Publications by authors named "Lena-Christin Conradi"

52 Publications

Low expression of CD24 is associated with poor survival in colorectal cancer.

Biochimie 2021 Oct 9. Epub 2021 Oct 9.

Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; SRC Bioclinicum, Moscow, Russia. Electronic address:

In this study we analyzed expression of CD24 in a cohort of colorectal cancer patients using immunohistochemistry staining of CD24. We found a significant association between absence or low expression of CD24 (10% of membranous and 55% of cytoplasmic staining) and shortened patient survival. Protein localization played a crucial role in the prognosis: membranous form was the major and prognostic one in primary tumors, while cytoplasmic expression was elevated in liver metastases compared to the primary tumors and contained prognostic information. Then, using The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) RNA-seq data, we showed that CD24 mRNA level was two-fold decreased in primary colorectal cancers compared to adjacent normal mucosa. Like the protein staining data, ten percent of patients with the lowest mRNA expression levels of CD24 in primary tumors had reduced survival compared to the ones with higher expression. To explain these findings mechanistically, shRNA-mediated CD24 knockdown was performed in HT-29 colorectal cancer cells. It resulted in the increase of cell migration in vitro, no changes in proliferation and apoptosis, and a slight decrease in cell invasion. As increased cell migration is a hallmark of metastasis formation, this finding corroborates the association of a decreased CD24 expression with poor prognosis. Differential gene expression analysis revealed upregulation of genes involved in cell migration in the group of patients with low CD24 expression, including integrin subunit α3 and α3, β3 subunits of laminin 332. Further co-expression analysis identified SPI1, STAT1 and IRF1 transcription factors as putative master-regulators in this group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2021.10.004DOI Listing
October 2021

[Influence of molecular markers on oncological surgery of colorectal cancer].

Chirurg 2021 Aug 27. Epub 2021 Aug 27.

Klinik für Allgemein‑, Viszeral- und Kinderchirurgie, Universitätsmedizin Göttingen, Göttingen, Deutschland.

Colorectal cancer (CRC) is still a very common disease and one of the best characterized malignancies on a molecular level. Interdisciplinary and multimodal treatment strategies should be preferred. In addition to surgical resection in localized stages as well as metastasectomy for oligometastatic advanced stages, neoadjuvant chemoradiotherapy for localized rectal cancer and cytostatic treatment, targeted treatment approaches should also be considered. This overview presents established and novel prognostic and predictive molecular markers of (metastasized) CRC and describes these as targeted therapy options. The determination of high microsatellite instability (MSI-H) has a therapeutic influence when planning adjuvant therapy and also now in the treatment of metastatic CRC. Furthermore, circulating tumor DNA represents a promising marker with respect to a recurrence in early as well as in advanced stages of disease. In addition to the RAS and BRAF mutation status and the localization of the primary tumor, an MSI‑H is also important with respect to the treatment strategy and should be determined before initiation of first-line treatment in metastasized CRC. New pharmaceutical approaches enable targeted interventions at the immunological or molecular level. The understanding of CRC as a heterogeneous disease has been increased using recently established analyses at the molecular level; however, it also generated many hypotheses that require further evaluation with respect to their clinical importance. Special attention is paid to patients affected by hereditary syndromes because of the early onset of disease and the considerable consequences individually and for the patient's family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00104-021-01486-7DOI Listing
August 2021

Tumor vessel co-option probed by single-cell analysis.

Cell Rep 2021 Jun;35(11):109253

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 510275, Guangzhou, Guangdong, P.R. China; Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark. Electronic address:

Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109253DOI Listing
June 2021

Volumetric Modulated Arc Therapy Improves Outcomes in Definitive Radiochemotherapy for Anal Cancer Whilst Reducing Acute Toxicities and Increasing Treatment Compliance.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

Background: Intensity-modulated radiotherapy (IMRT) is the standard of care in chemoradiotherapy (CRT) for anal cancer. Until now, only a limited number of studies have analyzed the results with VMAT (volumetric modulated arc therapy). We conducted a retrospective study on patients treated at our institution.

Patients And Methods: We included patients who received curative CRT for anal cancer. We compared VMAT-treated and 3DCRT (3D conformal radiotherapy)-treated patients. We analyzed toxicities (acute: CTCAE criteria; late: LENT/SOMA criteria), treatment compliance, overall survival, cancer-specific survival (CSS), distant control (DC), and locoregional control.

