RESUMEN
The CXCL4 paralog CXCL4L1 is a less studied chemokine that has been suggested to exert an antiangiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines, and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic ductal adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell coculture experiments, murine, and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment, which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands, which were mapped. CXCL4L1 inhibited angiogenesis but also affected tumor development more directly, depending on the tumor cell type. In vivo administration of an mAb against CXCL4L1 demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a protumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its antiangiogenic function. Cancer Res; 76(22); 6507-19. ©2016 AACR.
Asunto(s)
Inhibidores de la Angiogénesis/genética , Neoplasias Pancreáticas/genética , Receptores CXCR3/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Quimiocinas , Humanos , Ratones , Neovascularización Patológica , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Factor Plaquetario 4 , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Endometrial cancers with peritoneal spread are stage IVB of FIGO classification. Their pattern is similar to that of ovarian cancer. Optimal debulking surgery and chemotherapy are predictor of better overall and disease free survival. Despite the poor outcome, there is a need for new treatment options. Recommended management for this group of patients should consist of surgical cytoreduction followed by chemotherapy. There may be a role for neoadjuvant chemotherapy followed by interval surgery in selected subgroups of patients.
Asunto(s)
Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/cirugía , Terapia Neoadyuvante/métodos , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias Endometriales/patología , Femenino , Humanos , Estadificación de Neoplasias/métodos , Carga TumoralRESUMEN
OBJECTIVES: Interval debulking surgery (IDS) following neo-adjuvant chemotherapy (NAC) is a treatment option in advanced ovarian cancer. It is recommended to perform IDS early, after 3 cycles of NAC, but late IDS (after 6 cycles) may yield better results. Delaying IDS, however, harbours the risk of loosing the opportunity for debulking surgery. STUDY DESIGN: Retrospective comparison of two groups of patients with advanced ovarian carcinoma (stages IIC-IV) treated by platinum-based chemotherapy (CT) having undergone early IDS (after 3.6 cycles, group 1, n=33) or late IDS (after 6.3 cycles, group 2, n=104). Contemporary patients who had undergone standard treatment by primary debulking surgery (PDS)+CT (group 3, n=446) and those treated by CT alone (group 4, n=64 patients) served as internal controls. RESULTS: Prognosis in IDS patients (groups 1+2) was comparable to that in PDS patients (group 3). Only a few patients in group 4 potentially had lost an opportunity for debulking surgery. Groups 1 and 2 were well-matched concerning usual prognostic factors. Surgery extent and post-operative outcomes were similar in both. In contrast, complete cytoreductions were significantly more frequent in late than in early IDS (group 2 vs.1: 58% vs. 36%, p=0.03) and survival was not inferior in the late IDS group compared to the early IDS group with 37 vs. 22 months, respectively (p=0.09). CONCLUSION: Late IDS yields higher complete resection rates than early IDS and should be evaluated prospectively for outcome in further trials.
Asunto(s)
Neoplasias Ováricas/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Registros Médicos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
Anti-angiogenic treatments have recently been incorporated as a milestone in the management of metastatic renal cell carcinoma. This retrospective study explores this new practice in 94 patients treated by sorafenib, bevacizumab or sunitinib in the department of oncology of CHU of Bordeaux in a 32 months period. The adverse effects reported are similar than those from prospective trials but for some different in frequency or severity. Efficacy of these drugs appeared more modest than expected from phase III trials. An objective response rate or stabilisation longer than six month was seen in 35% of the patients. Median overall survival was 14.1 months (IC 95%: 8.3-18.7 months). Nevertheless, the population considered in this study had a worse prognosis with more patients with an altered general status (OMS 2 or 3: 13.8%).
