docetaxel therapy was not associated with problems in wound healing. Using the HN6, HN12, and HN30 HNSCC xenograft model, IW docetaxel prevented tumor growth and improved survival when compared with controls. No local or systemic toxic effect or wound-healing problem was noted. Using taxane-resistant xenograft lung cancer (H460/T800) and syngeneic salivary cancer (BALB/c mucoepidermoid carcinoma) models, IW therapy did not delay tumor growth. An antitumor effect was detected with repeated docetaxel injections in the H460/T800 taxane-resistant model but not in the BALB/c mucoepidermoid carcinoma model. Docetaxel inhibited the expression of growth factors and receptors in tumor cells; however, it did not inhibit the level of wound-healing growth factors in the surgical tumor microenvironment. CONCLUSIONS: These preclinical results support further testing of IW docetaxel treatment in HNSCC. Docetaxel appears to exert antitumor activity without affecting factors involved in wound healing in the tumor microenvironment.