Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78698 | GEO | 2016/04/19
SECONDARY ACCESSION(S): PRJNA313284
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC4870473 | biostudies-literature
Project description:In the tumor microenvironment the extracellular matrix molecule tenascin-C is highly expressed which correlates with worsened survival prognosis. Tenascin-C promotes multiple steps in cancer progression. In particular, tenascin-C promotes the tumor angiogenic switch and the formation of more but poorly functional blood vessels by ill defined mechanisms. Here, we studied tenascin-C angio-modulatory functions by tumor and stromal cells. Unexpectedly, we observed that direct contact of endothelial cells with tenascin-C impairs angiogenesis through disruption of actin polymerization. This resulted in cytoplasmic retention of the F-actin sensor and co-transcription factor YAP and led to downregulation of YAP pro-angiogenic target genes. Conversely, tumor cells and carcinoma associated fibroblasts exposed to tenascin-C secreted pro-angiogenic factors that promoted endothelial cell survival and tubulogenesis. We identified and functionally validated CXCL12 and Ephrin- B2 as important pro-angiogenic effectors of tenascin-C. Proteomic analysis of the secretome of tumor cells exposed to tenascin-C revealed a signature that predicts shorter survival of patients with low grade glioma and glioblastoma with a particular significance for a combined expression of tenascin-C and Ephrin-B2. Altogether, we demonstrated a dual mechanism of action of tenascin-C in tumor angiogenesis where direct contact of endothelial cells with tenascin-C impairs angiogenesis, and paracrine signals derived from contact of tumor cells and carcinoma associated fibroblasts with tenascin-C promotes angiogenesis. These opposing effects provide for the first time an explanation of divergent mechanisms controlled by tenascin-C which can result in a denser but less functional tumor blood vasculature and might unveil new targeting and prediction opportunities.
2016-11-07 | PXD005217 | Pride
Project description:Angiogenesis represents a rate-limiting step during tumor progression. Molecular mechanisms driving tumor angiogenesis (e.g. implicating signaling by VEGFs and their receptors) have been elucidated and allowed to design targeted therapies. However, limits of such anti-angiogenic therapies have emerged, notably because tumor cells adapt and tumors recur in more aggressive fashions. There is therefore a need to identify novel mechanisms implicated in tumor angiogenesis that have a potential towards translational applications. Using a transgenic murine model of pancreatic neuroendocrine cancer (Hanahan, Nature 315, 1985) where angiogenesis represents an early and discrete step of multi-stage tumor progression (Folkman et al. , Nature 339, 1989), we compared non-angiogenic and angiogenic early tumors to obtain a comprehensive description of the tumor angiogenic switch at the level of gene expression.
2015-01-01 | GSE51637 | GEO
Project description:Naba A, Clauser KR, Mani DR, Carr SA, Hynes RO. The angiogenic switch, the time at which a tumor becomes vascularized, is a critical step in tumor progression. Indeed, it has been demonstrated that without blood supply, tumors will fail to grow beyond 1mm3 and are unlikely to disseminate. The extracellular matrix (ECM), a major component of the tumor microenvironment, is known to undergo significant changes during tumor progression and, in particular, during angiogenesis. However the extent of these changes remains unknown. In this study, we used quantitative proteomics to characterize the composition of the ECM of pancreatic islets in a transgenic mouse model of insulinoma characterized by a precisely timed angiogenic switch. Out of the 120 ECM proteins quantified, 35 were detected in significantly different abundance as pancreatic islets progressed from being hyperplastic to angiogenic to insulinomas. Among these, the core ECM proteins, EFEMP1, Fibrillin 1 and periostin were found in higher abundance, and decorin, Dmbt1, hemicentin and Vwa5 in lower abundance during tumor progression. The angiogenic switch being a common feature of solid tumors, we propose that some of the proteins identified represent potential novel anti-angiogenic targets. In addition, we report here the characterization of the ECM composition of normal pancreatic islets and propose that this could be of interest for the design of tissue engineering and regenerative strategies for treatment of diabetes.
| MSV000080124 | MassIVE
Project description:Angiogenesis is crucial for cancer progression and anti-angiogenic drugs are in use for its treatment. However, their clinical benefits are unsatisfactory. Thus, a deeper understanding of the mechanisms sustaining cancer vessel growth is crucial to identify better biomarkers and novel therapeutic targets. Alternative Splicing (AS) is an essential modifier of human proteome diversity. Nevertheless, its contribution to tumor vasculature development is poorly known. NOVA2 is an important AS regulator of angiogenesis and vascular development and it is up-regulated in tumor endothelial cells (ECs) of different cancers, thus representing a potential driver of tumor blood vessels aberrancies. Here, we identified novel AS transcripts generated upon NOVA2 upregulation in ECs, suggesting a pervasive role of NOVA2 in vascular biology. In addition, we report that NOVA2 is also upregulated in ECs of gastric cancer (GC), with its expression correlating with poor overall survival of the GC patients. We also found that the AS of the newly identified NOVA2 target RapGEF6 is altered in GC patients and associated with NOVA2 expression, tumor angiogenesis and poor patient outcome. Our findings provide a better understanding of GC biology and suggest that AS might represent a potential source of biomarkers and therapeutics for novel anti-angiogenic GC treatments.