Results: A total of 149 patients (3DCRT: = 87, VMAT: = 62) were included. The median follow-up was longer in 3DCRT-treated patients (3DCRT: 61.3 months; VMAT: 39.1 months; < 0.05). VMAT-treated patients had more G3 tumors (3DCRT: 12/87 (13.8%); VMAT: 18/62 (29.0%), < 0.001). VMAT reduced acute toxicities ≥grade 3 (3DCRT: = 48/87 (55.2%); VMAT: = 11/62 (17.7%), < 0.001). VMAT improved treatment compliance (less interruptions/delays) (3DCRT: 37/87, 42.5%; VMAT: 4/62, 6.5%; < 0.001), provided a shorter median overall treatment time (3DCRT: 41 days; VMAT: 38 days; = 0.02), and gave a higher median absolute 5-fluorouracil dose (3DCRT: 13,700 mg; VMAT: 14,400 mg; = 0.001). Finally, we found improved CSS ( = 0.02; 3DCRT: 81.9% at 3 years; VMAT: 94.1% at 3 years) and DC ( = 0.01; 3DCRT: 89.4% at 3 years; VMAT: 100.0% at 3 years) with VMAT.

Summary: Our study is the first to demonstrate improved treatment compliance and outcomes with VMAT for anal cancer. Previous studies have indicated that organs at risk sparing might be more improved with the use of VMAT vs. with conventional IMRT. Future studies should address whether these advantages lead to a further reduction in CRT-associated morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196749PMC
May 2021

Preoperative Radiochemotherapy in Esophageal Squamous Cell Cancer with 5-Fluorouracil/Cisplatin or Carboplatin/Paclitaxel: Treatment Practice over a 20-Year Period and Implications for the Individual Treatment Modalities.

Cancers (Basel) 2021 Apr 12;13(8). Epub 2021 Apr 12.

Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

We retrospectively studied outcomes in patients treated with preoperative radiochemotherapy and surgery for esophageal squamous cell cancer. We put special focus on the comparison of patients treated with 5-fluorouracil/cisplatin ('Walsh') or carboplatin/paclitaxel ('CROSS'). We compared characteristics between patients treated according to 'Walsh' vs. 'CROSS'. Cox regression was performed to test for an association of parameters with outcomes. Study eligibility was met by 90 patients. First, the higher age and more comorbidities of the 'CROSS' patients, along with a shorter intensive care/intermediate care stay, might reflect an improvement in supportive and surgical/perioperative procedures over the periods. Second, the 'CROSS' patients experienced more hematologic toxicity and were less likely to complete chemotherapy as per protocol. This indicates that efforts should be taken to guide patients through a toxic treatment regimen by supportive measures. Third, the negative prognostic impact of radiochemotherapy-related toxicities (i.e., dysphagia and hematologic toxicities) and the duration of the intensive care/intermediate care unit stay underlines that further optimization of treatment procedures remains an important goal. We found no differences in tumor downstaging and survival between treatment regimen. Toxicity profiles could be improved by tailoring the regimen to individual patients (e.g., careful use of the taxane-based regimen in elderly patients).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13081834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068912PMC
April 2021

Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases.

Front Cell Dev Biol 2021 12;9:612774. Epub 2021 Apr 12.

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.612774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072376PMC
April 2021

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo.

Cancers (Basel) 2021 02 28;13(5). Epub 2021 Feb 28.

Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany.

Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients' long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets.

Materials And Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice.

Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo.

Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13051011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957803PMC
February 2021

Prognostic value of the micronucleus assay for clinical endpoints in neoadjuvant radiochemotherapy for rectal cancer.

BMC Cancer 2021 Mar 4;21(1):219. Epub 2021 Mar 4.

University Medical Center Göttingen, Göttingen, Germany.

Background: The question whether lymphocyte radiosensitivity is representative of patients' response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients' and RCT characteristics on cytogenetic damage, and tested for correlations with patients' outcome in terms of tumor response, survival and treatment-related toxicity.

Methods: The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3 Gy. RCT included 50.4 Gy of pelvic RT with 5-fluorouracil (5-FU) alone (n = 78) or 5-FU plus oxaliplatin (n = 56). The analyzed variables included patients' age, gender, RT characteristics (planning target volume size [PTV size], RT technique), and chemotherapy characteristics (5-FU plasma levels, addition of oxaliplatin). Outcome was analyzed as tumor regression, patient survival, and acute and late toxicity.

