Monitoring of circulating angiogenic factors in dendritic cell–based cancer immunotherapy

Brostjan, Christine; Bayer, A.; Zommer, Anna; Gornikiewicz, Alexander; Roka, R.; Benkö, Thomas; Yaghubian, Rubina; Jakesz, R.; Steger, G.; Gnant, Michael; Friedl, Josef; Stift, Anton

doi:10.1002/cncr.11776

Cited by 18 publications

(16 citation statements)

References 41 publications

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“…Commercially available ELISA tests were applied for VEGF (Quantikine; R&D Systems) and TSP-1 (Accucyte; Cytimmune Sciences, Inc.). A comparable ''sandwich'' ELISA system for PD-ECGF (detection range, 1-100 ng/mL) has previously been reported by us (31) and is based on the following antibodies: gelatin-free goat polyclonal a-human PD-ECGF antiserum (sc-9523; Santa Cruz Biotechnology, Inc.) diluted to 5 Ag/mL for coating, and murine monoclonal IgG1 clone P-GF.44C diluted to 500 ng/mL for detection (Neomarkers Lab Vision Corp.). The detection antibody was biotinylated using the FluoReporter Mini-Biotin-XX Protein Labeling kit (Molecular Probes, Inc.) according to manufacturer's instructions and was further complexed with a conjugate of streptavidin -horseradish peroxidase (Pierce Biotechnology).…”

Section: Methodssupporting

confidence: 56%

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Brostjan

Gebhardt

Gruenberger

et al. 2008

Clinical Cancer Research

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Purpose: Colorectal cancer patients receiving neoadjuvant treatment with bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor (VEGF), may suffer from wound healing complications after surgery as the antibody persists in patient blood. We characterized the systemic angiogenic balance in the perioperative period to evaluate its effect on physiologic angiogenesis. Experimental Design: Nineteen patients receiving combination chemotherapy and bevacizumab for six neoadjuvant cycles were compared with 14 patients receiving chemotherapy without bevacizumab. Plasma from perioperative days −1, +1, +7, and +21 was analyzed for VEGF, thrombospondin-1 (TSP-1), and PD-ECGF concentrations. The angiogenic capacity was further tested in an in vitro assay of endothelial cell proliferation and migration. Results: On day +1, the onset of wound healing was reflected in a change of balance, i.e., an increase of proangiogenic factors VEGF and platelet-derived endothelial cell growth factor compared with low TSP-1 inhibitor levels in both treatment groups. Patients with bevacizumab therapy showed significantly higher blood levels of total VEGF throughout the evaluation period. However, most VEGF molecules were inactive, i.e., complexed with antibody. Nevertheless, the capacity to stimulate endothelial growth was higher for these plasma samples and was reflected in low TSP-1 levels and an altered TSP-1 sensitivity. When purified TSP-1 protein was added, plasma samples of the bevacizumab but not the chemotherapy group showed reduced endothelial growth. Conclusions: Feedback mechanisms of bevacizumab therapy are not restricted to VEGF expression but seem to involve additional factors, such as TSP-1, which influences the systemic angiogenic balance and permits endothelial growth.

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Section: Methodssupporting

confidence: 56%

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Brostjan

Gebhardt

Gruenberger

et al. 2008

Clinical Cancer Research

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“…1H). This effect was achieved using a TSP1 concentration (2.2 nM) detected in the plasma of diseased patients (28, 29) and was not enhanced by higher concentrations (fig. S1, B and C).…”

Section: Resultsmentioning

confidence: 99%

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

et al. 2017

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Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue. In human endothelial cells, TSP1 promoted senescence and attenuated cell cycle progression and proliferation. At the molecular level, TSP1 increased Nox1-dependent generation of reactive oxygen species (ROS), leading to the increased abundance of the transcription factor p53. p53 mediated a DNA damage response that led to senescence through Rb and p21cip, both of which inhibit cell cycle progression. Nox1 inhibition blocked the ability of TSP1 to increase p53 nuclear localization and p21cip abundance and its ability to promote senescence. Mice lacking TSP1 showed decreases in ROS production, p21cip expression, p53 activity, and aging-induced senescence. Conversely, lung tissue from aging humans displayed increases in the abundance of vascular TSP1, Nox1, p53, and p21cip. Finally, genetic ablation or pharmacological blockade of Nox1 in human endothelial cells attenuated TSP1-mediated ROS generation, restored cell cycle progression, and protected against senescence. Together, our results provide insights into the functional interplay between TSP1 and Nox1 in the regulation of endothelial senescence and suggest potential targets for controlling the aging process at the molecular level.

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“…In addition, it is important to bear in mind that the use of autologous serum may indeed harbor several disadvantages. For example, in some tumor stage IV patients, we found very high serum levels of vascular endothelial growth factor, which is well known as an inhibitor of DC maturation (27,28). We are currently looking into other possibilities to avoid the use of FCS in the culture medium for generating high quality mature DCs and have obtained some promising preclinical results.…”

Section: Discussionmentioning

confidence: 97%

Dendritic Cell Vaccination in Medullary Thyroid Carcinoma

Stift

Sachet

Yagubian

et al. 2004

Clinical Cancer Research

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Purpose: Prognosis and treatment effectiveness for medullary thyroid carcinoma (MTC) are strictly related to tumor stage. Palliative treatment options show no significant benefit. A promising treatment approach for human cancer is based on the vaccination of autologous dendritic cells (DCs).Experimental Design: The objective of this study was to evaluate the effectiveness of DC vaccines in MTC patients. Therefore, we generated autologous tumor lysate-pulsed DCs from 10 patients suffering from advanced MTC for repeated vaccination. Mature DCs were derived from peripheral blood monocytes by using CD14 magnetic bead selection and subsequent culture in the presence of granulocyte macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor ␣ with or without addition of IFN-␥. DCs were loaded with tumor lysate and further injected into a groin lymph node. Toxicity, tumor marker profile, immune response, and clinical response were determined.Results: Vaccination was well tolerated and induced a positive immunological response in all of the tested patients as evaluated by in vivo delayed-type hypersensitivity reactivity or in vitro intracytoplasmic IFN-␥ detection assay. Three patients had a partial response, 1 patient presented a minor response, and 2 patients showed stable disease. The remaining 4 patients had progressive disease.Conclusions: These data provide strong evidence that vaccination with tumor-lysate pulsed DCs results in the induction of a specific immune response in patients suffering from MTC. Objective clinical responses could be observed even for far-advanced disease. Therefore, we suggest that MTC is particularly suited for DC-based immunotherapy.

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Monitoring of circulating angiogenic factors in dendritic cell–based cancer immunotherapy

Cited by 18 publications

References 41 publications

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1

Dendritic Cell Vaccination in Medullary Thyroid Carcinoma

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