scholarly journals Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

2020 ◽  
Author(s):  
Max P. Horowitz ◽  
Zahraa Alali ◽  
Tyler Alban ◽  
Changjin Hong ◽  
Emily L. Esakov ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Single Cell ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Single Cells ◽  
Killer Cell ◽  
Tissue Response ◽  
Metabolic Reprogramming ◽  
Cell Populations ◽  
Cancer Tissue

SummaryHyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a clinical regimen that prolongs overall survival for patients with advanced Epithelial Ovarian Cancer (EOC). However, the mechanism of action of HIPEC remains poorly understood. To provide insights into the rapid changes that accompany HIPEC, tumors from five patients with high grade serous ovarian cancer were harvested from the omentum at time of debulking and after 90 minutes of HIPEC treatment. Specimens were rapidly dissociated into single cells and processed for single cell RNA-seq. Unbiased clustering identified 19 cell clusters that were annotated based on cellular transcriptome signatures to identify the epithelial, stromal, T and B immune cells, macrophages, and natural killer cell populations. Hallmark pathway analysis revealed heat shock, metabolic reprogramming, inflammatory, and EMT pathway enrichment in distinct cell populations upon HIPEC treatment. Collectively, our findings provide the foundation for mechanistic studies focused on how HIPEC orchestrates the ovarian cancer tissue response.

scholarly journals Pharmacokinetics and toxicity of carboplatin used for hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment of epithelial ovarian cancer

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Mette Schou Mikkelsen ◽  
Jan Blaakaer ◽  
Lone Kjeld Petersen ◽  
Luise Gram Schleiss ◽  
Lene Hjerrild Iversen
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Intraperitoneal Chemotherapy ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Systemic Exposure ◽  
Hematological Toxicity ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Severe Toxicity ◽  
Perfusion Time

AbstractObjectivesCarboplatin is frequently used in various doses for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of epithelial ovarian cancer (EOC) although its pharmacokinetics, including focus on the perfusion time, has not been evaluated when used in modern era cytoreductive surgery (CRS). The aim was to evaluate the pharmacokinetics and hematological toxicity of carboplatin used for HIPEC with a perfusion time of 90 min.MethodsFifteen patients with stage III–IV primary EOC received CRS and 90 min of HIPEC with carboplatin at dose 800 mg/m2. For the pharmacokinetic analysis, perfusate and blood samples were obtained during HIPEC and up to 48 h after HIPEC (blood only). Hematological toxicity within 30 days was graded according to Common Terminology Criteria for Adverse Events. Severe toxicity (grades 3–5) is reported.ResultsMean maximum concentration of carboplatin was 12 times higher in perfusate than plasma (mean CmaxPF=348 µg/mL (range: 279–595 µg/mL) versus mean CmaxPL=29 µg/mL (range: 21–39 µg/mL)). Mean terminal half-life of carboplatin in perfusate was 104 min (range: 63–190 min) and mean intraperitoneal-to-plasma area under the concentration-time curve (AUC) ratio was 12.3 (range: 7.4–17.2). Two patients (13%) had grade 3 neutropenia within 30 days. No grade 4–5 hematological toxicities were identified.ConclusionsCarboplatin has a favorable pharmacokinetic profile for 90 min HIPEC administration, and the hematological toxicity was acceptable at dose 800 mg/m2. Large interindividual differences were found in the pharmacokinetic parameters, making risk of systemic exposure difficult to predict.

scholarly journals The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties

2022 ◽  
Vol 11 ◽  
Author(s):  
Dingju Wei ◽  
Meng Xu ◽  
Zhihua Wang ◽  
Jingjing Tong
Keyword(s):  
Tumor Cell ◽  
Single Cell ◽  
Immune Escape ◽  
Cell Metabolism ◽  
Single Cells ◽  
Metabolic Reprogramming ◽  
Biological Information ◽  
Emergent Properties ◽  
Anti Cancer ◽  
Cell Metabolomics

Metabolic reprogramming is one of the hallmarks of malignant tumors, which provides energy and material basis for tumor rapid proliferation, immune escape, as well as extensive invasion and metastasis. Blocking the energy and material supply of tumor cells is one of the strategies to treat tumor, however tumor cell metabolic heterogeneity prevents metabolic-based anti-cancer treatment. Therefore, searching for the key metabolic factors that regulate cell cancerous change and tumor recurrence has become a major challenge. Emerging technology––single-cell metabolomics is different from the traditional metabolomics that obtains average information of a group of cells. Single-cell metabolomics identifies the metabolites of single cells in different states by mass spectrometry, and captures the molecular biological information of the energy and substances synthesized in single cells, which provides more detailed information for tumor treatment metabolic target screening. This review will combine the current research status of tumor cell metabolism with the advantages of single-cell metabolomics technology, and explore the role of single-cell sequencing technology in searching key factors regulating tumor metabolism. The addition of single-cell technology will accelerate the development of metabolism-based anti-cancer strategies, which may greatly improve the prognostic survival rate of cancer patients.

scholarly journals Metabolic Reprogramming from Glycolysis to Fatty Acid Uptake and beta-Oxidation in Platinum-Resistant Cancer Cells

2021 ◽  
Author(s):  
Junjie Li ◽  
Yuying Tan ◽  
Guangyuan Zhao ◽  
Kai-Chih Huang ◽  
Horacio Cardenas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Single Cell ◽  
Cancer Cell ◽  
Aerobic Glycolysis ◽  
Fatty Acid Uptake ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Acid Uptake ◽  
Beta Oxidation

Increased aerobic glycolysis is widely considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during development of therapeutic resistance is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we found that cisplatin-resistant cells exhibit increased uptake of exogenous fatty acids, accompanied with decreased glucose uptake and de novo lipogenesis, indicating a reprogramming from glucose and glycolysis dependent to fatty acid uptake and beta-oxidation dependent anabolic and energy metabolism. A metabolic index incorporating measurements of glucose derived anabolism and fatty acid uptake correlates linearly to the level of resistance to cisplatin in ovarian cancer cell lines and in primary cells isolated from ovarian cancer patients. Mechanistically, the increased fatty acid uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing energy production through beta-oxidation. Consequently, blocking fatty acid beta-oxidation by a small molecule inhibitor in combination with cisplatin or carboplatin synergistically suppressed ovarian cancer proliferation in vitro and growth of patient-derived xenograft in vivo. Collectively, these findings support a new way for rapid detection of cisplatin-resistance at single cell level and a new strategy for treatment of cisplatin-resistant tumors.

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