RESUMO
Secondary lymphoid tissue chemokine (SLC/CCL21), one of the CC chemokines, exerts potent antitumor immunity by co-localizing T cells and dendritic cells at the tumor site and is currently tested against human solid tumors. Here, we investigated whether the combination of recombinant adenovirus encoding murine CCL21 (Ad-mCCL21) with low-dose paclitaxel would improve therapeutic efficacy against murine cancer. Immunocompetent mice bearing B16-F10 melanoma or 4T1 breast carcinoma were treated with either Ad-mCCL21, paclitaxel, or both agents together. Our results showed that Ad-mCCL21 + low-dose paclitaxel more effectively reduced the growth of tumors as compared with either treatment alone and significantly prolonged survival time of the tumor-bearing animals. These antitumor effects of the combined therapy were linked to altered cytokine network at the tumor site, enhanced apoptosis of tumor cells, and decreased formation of new vessels in tumors. Importantly, the combined therapy elicited a strong therapeutic antitumor immunity, which could be partly abrogated by the depletion of CD4(+) or CD8(+) T lymphocytes. Collectively, these preclinical evaluations may provide a combined strategy for antitumor immunity and should be considered for testing in clinical trials.
Assuntos
Adenoviridae/genética , Antineoplásicos Fitogênicos/farmacologia , Quimiocina CCL21/genética , Vetores Genéticos/genética , Neoplasias/genética , Paclitaxel/farmacologia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Expressão Gênica , Terapia Genética , Vetores Genéticos/administração & dosagem , Humanos , Melanoma Experimental , Camundongos , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Neoplasias/terapia , Neovascularização Patológica , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga TumoralRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer. METHODS: Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan's blue lymphangiography. Tumoral lymphatics were delineated with both Evan's blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing. RESULTS: Mice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls. CONCLUSIONS: Our data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.
Assuntos
Linfangiogênese/fisiologia , Neoplasias Ovarianas/metabolismo , Fator D de Crescimento do Endotélio Vascular/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologiaRESUMO
Esophageal duplication cysts are rare and frequently asymptomatic anomalies of the adult gastrointestinal tract that are often misdiagnosed in clinical practice. Identifying the unique features of esophageal duplication cysts is therefore important. We report a unique case of esophageal duplication cyst in a 52-year-old woman with rapidly progressing chest pain and dysphagia. The cyst was found to share, in part, a remarkably inflammatory and edematous inner lining with the esophagus. Enucleation was not feasible, and therefore, esophagectomy was performed. The only long-term side effect that occurred after 44 months of follow-up examinations was slight acid reflux esophagitis.