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4 Publications visible to you, out of a total of 4
Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment.

Abstract (Expand)

Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and … intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated beta-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC.

Authors: N. Berndt, J. Eckstein, N. Heucke, T. Wuensch, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 8th Oct 2020

Publication Type: Journal

Characterization of Lipid and Lipid Droplet Metabolism in Human HCC.

Abstract (Expand)

Human hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the most common cause of death in people with cirrhosis. While previous metabolic studies of HCC have … mainly focused on the glucose metabolism (Warburg effect), less attention has been paid to tumor-specific features of the lipid metabolism. Here, we applied a computational approach to analyze major pathways of fatty acid utilization in individual HCC. To this end, we used protein intensity profiles of eleven human HCCs to parameterize tumor-specific kinetic models of cellular lipid metabolism including formation, enlargement, and degradation of lipid droplets (LDs). Our analysis reveals significant inter-tumor differences in the lipid metabolism. The majority of HCCs show a reduced uptake of fatty acids and decreased rate of beta-oxidation, however, some HCCs display a completely different metabolic phenotype characterized by high rates of beta-oxidation. Despite reduced fatty acid uptake in the majority of HCCs, the content of triacylglycerol is significantly enlarged compared to the tumor-adjacent tissue. This is due to tumor-specific expression profiles of regulatory proteins decorating the surface of LDs and controlling their turnover. Our simulations suggest that HCCs characterized by a very high content of triglycerides comprise regulatory peculiarities that render them susceptible to selective drug targeting without affecting healthy tissue.

Authors: N. Berndt, J. Eckstein, N. Heucke, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 27th May 2019

Publication Type: Not specified

Hepatic CYP1A2 activity in liver tumors and the implications for preoperative volume-function analysis.

Abstract (Expand)

Dynamic liver function assessment by the (13)C-methacetin maximal liver function capacity (LiMAx) test reflects the overall hepatic CYP1A2 activity. One proven strategy for preoperative risk assessement … in liver surgery includes the combined assessment of the dynamic liver function by the LiMAx test, the volumetric analysis of the liver and calculation of future liver remnant function. This so-called volume-function analysis assumes that the remaining CYP1A2 activity in any tumor lesion is zero. The here presented study aims to assess the remaining CYP1A2 activities in different hepatic tumor lesions and its consequences for the preoperative volume-function analysis in patients undergoing liver surgery. The CYP1A2 activity analysis of neoplastic lesions and adjacent non-tumor liver tissue from resected tumor specimens revealed a significantly higher CYP1A2 activity (median, interquartile range) in non-tumor tissues (35.5, 15.9-54.4 microU/mg) as compared to hepatocellular adenomas (7.35, 1.2-32.5 microU/mg), hepatocellular carcinomas (0.18, 0.0-2.0 microU/mg) or colorectal liver metastasis (0.17, 0.0-2.1 microU/mg), respectively. In non-tumor liver tissue a gradual decline in CYP1A2 activity with exacerbating fibrosis was observed. The CYP1A2 activity differences were also reflected in CYP1A2 protein signals in the assessed hepatic tissues. Volume-function analysis showed a minimal deviation compared to the current standard calculation for hepatocellular carcinomas or colorectal liver metastasis (<1% difference), while a difference of 11.9% was observed for hepatocellular adenomas. These findings are important for a refined preoperative volume-function analysis and improved surgical risk assessment in hepatocellular adenoma cases with low LiMAx values.

Authors: T. Wuensch, N. Heucke, J. Wizenty, J. Quint, B. Sinn, R. Arsenic, M. Jara, M. Kaffarnik, J. Pratschke, M. Stockmann

Date Published: 14th Mar 2019

Publication Type: Not specified

Non-invasive structure-function assessment of the liver by 2D time-harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.

Abstract (Expand)

BACKGROUND AND AIM: Accurate assessment of structural and functional characteristics of the liver could improve the diagnosis and the clinical management of patients with chronic liver diseases. However, … the structure-function relationship in the progression of chronic liver disease remains elusive. The aim of this study is the combined measurement of liver function by the (13) C-methacetin Liver MAximum capacity (LiMAx) test and tissue-structure related stiffness by 2D time-harmonic elastography for the assessment of liver disease progression. METHODS: LiMAx test and time-harmonic elastography were applied, and the serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were calculated in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). In 47 patients who underwent surgery, fibrosis was graded by histological examination of the resected liver tissue. RESULTS: LiMAx values correlated negatively with liver stiffness (r = -0.747), aminotransferase to platelet ratio index (r = -0.604), and fibrosis 4 (r = -0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 mug/kg/h (371-460 mug/kg/h) in participants with no fibrosis to 173 mug/kg/h (126-309 mug/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52-1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54-1.67 m/s]) to severe fibrosis (1.85 m/s [1.76-1.92 m/s]). CONCLUSION: Our findings show that structural changes in the liver due to progressing liver diseases and reflected by increased tissue stiffness correlate with a functional decline of the organ as reflected by a decreased metabolic capacity of the liver.

Authors: N. Heucke, T. Wuensch, J. Mohr, M. Kaffarnik, R. Arsenic, B. Sinn, T. Muller, J. Pratschke, M. Stockmann, I. Sack, H. Tzschatzsch

Date Published: 13th Feb 2019

Publication Type: Not specified

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