Results: Cytogenetic damage increased significantly with the radiation dose and varied substantially between individuals. Women were more sensitive than men; no significant age-dependent differences were observed. There was a significant correlation between the cytogenetic damage after in-vitro irradiation and in-vivo RCT. We found a significant effect of the PTV size on the yields of cytogenetic damage after RCT, while the RT technique had no effect. Neither the addition of oxaliplatin nor the 5-FU levels influenced cytogenetic damage. We found no correlation between patient outcome and the cytogenetic damage.

Conclusions: We found consistent cytogenetic damage in lymphocytes after in-vivo RCT and in-vitro irradiation. Gender was confirmed as a well-known, and the PTV size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation. A consistent level of cytogenetic damage after in-vivo and in-vitro irradiation may indicate the importance of genetic factors for individual radiosensitivity. However, we found no evidence that in-vivo or in-vitro irradiation-induced cytogenetic damage is an adequate biomarker for the response to RCT in rectal cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-07914-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931609PMC
March 2021

Late-stage stitching enabled by manganese-catalyzed C─H activation: Peptide ligation and access to cyclopeptides.

Sci Adv 2021 Feb 26;7(9). Epub 2021 Feb 26.

Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany.

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies heavily rely on noble-metal catalysis. Herein, we report on a manganese(I)-catalyzed peptide C─H hydroarylation that enabled the stitching of peptidic and sugar fragments, under exceedingly mild and racemization-free conditions. This convergent approach represents an atom-economical alternative to traditional iterative peptide synthesis. The robustness of the manganese(I) catalysis regime is reflected by the full tolerance of a plethora of sensitive functional groups. Our strategy enabled an expedient access to challenging cyclic peptides by a modular late-stage macrocyclization of structurally complex peptides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abe6202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909873PMC
February 2021

Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer.

Cell Death Dis 2021 02 4;12(2):155. Epub 2021 Feb 4.

Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany.

Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-021-03426-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862487PMC
February 2021

NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy.

Cancers (Basel) 2021 Jan 26;13(3). Epub 2021 Jan 26.

Institute of Cellular and Molecular Immunology, University Medical Center Goettingen, 37073 Goettingen, Germany.

Resistance of tumor cells to chemoradiotherapy represents a fundamental problem in clinical oncology. The underlying mechanisms are actively debated. Here we show that blocking inflammatory cytokine receptor signaling via STAT3 re-sensitized treatment-refractory cancer cells and abolished tumor growth in a xenograft mouse model when applied together with chemoradiotherapy. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. The mandatory RBPJ interaction partner, NOTCH intracellular domain, was provided by tumor cell-intrinsic expression of NOTCH ligands that caused tonic NOTCH proteolysis. In fact, NOTCH inhibition phenocopied the effect of blocking STAT3 signaling. Moreover, genetic profiling of rectal cancer patients revealed the importance of the STAT3/NOTCH axis as NOTCH expression correlated with clinical outcome. Our data uncovered an unprecedented signal alliance between inflammation and cellular development that orchestrated resistance to chemoradiotherapy. Clinically, our findings allow for biomarker-driven patient stratification and offer novel treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865718PMC
January 2021

Vascular Heterogeneity With a Special Focus on the Hepatic Microenvironment.

Front Physiol 2020 11;11:591901. Epub 2020 Nov 11.

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

Utilizing single-cell sequencing, recent studies were able to analyze at a greater resolution the heterogeneity of the vasculature and its complex composition in different tissues. Differing subpopulations have been detected, distinguishable only by their transcriptome. Designed to provide further insight into the heterogeneity of the functional vascular tissue, endothelial cells have been the main target of those studies. This review aims to present a synopsis of the variability of the different vascular beds, their endothelial variety, and the supporting cells that allow the vessels to serve their various purposes. Firstly, we are going to chart vascular tissue heterogeneity on a cellular level, describing endothelial diversity as well as stromal microenvironmental variety and interaction in a physiological setting. Secondly, we will summarize the current knowledge of pathological vessel formation in the context of cancer. Conventional anti-tumor therapeutic targets as well as anti-angiogenetic therapy is frequently limited by poor response of the tumor tissue. Reasons for moderate response and resistance to treatment can be found through different drivers of angiogenesis, different mechanisms of blood supply, but also in poorly understood tissue diversity. Based on this, we are comparing how pathologies alter the normal structure of vascular tissues highlighting the involved mechanisms. Lastly, illustrating the concept above, we will focus on the hepatic microenvironment, an organ of frequent metastatic spreading (e.g., from colorectal, breast, and lung cancers). We will address how the hepatic vasculature usually develops and subsequently we will describe how common liver metastases vary in their vasculature and the way they supply themselves (e.g., angiogenesis versus vessel co-option).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.591901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686534PMC
November 2020

Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis.

