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Many Malignancies (many + malignancy)
Selected AbstractsNuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissuesHISTOPATHOLOGY, Issue 5 2009Juan Carlos Martinez Aims:, Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a ,brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. Methods and results:, The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. Conclusions:, Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target. [source] Paxillin modulates squamous cancer cell adhesion and is important in pressure-augmented adhesionJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2006William C. Conway Abstract Paxillin is an adapter protein regulating signaling and focal adhesion assembly that has been linked to malignant potential in many malignancies. Overexpression of paxillin has been noted in aggressive tumors. Integrin-mediated binding through the focal adhesion complex is important in metastatic adhesion and is upregulated by extracellular pressure in malignant colonocytes through FAK and Src activation. Neither head and neck cancers nor paxillin have been studied in this regard. We hypothesized that paxillin would play a role in modulating squamous cancer adhesion both at baseline and under conditions of increased extracellular pressure. Using SCC25 tongue squamous cancer cells stably transfected with either an empty selection vector or paxillin expression and selection vectors, we studied adhesion to collagen, paxillin, FAK, and Src expression and phosphorylation in cells maintained for 30 min under ambient or 15 mmHg increased pressure conditions. Paxillin-overexpressing cells exhibited adhesion 121,±,2.9% of that observed in vector-only cells (n,=,6, P,<,0.001) under ambient pressure. Paxillin-overexpression reduced FAK phosphorylation. Pressure stimulated adhesion to 118,±,2.3% (n,=,6, P,<,0.001) of baseline in vector-only cells, similar to its effect in the parental line, and induced paxillin, FAK, and Src phosphorylation. However, increased pressure did not stimulate adhesion or phosphorylate paxillin, FAK, or Src further in paxillin-overexpressing cells. Metastasizing squamous cancer cell adhesiveness may be increased by paxillin-overexpression or by paxillin activation by extracellular pressure during surgical manipulation or growth within a constraining compartment. Targeting paxillin in patients with malignancy and minimal tumor manipulation during surgical resection may be important therapeutic adjuncts. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Angiosarcoma developing in a non-functioning arteriovenous fistula post-renal transplantJOURNAL OF SURGICAL ONCOLOGY, Issue 6 2010Yassar A. Qureshi MBBS Abstract Background Angiosarcomas comprise less than 1% of all sarcomas, arising from endothelial cells of blood or lymph vessels. Chronic immunosuppression increases the risk of many malignancies and an association between the development of angiosarcoma with an immunosuppressed state is established. A few cases have been reported of angiosarcomas arising in the post-renal transplant patient. Specifically, there have been six cases of an angiosarcoma arising in arteriovenous (AV) fistulae in this patient population. We describe a further case and review the relevant literature with specific emphasis on a possible mechanism for the development of angiosarcoma in the post-transplant patient. Case Presentation We report the case of a 48-year-old male who developed an angiosarcoma in a ligated native AV fistula. The lesion arose on the background of immunosuppression following a successful ABO-incompatible renal transplant for chronic renal failure. Conclusion Angiosarcomas are extremely rare tumours but should be considered as a differential diagnosis for an evolving mass near the site of an AV fistula. Diagnosis relies on an index of suspicion and obtaining a definitive histological diagnosis. Both clinicians and patients should be aware that an evolving mass within or around an AV fistula should prompt urgent biopsy. J. Surg. Oncol. 2010; 101:520,523. © 2010 Wiley-Liss, Inc. [source] Socio-economic deprivation and survival in bladder cancerBJU INTERNATIONAL, Issue 4 2004Gulnaz Begum OBJECTIVES To investigate the relationship between deprivation, delay and survival from bladder cancer in the West Midlands, as socio-economic deprivation is associated with worse survival in many malignancies, and it has been suggested that treatment differences and delay in seeking care are major contributing causes. PATIENTS AND METHODS Data were prospectively collected on 1537 newly diagnosed cases of urothelial cancer presenting in the West Midlands between January 1991 and June 1992. Survival was censored at 31 July 2000, when 785 (51%) patients had died. The influence of deprivation on survival was explored using cause-specific and all-cause mortality. RESULTS Patients in less affluent groups had significantly worse survival than patients in more affluent groups when considering deaths from all causes (P = 0.02), which