RESUMEN
BACKGROUND: We and others have previously demonstrated that the µ-opioid receptor (MOR) is overexpressed in several human malignancies. There is a seven-fold increase in MOR in cell lines of human lung cancer. In animal models, overexpression of MOR promotes tumour growth and metastasis. We, therefore, examined whether MOR expression is increased in metastatic lung cancer. METHODS: In this study, we examined the association between MOR expression and metastasis in archived biopsy samples from patients with lung cancer. Paraffin-embedded patient material was stained using MOR antibody and scored qualitatively by two independent pathologists using a four-point scale. RESULTS: In human lung cancer and normal adjacent lung samples obtained from 34 lung cancer patients, MOR expression was increased significantly in cancer samples from patients with lung cancer compared with adjacent control tissue (P=0.0242). When the samples from patients with metastatic lung cancer were separated from the cohort of the total number of patients with lung cancer, we observed an approximately two-fold increase in MOR expression (P=0.0013). CONCLUSIONS: The association between the expression of MOR and the progression of the tumour is consistent with the hypothesis of a direct effect of MOR on cancer progression.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/metabolismo , Receptores Opioides mu/metabolismo , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Estadificación de NeoplasiasRESUMEN
Cervical cancer is associated with human papilloma virus infection. However, this infection is insufficient to induce transformation and progression. Loss of heterozygosity analyses suggest the presence of a tumor suppressor gene (TSG) on chromosome 6p21.3-p25. Here we report the cloning NOL7, its mapping to chromosome band 6p23, and localization of the protein to the nucleolus. Fluorescence in situ hybridization analysis demonstrated an allelic loss of an NOL7 in cultured tumor cells and human tumor samples. Transfection of NOL7 into cervical carcinoma cells inhibited their growth in mouse xenografts, confirming its in vivo tumor suppressor activity. The induction of tumor dormancy correlated with an angiogenic switch caused by a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These data suggest that NOL7 may function as a TSG in part by modulating the expression of the angiogenic phenotype.
Asunto(s)
Nucléolo Celular/química , Genes Supresores de Tumor , Neovascularización Patológica/prevención & control , Neoplasias del Cuello Uterino/genética , Animales , Línea Celular Tumoral , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trombospondina 1/genética , Neoplasias del Cuello Uterino/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Angiogenesis, an essential step in the development of neoplasia, is a complex process that involves the interaction of tumor cells with stromal cells. Tumor-associated macrophages (TAMs) can participate in the induction of tumor angiogenesis and are thought to be of prognostic value in some neoplasms. We have investigated how macrophages contribute to angiogenesis in head-and-neck squamous-cell carcinoma (HNSCC) and have found that tumor cells attract monocytes and activate them to secrete angiogenic factors. The attraction of macrophages was due to the secretion of monocyte chemotactic protein-1 and TGF-beta1 by tumor cells, while tumor production of TGF-beta1 was responsible for activating macrophages. In addition, activated macrophages produced cytokines that acted in a paracrine fashion by secreting both TNF-alpha and IL-1, which in turn stimulated tumor cells to secrete increased levels of IL-8 and VEGF. These data demonstrate that TAMs play an important role in the in vivo induction of angiogenesis in HNSCC and suggest that anti-angiogenic therapies for HNSCC and perhaps other neoplasms must include strategies that will block the ability of tumor cells to recruit macrophages into the tumor micro-environment.
Asunto(s)
Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/irrigación sanguínea , Neoplasias de Cabeza y Cuello/metabolismo , Macrófagos/fisiología , Neovascularización Fisiológica , Animales , Anticuerpos Monoclonales/metabolismo , Línea Celular , Movimiento Celular , Quimiocina CCL2/metabolismo , Técnicas de Cocultivo , Córnea/irrigación sanguínea , Medios de Cultivo Condicionados/farmacología , Factores de Crecimiento Endotelial/metabolismo , Femenino , Humanos , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Queratinocitos/metabolismo , Linfocinas/metabolismo , Pronóstico , Ratas , Ratas Endogámicas F344 , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1 , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that develops after years of chronic exposure to alcohol and tobacco products. Exposure to these agents results in alterations of genes that are important in the regulation of various cellular functions. This loss of regulation allows the tumor cells to survive and grow in an unchecked manner by allowing the cells to perform functions that contribute to the growth of the tumor. Some of these important changes include the acquisition of immortality and the ability to invade tissue and/or metastasize to other sights, as well as acquiring the ability to induce angiogenesis. Angiogenesis, the growth of new blood vessels from pre-existing ones, is a complex phenomenon that is absolutely required for the continued growth and survival of solid neoplasms. Without new blood vessels to provide nutrients and remove waste, tumors would be unable to grow larger than 2-3 mm in diameter. Therefore, one could envision its potential role in both the treatment and prevention of malignancies such as HNSCC. The concept of chemoprevention is extremely important in HNSCC since patients often develop multiple independent lesions throughout the mucosa of the upper aerodigestive tract. Therefore, the comprehensive treatment of this disease must address not only the initial primary neoplasm, but also prevent the progression of the premalignant lesions lurking throughout the rest of the mucosal surfaces. This review will outline the basic changes that occur in tumor cells that result in the switch to angiogenic phenotype. In addition, it will discuss the present status of using antiangiogenic agents in the treatment of cancer. Finally, this paper will present a rationale for the use of multiple antiangiogenic agents as a means of developing new chemotherapeutic and chemopreventive protocols that may result in reduced patient toxicity while maintaining similar clinical efficacies.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Escamosas/irrigación sanguínea , Neoplasias de la Boca/irrigación sanguínea , Neovascularización Patológica , Carcinoma de Células Escamosas/tratamiento farmacológico , Quimioprevención , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológicoRESUMEN
Invasive potentials of malignant cancer cells are regulated by cell motility factors. To examine the regulation of motility and invasiveness in oral squamous carcinoma, we investigated autocrine- and/or paracrine-acting cell motility factors, using a newly established human cell line (IF cells) from oral squamous cell carcinoma, which has highly invasive and metastatic characteristics. Conditioned medium derived from IF cells stimulated cell scattering and migration of GB-d1 gallbladder carcinoma cells, indicating that IF cells secreted cell motility factors. Using antibodies, IF-derived cell motility factors proved to be transforming growth factor (TGF)-alpha and TGF-beta1. Antibodies against TGF-alpha and TGF-beta1 inhibited autonomous migration of the IF cells. On the other hand, in vitro invasion of IF cells was strongly enhanced by hepatocyte growth factor (HGF) but only slightly by TGF-alpha and TGF-beta1. The conditioned medium from fibroblasts enhanced in vitro invasion of IF cells, an event abrogated by anti-HGF antibody, but not by antibodies against TGF-alpha and TGF-beta1. Importantly, IF cells secreted a factor inducing HGF production in fibroblasts and the factor was identified as interleukin-1, which means that a mutual interaction exists between tumour cells and fibroblasts, as mediated by the HGF/HGF-inducer loop. These results indicate that IF cells utilize TGF-alpha and TGF-beta1 as autocrine-acting motility factors and HGF as a paracrine-acting motility factor, and that invasiveness of IF cells is particularly stimulated by HGF derived from stromal fibroblasts. Utilization of multiple cell motility/invasion factors that act in distinct pathways may confer highly invasive and metastatic potentials in IF oral squamous carcinoma cells.