Cell Metab 2020 04;31(4):862-877.e14

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium.

Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.03.009DOI Listing
April 2020

An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates.

Cancer Cell 2020 01;37(1):21-36.e13

Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium.

Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.12.001DOI Listing
January 2020

Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.

Digestion 2021 6;102(2):227-235. Epub 2019 Nov 6.

Institute of Pathology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany.

Background: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities.

Patients And Methods: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial.

Results: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts.

Conclusion: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000504093DOI Listing
August 2021

Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer.

BMC Cancer 2019 Sep 5;19(1):880. Epub 2019 Sep 5.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany.

Background: Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837.

Methods: Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation.

Results: The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors' mode of action, as targeting HER-2 alone is not sufficient.

Conclusion: Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-6051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727342PMC
September 2019

EndoDB: a database of endothelial cell transcriptomics data.

Nucleic Acids Res 2019 01;47(D1):D736-D744

Department of Oncology and Leuven Cancer Institute (LKI), Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven, 3000 Leuven, Belgium.

Endothelial cells (ECs) line blood vessels, regulate homeostatic processes (blood flow, immune cell trafficking), but are also involved in many prevalent diseases. The increasing use of high-throughput technologies such as gene expression microarrays and (single cell) RNA sequencing generated a wealth of data on the molecular basis of EC (dys-)function. Extracting biological insight from these datasets is challenging for scientists who are not proficient in bioinformatics. To facilitate the re-use of publicly available EC transcriptomics data, we developed the endothelial database EndoDB, a web-accessible collection of expert curated, quality assured and pre-analyzed data collected from 360 datasets comprising a total of 4741 bulk and 5847 single cell endothelial transcriptomes from six different organisms. Unlike other added-value databases, EndoDB allows to easily retrieve and explore data of specific studies, determine under which conditions genes and pathways of interest are deregulated and assess reprogramming of metabolism via principal component analysis, differential gene expression analysis, gene set enrichment analysis, heatmaps and metabolic and transcription factor analysis, while single cell data are visualized as gene expression color-coded t-SNE plots. Plots and tables in EndoDB are customizable, downloadable and interactive. EndoDB is freely available at https://vibcancer.be/software-tools/endodb, and will be updated to include new studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gky997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324065PMC
January 2019

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis.

Oncotarget 2018 Aug 14;9(63):32204-32218. Epub 2018 Aug 14.

Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.

Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established.

Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors () and their ligands ( and ) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression . Results were correlated with clinico-pathologic data and molecular subtypes.

Results: Primary tumors showed (6.3%) and (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111).

Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114946PMC
August 2018

Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis.

Cell Metab 2018 12 23;28(6):881-894.e13. Epub 2018 Aug 23.

Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, 3000 Leuven, Belgium.

Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid β-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1A mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1A mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1A mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.07.016DOI Listing
December 2018

Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation.

Cell Metab 2018 12 23;28(6):866-880.e15. Epub 2018 Aug 23.

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, P.R. China. Electronic address:

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASN elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASN ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057116PMC
December 2018

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion.

Cancer Cell 2018 08;34(2):298-314.e7

Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen 37077, Germany; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address:

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53 allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53 are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582949PMC
August 2018

Tumor vessel disintegration by maximum tolerable PFKFB3 blockade.

Angiogenesis 2017 Nov 5;20(4):599-613. Epub 2017 Sep 5.

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000, Leuven, Belgium.

Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10456-017-9573-6DOI Listing
November 2017

Simultaneous inhibition of IGF1R and EGFR enhances the efficacy of standard treatment for colorectal cancer by the impairment of DNA repair and the induction of cell death.

Cancer Lett 2017 10 18;407:93-105. Epub 2017 Aug 18.

