Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma

Bağırsakçı, Ezgi; Şahin, Erdem; Atabey, Neşe; Erdal, Esra; Guerra, Vito; Carr, Brian I.

doi:10.1159/000471807

Cited by 83 publications

(75 citation statements)

References 24 publications

(24 reference statements)

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“…Studies have shown that serum albumin levels have prognostic significance in HCC, with lower serum albumin levels having significantly larger maximum tumor diameters. [24][25][26] In fact, serum albumin level is already being used as a criterion for the HCC staging systems.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Bayesian nonparametric estimation of ROC surface under verification bias

Zhu

Ghosal

2019

Statistics in Medicine

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The receiver operating characteristic (ROC) surface, as a generalization of the ROC curve, has been widely used to assess the accuracy of a diagnostic test for three categories. A common problem is verification bias, referring to the situation where not all subjects have their true classes verified. In this paper, we consider the problem of estimating the ROC surface under verification bias. We adopt a Bayesian nonparametric approach by directly modeling the underlying distributions of the three categories by Dirichlet process mixture priors. We propose a robust computing algorithm by only imposing a missing at random assumption for the verification process but no assumption on the distributions.The method can also accommodate covariates information in estimating the ROC surface, which can lead to a more comprehensive understanding of the diagnostic accuracy. It can be adapted and hugely simplified in the case where there is no verification bias, and very fast computation is possible through the Bayesian bootstrap process. The proposed method is compared with other commonly used methods by extensive simulations. We find that the proposed method generally outperforms other approaches. Applying the method to two real datasets, the key findings are as follows: (1) human epididymis protein 4 has a slightly better diagnosis ability compared to CA125 in discriminating healthy, early stage, and late stage patients of epithelial ovarian cancer. (2) Serum albumin has a prognostic ability in distinguishing different stages of hepatocellular carcinoma.

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Section: Hepatocellular Carcinomamentioning

confidence: 99%

Bayesian nonparametric estimation of ROC surface under verification bias

Zhu

Ghosal

2019

Statistics in Medicine

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“…Although, the effects of albumin on the proliferation of hepatocellular carcinoma cells have been previously studied, the outcomes of those studies are debatable. They argued that albumin inhibits tumour evidenced by its increased levels correlating with cancer remission and addition of albumin to serum starved hepatoma cells caused G1 arrest (Nojiri & Joh, 2014;Bağırsakçı et al, 2017). It is worth noting that serum is essential for hepatocellular carcinoma growth (Zhuge & Cederbaum, 2006;Liang et al, 2013) whereas serum starvation is routinely carried out to arrest cells in G1 phase (Davis, Ho & Dowdy, 2001;Langan, Rodgers & Chou, 2017).…”

Section: Discussionmentioning

confidence: 99%

Peer Review #2 of "Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells (v0.1)"

2020

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Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery into target cells. The immediate effects of albumin on cells however require further understanding. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We observed that the reduced cell counts in serum starved HepG2/C3A cultures were increased by the inclusion of albumin. Cell cycle analysis demonstrated that the percentage of cells in G1 phase during serum starvation was reduced from 86.4±2.3 % to 78.3±3.2 % by the inclusion of albumin whereas the percentage of cells in S phase was increased from 6.5±1.5 % to 14.3±3.6 %. A significant reduction in the cell cycle inhibitor protein, P21, accompanied the changes in the proportions of cell cycle phases upon treatment with albumin. We have also observed that the levels of dead cells determined by DNA fragmentation and membrane permeabilization caused by serum starvation (TUNEL: 16.6 ± 7.2 %, ethidium bromide: 13.8±4.8 %) were not significantly altered by the inclusion of albumin (11.6 ± 10.2 %, ethidium bromide: 16.9 ± 8.9 %). Therefore, the increase in cell number was mainly caused by albumin promoting proliferation rather than protection against cell death. These primary findings demonstrate that albumin has immediate effects on HepG2/C3A hepatocellular carcinoma cells. These effects should be taken into consideration when studying the effects of albumin bound drugs or pathological ligands bound to albumin on HepG2/C3A cells.

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“…Proliferation was evaluated through changes in cell counts and cell cycle analysis whereas cell death was measured by analysing apoptotic DNA fragmentation and membrane permeabilization. Similar studies have been performed on the HepG2 hepatocellular carcinoma parent clone demonstrating that albumin prevents proliferation (Nojiri & Joh, 2014;Bağırsakçı et al, 2017a). In this study, the experiments were carried out on the HepG2/C3A subclone and were contradictory to these earlier findings.…”

Section: Introductionmentioning

confidence: 51%

“…Although, the effects of albumin on the cell cycle of hepatocellular carcinoma cells have been previously studied, the outcomes of those studies are debatable. They argued that albumin inhibits tumour evidenced by its increased levels correlating with cancer remission and addition of albumin to serum starved hepatoma cells caused G1 arrest (Nojiri & Joh, 2014;Bağırsakçı et al, 2017b). It is worth noting that serum is essential for hepatocellular carcinoma growth (Zhuge & Cederbaum, 2006;Liang et al, 2013) whereas serum starvation is routinely carried out to arrest cells in G1 phase (Davis, Ho & Dowdy, 2001;Langan, Rodgers & Chou, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Effects of albumin on hepatocellular carcinoma cell line have been previously studied demonstrating conflicting outcomes. While one study suggested that albumin stimulates proliferation of hepatocellular carcinoma cells that were inhibited by fatty acids (Lystad et al, 1994), other studies suggested hepatocellular carcinoma cells cease proliferation in response to albumin (Nojiri & Joh, 2014;Bağırsakçı et al, 2017a). From the collectively reviewed experiments, it can be extrapolated that the diverse cellular responses to albumin are attributed to the varying albumin receptors in the cell as well as the varying ligand profiles of albumin.…”

Section: Introductionmentioning

confidence: 99%

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Supplemental Information 2: Individual Cell Cycle Histograms

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Albumin is the most abundant plasma protein and functions as a transport molecule that continuously interacts with various cell types. Because of these properties, albumin has been exploited by the pharmaceutical industry to improve drug delivery to target cells. The immediate effects of albumin on cells however requires further understanding. The cell interacting properties and pharmaceutical applications of albumin incentivises continual research into the immediate effects of albumin on cells. The HepG2/C3A hepatocellular carcinoma cell line is used as a model for studying cancer pathology as well as liver biosynthesis and cellular responses to drugs. Here we investigated the direct effect of purified albumin on HepG2/C3A cell proliferation in the absence of serum, growth factors and other serum originating albumin bound molecules. We demonstrated that serum starvation causes HepG2/C3A cell numbers to stagnate, whereas inclusion of albumin allows an increase in cell numbers. Cell cycle analysis demonstrated that the percentage of cells in G1 phase during serum starvation was reduced by the inclusion of albumin whereas percentage of cells in S phase was increased. We have also observed that the levels of dead cells determined by DNA fragmentation and membrane permeabilization caused by serum starvation were not significantly altered by the inclusion of albumin. Therefore, the increase in cell number was mainly caused by albumin promoting proliferation rather than protection against cell death. These primary findings demonstrate that albumin has immediate effects on HepG2/C3A hepatocellular carcinoma cells. These effects should be taken into consideration when studying the effects of albumin bound drugs or pathological ligands bound to albumin on HepG2/C3A cells.

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Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma

Cited by 83 publications

References 24 publications

Bayesian nonparametric estimation of ROC surface under verification bias

Bayesian nonparametric estimation of ROC surface under verification bias

Peer Review #2 of "Albumin promotes proliferation of G1 arrested serum starved hepatocellular carcinoma cells (v0.1)"

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