held true when adjusting for independent prognostic factors (age, smoking history, and tumour grade, stage, type and size). Bladder cancer-specific mortality showed no significant difference between socio-economic groups (P = 0.30). CONCLUSION Socio-economic deprivation is a significant predictor of survival when death from all causes is considered. However, this does not hold true for bladder cancer-specific death. The perceived differences in treatment and delay between socio-economic groups do not seem to occur for bladder cancer in the West Midlands. [source] Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivoCANCER, Issue 13 2010Kristen N. Richards MS Abstract BACKGROUND: ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. METHODS: The authors examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot, and quantitative real time polymerase chain reaction (Q-PCR). Response to ERBB inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements. RESULTS: A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with HER-2 in some tumors. HER-4 mRNA was expressed predominantly in cleavable isoforms. Whereas EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, although CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. CONCLUSIONS: Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, although EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma. Cancer 2010. © 2010 American Cancer Society. [source] A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimensCANCER, Issue 2 2006Ph.D., William Wierda M.D. Abstract BACKGROUND Combining therapeutics with single-agent activity has improved treatment for patients with many malignancies. Debate continues about the impact of treatment on survival in patients with chronic lymphocytic leukemia (CLL). Purine analogues are the most active agents for treatment of patients with CLL. Recently, it was shown that a chemoimmunotherapy regimen combining fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) was very effective in treating patients with recurrent and/or refractory CLL. The objective of the current analysis was to determine whether improvements in treatment have had an impact on survival for patients with CLL. METHODS Three nonoverlapping, sequential groups of patients enrolled on Phase II studies who received treatment with F (n = 251 patients), FC (n = 111 patients), or FCR (n = 143 patients) were analyzed. Pretreatment characteristics, responses to treatment, and overall survival were compared. RESULTS Patients who were treated with FCR had a higher complete remission rate compared with patients who were treated with combined F and C or with F alone. Statistically significantly longer estimated median survival was noted for patients who received FCR. A Cox proportional hazards, multivariable model for overall survival that included all patients (n = 505) showed that patients who received FCR had longer survival (P < 0.0001) after adjusting for other significant (P < 0.05) pretreatment characteristics, including age, hemoglobin, ,-2 microglobulin, and the number of prior treatments. CONCLUSIONS The results of this retrospective comparison of patients with recurrent and refractory CLL indicated a higher complete remission rate and the longest estimated survival for patients who were treated with FCR, providing the basis for randomized clinical trials of this regimen. Cancer 2006. © 2005 American Cancer Society. [source] Immune complex-stimulated production of interleukin-12 in peripheral blood mononuclear cells is regulated by the complement systemCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2004A. TEJDE SUMMARY Immune complexes (IC) can induce cytokine production in vitro. While immune aggregates (IA) consisting of heat-aggregated gamma globulin (HAGG) as model IC increased interleukin (IL)-10 levels in cell cultures with native human serum, IL-12p40/p70 production was inhibited. Three series of experiments suggested that the effects of IA on IL-12 production depended on a functionally intact complement system: (1) heat-inactivation of serum inverted the inhibitory effect of IA on IL-12p40/p70 production; (2) IA-induced IL-12p40 production in a C4 deficient serum was lowered by addition of C4; and (3) addition of the peptide compstatin, which blocks C3 activation, mimicked the effects of heat inactivation on IL-12p40 levels. Neutralization of IL-12 resulted in modestly increased IL-10 levels, while neutralization of IL-10 had no effects on IL-12p40 production. IA-induced production of IL-10 was partially blocked by anti-Fc,,RII antibodies, whereas Fc,,R or CR blockade had no effect on IL-12p40 production. IC and local or systemic complement activation characterize rheumatoid arthritis, systemic lupus erythematosus and many malignancies. Different and complement-dependent effects on the production of IL-10 and IL-12 can be of importance in these diseases, where control of the complement system might be a way to direct IC-induced cytokine production in either a type 1 or type 2 direction. [source] | ||||||||||