Institute of Human Genetics, University Medical Centre Göttingen, Germany. Electronic address:

Overexpression and activation of receptor tyrosine kinases (RTKs), such as the insulin-like growth factor 1 receptor (IGF1R) and the epidermal growth factor receptor (EGFR), are frequent phenomena in colorectal cancer (CRC). Here, we evaluated the effect and the cellular mechanisms of the simultaneous inhibition of these two RTKs both in vitro and in vivo in addition to a 5-fluoruracil (5-FU)-based radiochemotherapy (RCT), which is a standard treatment scheme for CRC. Using the small molecule inhibitors AEW541 and erlotinib, specific against IGF1R and EGFR, respectively, different CRC cell lines exhibited a reduced survival fraction after RCT, with the highest effect after the simultaneous inhibition of IGF1R/EGFR. In vivo, xenograft mice simultaneously treated with low dose AEW541/erlotinib plus RCT revealed a significant reduction in tumour volume and weight compared with the tumours of mice treated with either AEW541 or erlotinib alone. In vitro, the combined inhibition of IGF1R/EGFR resulted in a stronger reduction of downstream signalling, an increase in DNA double strand breaks (DSBs), apoptosis and mitotic catastrophe after RCT depending on the cell line. Moreover, the existence of IGF1R/EGFR heterodimers in CRC cells and human rectal cancer samples was proven. The heterodimerisation of these RTKs was dependent on the presence of both ligands, IGF-1 and EGF, and functional receptors. In conclusion, these results demonstrate that the strategy of targeting both IGF1R and EGFR, in addition to basic RCT, could be of intriguing importance in CRC therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2017.08.009DOI Listing
October 2017

The utilization of multidisciplinary tumor boards (MDT) in clinical routine: results of a health care research study focusing on patients with metastasized colorectal cancer.

Int J Colorectal Dis 2017 Oct 5;32(10):1463-1469. Epub 2017 Aug 5.

Department of General, Visceral and Pediatric Surgery, University Medical Center Georg-August-University, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.

Purpose: Multidisciplinary tumor boards (MDT) have been advocated as standard of care in modern oncology. German guidelines for metastasized colorectal cancer (mCRC) recommend MDT discussion of colon cancer patients after completion of primary tumor therapy but stage IV colon cancer as well as rectal cancer patients prior to any therapy. In this health care research study, we evaluated application and decisional consequences of this approach in clinical routine.

Methods: All major institutions providing oncological care in southern Lower Saxony and Northern Hesse (N = 11) were invited. Patients with mCRC diagnosed between 01/2011 and 12/2013 were eligible. Data were collected using a standardized patient report form and stored in a GCP-conform EDC-system (secuTrial®).

Results: A university medical center, four teaching hospitals, one communal hospital, and three oncological focus practices participated in the study. In total, 470 patients with a median age of 70 years were enrolled. Guideline conform MDT discussion was performed in 63% of operated colon cancer patients, 38% of stage IV colon cancer patients and 47% of rectal cancer patients, respectively. Resection of metastases was performed in 41% of cases. Patients ≥70 years (n = 250) received significantly more often treatment following MDT discussion (86 versus 64%, p = 0.0002). Not the resection rate (48 versus 57%, p = 0.1574) but indication for preoperative chemotherapy (57 versus 33%, p = 0.0056) significantly differed when patients with single organ metastases experienced MDT discussion.

Conclusions: MDT discussion is not as established as advocated by national guidelines. Treatment decisions differ especially in older patients and those with single organ metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00384-017-2871-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596058PMC
October 2017

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer.

J Cancer 2017 10;8(7):1229-1237. Epub 2017 Apr 10.

Department of General, Visceral, and Pediatric Surgery, University Medical Center, Göttingen, Germany.

The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.16980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463438PMC
April 2017

Central Role of Metabolism in Endothelial Cell Function and Vascular Disease.

Physiology (Bethesda) 2017 03;32(2):126-140

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, University of Leuven, Leuven, Belgium; and

The importance of endothelial cell (EC) metabolism and its regulatory role in the angiogenic behavior of ECs during vessel formation and in the function of different EC subtypes determined by different vascular beds has been recognized only in the last few years. Even more importantly, apart from a role of nitric oxide and reactive oxygen species in EC dysfunction, deregulations of EC metabolism in disease only recently received increasing attention. Although comprehensive metabolic characterization of ECs still needs further investigation, the concept of targeting EC metabolism to treat vascular disease is emerging. In this overview, we summarize EC-specific metabolic pathways, describe the current knowledge on their deregulation in vascular diseases, and give an outlook on how vascular endothelial metabolism can serve as a target to normalize deregulated endothelium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/physiol.00031.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337830PMC
March 2017

Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy.