2023-08-04 | GSE224823 | GEO
Project description:This model is based on:
Reinforcement learning-based control of tumor growth under anti-angiogenic therapy
Authors: Parisa Yazdjerdi, Nader Meskin, Mohammad Al-Naemi, Ala-Eddin Al Moustafa, Levente Kovacs
Abstract:
Background and objectives: In recent decades, cancer has become one of the most fatal and destructive diseases which is threatening humans life. Accordingly, different types of cancer treatment are studied with the main aim to have the best treatment with minimum side effects. Anti-angiogenic is a molecular targeted therapy which can be coupled with chemotherapy and radiotherapy. Although this method does not eliminate the whole tumor, but it can keep the tumor size in a given state by preventing the formation of new blood vessels. In this paper, a novel model-free method based on reinforcement learning (RL) framework is used to design a closed-loop control of anti-angiogenic drug dosing administration.
Methods: A Q-learning algorithm is developed for the drug dosing closed-loop control. This controller is designed using two different values of the maximum drug dosage to reduce the tumor volume up to a desired value. The mathematical model of tumor growth under anti-angiogenic inhibitor is used to simulate a real patient.
Results: The effectiveness of the proposed method is shown through in silico simulation and its robustness to patient parameters variation is demonstrated. It is demonstrated that the tumor reaches its minimal volume in 84 days with maximum drug inlet of 30 mg/kg/day. Also, it is shown that the designed controller is robust with respect to ± 20% of tumor growth parameters changes.
Conclusion: The proposed closed-loop reinforcement learning-based controller for cancer treatment using anti-angiogenic inhibitor provides an effective and novel result such that with a clinically valid and safe dosage of drug, the volume reduces up to 1mm3 in a reasonable short period compared to the literature.
2019-09-24 | BIOMD0000000821 | BioModels
Project description:Anti-angiogenic anticancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions. Targeting of extracellular vimentin presents a promising anti-angiogenic immunotherapy strategy against cancer. Here we describe profiling of the HUVEC (Human Umbilical Vein Endothelial Cell) proteome, with special emphasis on vimentin (variants) in the different fractions. We have evidence that vimentin is externalized and deposited in the matrix of cultured cells and is as such available for targeted antiangiogenic therapeutics. The aim of the experiment is to determine the protein variants of vimentin in the cell, the secretome, and in the matrix deposited by the cells.
2022-03-29 | PXD024426 | Pride
Project description:The Goal of this study is to explore the transcriptional differences between angiogenic and non-angiogenic tumors generated in Dr. Folkman's Lab, Harvard Medical School.<br>Referneces:<br>Almog N, Henke V, Flores L, Hlatky L, Kung AL, Wright RD, Berger R, Hutchinson L, Naumov GN, Bender E, Akslen LA, Achilles EG, Folkman J.<br>Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis.<br>FASEB J. 2006 May;20(7):947-9.<br><br>Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, Watnick RS, Straume O, Akslen LA, Folkman J, Almog N.<br>A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype.<br>J Natl Cancer Inst. 2006 Mar 1;98(5):316-25.<br>
2009-02-03 | E-TABM-390 | biostudies-arrayexpress
Project description:Previously, we have demonstrated that the recombinant adeno-associated virus carrying the kringle domain 1 of hepatocyte growth factor (rAAV-HGFK1) gene is a potential anti-angiogenic approach for the treatment of hepatocellular carcinoma (HCC) and exerts direct inhibition effects on tumor cells. Here, using genome-wide expression profiling technology, coupled with RT-PCR validation, we investigated the differentially expressed genes and proposed the mechanisms involved in HGFK1 anti-angiogenic and anti-tumor cell signaling networks. Keywords: HGFK1, anti-angiogenic signaling network, anti-tumor cell signaling network
2009-11-30 | GSE10854 | GEO
Project description:Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. We report here that tumor-infiltrating mast cells (MC) are powerful mediators decreasing efficacy of AAT in mice and cancer patients. They act in a cell-extrinsic manner by secreting granzyme B, which liberates pro-angiogenic mediators from the extracellular matrix. In addition, MC also diminish efficacy of anti-angiogenic agents in a cell-autonomous way, which can be blocked by the mast cell degranulation inhibitor cromolyn. Our findings are relevant in humans because patients harboring higher numbers of MC in their tumors have an inferior outcome after anti-angiogenic treatment in the Gepar Quinto randomized Phase 3 clinical trial. Thus, MC-targeting might represent a novel promising approach to increase efficacy of AAT.
2017-09-15 | GSE89395 | GEO