Christoph Reissfelder

Bio: Christoph Reissfelder is an academic researcher from Heidelberg University. The author has contributed to research in topics: Medicine & Colorectal cancer. The author has an hindex of 29, co-authored 112 publications receiving 4233 citations. Previous affiliations of Christoph Reissfelder include German Cancer Research Center & University Hospital Heidelberg.

Glypican-1 identifies cancer exosomes and detects early pancreatic cancer

Abstract: Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.

Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Abstract: Spontaneous antitumor T cell responses in cancer patients are strongly controlled by Tregs, and increased numbers of tumor-infiltrating Tregs correlate with reduced survival. However, the tumor antigens recognized by Tregs in cancer patients and the impact of these cells on tumor-specific T cell responses have not been systematically characterized. Here we used a broad panel of long synthetic peptides of defined tumor antigens and normal tissue antigens to exploit a newly developed method to identify and compare ex vivo the antigen specificities of Tregs with those of effector/memory T cells in peripheral blood of colorectal cancer patients and healthy subjects. Tregs in tumor patients were highly specific for a distinct set of only a few tumor antigens, suggesting that Tregs exert T cell suppression in an antigen-selective manner. Tumor-specific effector T cells were detectable in the majority of colorectal cancer patients but not in healthy individuals. We detected differences in the repertoires of antigens recognized by Tregs and effector/memory T cells in the majority of colorectal cancer patients. In addition, only effector/memory T cell responses against antigens recognized by Tregs strongly increased after Treg depletion. The selection of antigens according to preexisting T cell responses may improve the efficacy of future immunotherapies for cancer and autoimmune disease.

Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases

Abstract: Antiangiogenic therapy with drugs that block vascular endothelial growth factor (VEGF) signaling to inhibit formation of new blood vessels in tumors is commonly used in colorectal cancer. Unfortunately, the effects of this therapy usually do not last for long, and a study by Rahbari et al . shows why this might be the case. The authors found that VEGF inhibition increased the stiffness of colorectal cancer liver metastases, making them more difficult to treat with chemotherapy. In a mouse model, the researchers were able to overcome this difficulty by using an enzyme to degrade a component of the extracellular matrix in liver metastases, suggesting that the matrix may be a target for future cancer therapies.

Overexpression of ZEB2 at the Invasion Front of Colorectal Cancer Is an Independent Prognostic Marker and Regulates Tumor Invasion In Vitro

Abstract: Purpose: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in tumor invasion and dissemination. EMT occurs predominantly at the tumor edge where it is induced by cytokines, the extracellular matrix environment, or hypoxia. In the tumor cell, it is further mediated by several transcription factors and microRNAs. The aim of this study was to explore the expression of EMT-associated genes at the invasive front in colorectal cancer and to evaluate their prognostic significance. Experimental Design: We evaluated the expression of 13 EMT-associated genes at the invasion front of 30 colorectal liver metastases by quantitative real-time PCR. Immunostaining against zinc finger E-box–binding homeobox 2 (ZEB2) was carried out on 175 primary colorectal cancer specimens and 30 colorectal liver metastases and correlated to clinical and histopathologic data. DLD-1 cells were transfected with siRNA and subjected to migration and invasion assays. Results: Gene expression analysis and immunohistochemistry showed an upregulation of ZEB2 at the invasion front in primary colorectal cancer and liver metastases. Overexpression of ZEB2 at the invasion front correlated significantly with tumor stage in primary colorectal cancer. Moreover, univariate and multivariate analysis revealed overexpression of ZEB2 at the invasion front as an independent prognostic marker for cancer-specific survival. Downregulation of ZEB2 by siRNA decreased the migration and invasion capacity of DLD-1 cells in vitro . Conclusions: Overexpression of ZEB2 at the invasion front correlates with tumor progression and predicts cancer-specific survival in primary colorectal cancer. Therefore, ZEB2 may be interesting as biomarker and potential target for treatment of colorectal cancer. Clin Cancer Res; 17(24); 7654–63. ©2011 AACR .

Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study.

Abstract: Circulating tumour cells (CTC) in the blood have been accepted as a prognostic marker in patients with metastatic colorectal cancer (CRC) Only limited data exist on the prognostic impact of CTC in patients with early stage CRC using standardised detection assays The aim of this study was to elucidate the role of CTC in patients with non-metastatic CRC A total of 287 patients with potentially curable CRC were enrolled, including 239 patients with UICC stage I–III CTC were measured in the blood using the CellSearch system preoperatively and on postoperative days 3 and 7 The complete patient group (UICC I–IV) and the non-metastatic cohort (UICC I–III) were analysed independently Patients were followed for 28 (0–53) months Prognostic factors for overall and progression-free survival were analysed using univariate and multivariate analyses CTC were detected more frequently in patients with metastatic disease No clinicopathological variables were associated with CTC detection in non-metastatic patients CTC detection (⩾1 CTC per 75 ml blood) in the blood was significantly associated with worse overall survival (498 vs 384 months; P<0001) in the non-metastatic group (UICC I–III), as well as in the complete cohort (484 vs 336 months; P<0001) On multivariate analysis CTC were the strongest prognostic factor in non-metastatic patients (hazard ratio (HR) 55; 95% confidence interval (CI) 23–136) as well as in the entire study group (HR 56; 95% CI 26–120) Preoperative CTC detection is a strong and independent prognostic marker in non-metastatic CRC

Shedding light on the cell biology of extracellular vesicles.

Abstract: Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively They are present in biological fluids and are involved in multiple physiological and pathological processes Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles

The biology, function, and biomedical applications of exosomes

Abstract: The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

Multiple Imputation for Nonresponse in Surveys

Abstract: 25. Multiple Imputation for Nonresponse in Surveys. By D. B. Rubin. ISBN 0 471 08705 X. Wiley, Chichester, 1987. 258 pp. £30.25.

Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.

Abstract: Extracellular vesicles (EVs) have become the focus of rising interest because of their numerous functions in physiology and pathology. Cells release heterogeneous vesicles of different sizes and intracellular origins, including small EVs formed inside endosomal compartments (i.e., exosomes) and EVs of various sizes budding from the plasma membrane. Specific markers for the analysis and isolation of different EV populations are missing, imposing important limitations to understanding EV functions. Here, EVs from human dendritic cells were first separated by their sedimentation speed, and then either by their behavior upon upward floatation into iodixanol gradients or by immuno-isolation. Extensive quantitative proteomic analysis allowing comparison of the isolated populations showed that several classically used exosome markers, like major histocompatibility complex, flotillin, and heat-shock 70-kDa proteins, are similarly present in all EVs. We identified proteins specifically enriched in small EVs, and define a set of five protein categories displaying different relative abundance in distinct EV populations. We demonstrate the presence of exosomal and nonexosomal subpopulations within small EVs, and propose their differential separation by immuno-isolation using either CD63, CD81, or CD9. Our work thus provides guidelines to define subtypes of EVs for future functional studies.