Cancer Cell 2016 Dec 17;30(6):968-985. Epub 2016 Nov 17.

Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA; Section of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.

Abnormal tumor vessels promote metastasis and impair chemotherapy. Hence, tumor vessel normalization (TVN) is emerging as an anti-cancer treatment. Here, we show that tumor endothelial cells (ECs) have a hyper-glycolytic metabolism, shunting intermediates to nucleotide synthesis. EC haplo-deficiency or blockade of the glycolytic activator PFKFB3 did not affect tumor growth, but reduced cancer cell invasion, intravasation, and metastasis by normalizing tumor vessels, which improved vessel maturation and perfusion. Mechanistically, PFKFB3 inhibition tightened the vascular barrier by reducing VE-cadherin endocytosis in ECs, and rendering pericytes more quiescent and adhesive (via upregulation of N-cadherin) through glycolysis reduction; it also lowered the expression of cancer cell adhesion molecules in ECs by decreasing NF-κB signaling. PFKFB3-blockade treatment also improved chemotherapy of primary and metastatic tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675554PMC
December 2016

Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study.

Cancer 2017 Feb 20;123(4):638-649. Epub 2016 Oct 20.

Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

Background: In previous work, a single administration of anticarcinoembryonic antigen (anti-CEA) I-labetuzumab radioimmunotherapy (RIT) after complete resection of colorectal liver metastases was well tolerated and significantly improved survival compared with controls. In the current phase 2 trial, the authors studied repeated RIT in the same setting, examining safety, feasibility, and efficacy.

Methods: Sixty-three patients (median age, 64.5 years) received RIT at 40 to 50 millicuries/m per dose. Before the receipt of RIT, restaging was performed with computed tomography/magnetic resonance imaging and F-fluorodeoxyglucose-positron emission to confirm that patients were "truly adjuvant." Patients who had elevated serum CEA levels or radiographically inconclusive new lesions were classified as "possibly nonadjuvant," but they also received RIT. Time to progression (TTP), overall survival (OS), and cause-specific survival (CSS) were calculated. The median follow-up was 54 months.

Results: After the first course of RIT, 14 of 63 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity; 19 patients did not receive the second course of RIT because of impaired performance status (N = 5) or relapse (N = 14). After the second course of RIT, 9 of 44 patients experienced National Cancer Institute Common Toxicity Criteria grade 4 hematotoxicity. Five patients developed myelodysplastic syndrome (MDS) from 22 to 55 months after their last RIT. The median TTP, OS, and CSS for all patients were 16, 55, and 60 months, respectively. The "truly adjuvant" patients (N = 39) had an improved median TTP (not reached vs 6.1 months; hazard ratio, 0.12; P < .001), OS (75.6 vs 33.4 months; hazard ratio, 0.44; P = .014), and CSS (not reached vs 41.4 months; hazard ratio,0.42; P = .014) compared with "possibly nonadjuvant" patients (N = 24).

Conclusions: Repeated RIT with I-labetuzumab is feasible but is associated with hematotoxicity. Survival is very encouraging, especially for "truly adjuvant" patients. However, the maximum safe dose of I-labetuzumab is a single administration of 50 millicuries/m . Cancer 2017;123:638-649. © 2016 American Cancer Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.30390DOI Listing
February 2017

Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities.

EMBO Mol Med 2016 10 4;8(10):1134-1142. Epub 2016 Oct 4.

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, Leuven, Belgium

Cancer cell metabolism has received increasing attention. Despite a boost in the application of clinical metabolic profiling (CMP) in cancer patients, a meta-analysis has not been performed. The primary goal of this study was to assess whether public accessibility of metabolomics data and identification and reporting of metabolites were sufficient to assess which metabolites were consistently altered in cancer patients. We therefore retrospectively curated data from CMP studies in cancer patients published during 5 recent years and used an established vote-counting method to perform a semiquantitative meta-analysis of metabolites in tumor tissue and blood. This analysis confirmed well-known increases in glycolytic metabolites, but also unveiled unprecedented changes in other metabolites such as ketone bodies and amino acids (histidine, tryptophan). However, this study also highlighted that insufficient public accessibility of metabolomics data, and inadequate metabolite identification and reporting hamper the discovery potential of meta-analyses of CMP studies, calling for improved standardization of metabolomics studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.201606798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048364PMC
October 2016
-->