Time-Dependent Effect of Hypoxia on Tumor Progression and Liver Progenitor Cell Markers in Primary Liver Tumors

Abstract

Background & AimsExpression of liver progenitor cell (LPC) characteristics has been proposed as a negative prognostic marker in primary liver tumors. Hypoxia has been linked to activation of the Notch pathway which is responsible for activation and proliferation of LPCs and hypoxia-induced LPC activation has been shown in hepatocellular carcinoma. Our aim was to elucidate the time-dependent effects of hypoxia on the LPC niche in hepatocellular carcinoma which could aid in determining a safe time frame for use of hypoxia inducing therapies.MethodsWe used dimethyloxaloylglycine to mimic a hypoxic reaction in mice by stabilizing hypoxia-inducible factor 1 alpha at three distinct time points in diethylnitrosamine induced hepatocarcinogenesis. LPC, metastasis and Notch pathway markers were determined by quantitative PCR and (immune)histochemistry (heamatoxillin-eosin, reticulin, Sirius red and cytokeratin 19 staining).ResultsActivating the hypoxia inducible pathway early in hepatocarcinogenesis resulted in an increased incidence of both cholangioma and hepatocellular lesions, associated with high expression of LPC, metastatic and Notch pathway markers. Adversely, activating the hypoxic response during tumor development resulted in decreased incidence of hepatocellular lesions and increased cholangioma incidence, with an unaltered gene expression profile of LPC-, Notch pathway- and metastatic markers. A hypoxic insult at advanced stages of hepatocarcinogenesis severely increased the expression of LPC characteristics, however without increased expression of actors of the Notch pathway and metastatic markers and minor changes in incidence of hepatocellular and cholangioma lesions.ConclusionOur results indicate that increased hypoxia at the onset of tumor development has detrimental effects on tumor progression; patients with HCC developed in a background of fibrosis/cirrhosis might therefore represent a more difficult treatment group. In contrast, hypoxia during tumor development appears to favor tumor outcome, highlighting the importance of early detection. Finally, hypoxia in advanced stages resulted in increased expression of LPC characteristics indicating poor outcome.

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

“…S3). Although low glucose level could also induce a high level of GLUT-1, hypoxia would be the most possible cause of the increased GLUT-1 in our study due to the following reasons: GLUT-2, instead of GLUT-1, mediates glucose uptake in hepatocyte (14); therefore, a low glucose level in liver cancer cells may not trigger the overexpression of GLUT1; there is a documented strong association between hypoxia and liver tumor (15,16) that correlated the increased hypoxia with the observation of high level of the GLUT-1 in our study.…”

Mutational landscape of combined hepatocellular carcinoma and cholangiocarcinoma, and its clinicopathological significance

“…The first pathway is cHC‐CC that arises as a conventional HCC at the early stage, and acquires biliary and/or SC features during its progression . Ischaemia and previous treatments have been suggested to contribute to the acquisition of biliary features and the enrichment of ‘cancer SCs’ in liver carcinoma . As TERT mutations are frequently detected in HCC but not in CC, TERT mutations may indicate the histogenesis of cHC‐CC via HCC corresponding to INT.…”

“…8 Ischaemia and previous treatments have been suggested to contribute to the acquisition of biliary features and the enrichment of 'cancer SCs' in liver carcinoma. 29 As TERT mutations are frequently detected in HCC but not in CC, 9,10,16 TERT mutations may indicate the histogenesis of cHC-CC via HCC corresponding to INT. Another pathway is cHC-CC arising as a biphenotypic carcinoma at the early stage.…”

The prognostic role of lactate dehydrogenase serum levels in patients with hepatocellular carcinoma who are treated with sorafenib: the influence of liver fibrosis

“…If the increased serum LDH levels reflect whole liver hypoxia, as described above, and such circumstances decrease the effect of sorafenib, we hypothesize that a pretreatment hypoxic situation could increase tumor aggressiveness or promote drug resistance. Recently, using mouse models of primary liver tumors, Bogaerts et al showed that hypoxia in advanced stages resulted in increased expression of liver progenitor cell characteristics that indicate a poor outcome (23). Liu et al demonstrated that the targeted knock-down of hypoxia-inducible factor-2α, which is associated with cell proliferation under hypoxic conditions, in combination with sorafenib, markedly decreased proliferation in HCC cells (24).…”