Progression Of Hepatocellular Carcinoma Patients Research Articles

Mycoplasma infection promotes tumor progression via interaction of the mycoplasmal protein p37 and epithelial cell adhesion molecule in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer death worldwide. To study how mycoplasma infection affects HCC progression, we investigated the characteristics of mycoplasma-infected tumor tissues and circulating tumor cells (CTCs) in HCC patients. The mycoplasmal membrane protein p37 showed significant correlations with higher histologic stages and vascular invasion and predicted poor disease-free survival of HCC patients. p37-positive CTCs were detected in 42 out of 47 HCC patients (89%). p37-positive circulating cells were also detected in 4 out of 10 healthy donors (40%), and all were epithelial cell adhesion molecule (EpCAM)-positive. In HCC patients, most of p37-negative CTCs (95%) showed intermediate phenotype with neither EpCAM nor vimentin expression, but p37-positive CTCs were EpCAM-positive (44%), vimentin-positive (32%), and both negative (24%), suggesting that EpCAM-positive CTCs are enriched with mycoplasma infection. Mycoplasma infection promoted migratory capacity of HCC cells with increased expression of EpCAM. Immunoprecipitation analysis revealed that p37 associates with EpCAM. The results suggest that mycoplasma infection promotes tumor progression in HCC patients via interaction of the mycoplasmal p37 and EpCAM.

Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma

BackgroundThe molecular signaling events involving in high malignancy and poor prognosis of hepatocellular carcinoma (HCC) are extremely complicated. Blockade of currently known targets has not yet led to successful clinical outcome. More understanding about the regulatory mechanisms in HCC is necessary for developing new effective therapeutic strategies for HCC patients.MethodsThe expression of Rho GTPase-activating protein 11A (ARHGAP11A) was examined in human normal liver and HCC tissues. The correlations between ARHGAP11A expression and clinicopathological stage or prognosis in HCC patients were analyzed. ARHGAP11A was downregulated to determine its role in the proliferation, invasion, migration, epithelial-to-mesenchymal transition (EMT) development, and regulatory signaling of HCC cells in vitro and in vivo.ResultsARHGAP11A exhibited high expression in HCC, and was significantly correlated with clinicopathological stage and prognosis in HCC patients. Moreover, ARHGAP11A facilitated Hep3B and MHCC97-H cell proliferation, invasion, migration and EMT development in vitro. ARHGAP11A knockdown significantly inhibited the in vivo growth and metastasis of HCC cells. Furthermore, ARHGAP11A directly interacted with Rac1B independent of Rho GTPase- activating activity. Rac1B blockade effectively interrupted ARHGAP11A-elicited HCC malignant phenotype. Meanwhile, upregulation of Rac1B reversed ARHGAP11A knockdown mediated mesenchymal-to-epithelial transition (MET) development in HCC cells.ConclusionARHGAP11A facilitates malignant progression in HCC patients via ARHGAP11A-Rac1B interaction. The ARHGAP11A/Rac1B signaling could be a potential therapeutic target in the clinical treatment of HCC.

Hepatic SMARCA4 predicts HCC recurrence and promotes tumour cell proliferation by regulating SMAD6 expression

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is typically diagnosed at advanced stages. Identification and characterisation of genes within amplified and deleted chromosomal loci can provide new insights into the pathogenesis of cancer and lead to new approaches for diagnosis and therapy. In our previous study, we found a recurrent region of copy number amplification at 19p13.2 in hepatocellular carcinoma (HCC). In the present study, we performed integrated copy number analysis and expression profiling at this locus and a putative cancer gene, SMARCA4/BRG1, was uncovered in this region. BRG1 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF. The function of BRG1 in various cancers is unclear, including its role in HCC tumorigenesis. Here, we found that BRG1 is upregulated in HCC and that its level significantly correlates with cancer progression in HCC patients. Importantly, we also found that nuclear expression of BRG1 predicts early recurrence for HCC patients. Furthermore, we demonstrated that BRG1 promotes HCC cell proliferation in vitro and in vivo. BRG1 was observed not only to facilitate S-phase entry but also to attenuate cell apoptosis. Finally, we discovered that one of the mechanisms by which BRG1 promotes cell proliferation is the upregulation of SMAD6. These findings highlight the important role of BRG1 in the regulation of HCC proliferation and provide valuable information for cancer prognosis and treatment.

Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma

Circular RNAs (circRNAs) represent a class of endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression and pathological networks. However, their transcriptional activities and functional mechanisms in cancer remain largely unknown. Here, we present results from a global circRNA expression and functional analysis of patients with hepatocellular carcinoma (HCC). Using a circRNA microarray, we identified 226 differentially expressed circRNAs, of which 189 were significantly upregulated and 37 were downregulated. High expression of circRNA_100338, one of the upregulated circRNAs in HCC, is closely correlated with a low cumulative survival rate and metastatic progression in HCC patients with hepatitis B. Furthermore, our in silico and experimental analyses identified miR-141-3p as a direct target of circRNA_100338. Thus, circRNA_100338 functions as an endogenous sponge for miR-141-3p in HCC. In addition, we identified the crucial antagonistic roles of circRNA_100338 and miR-141-3p in the regulation of invasive potential in liver cancer cells. Overall, the differential expression of multiple circRNAs in HCC tissues and their clinical significance in hepatitis B-related HCC patients as revealed by our study suggests that circRNA_100338 is a potentially valuable biomarker for HCC diagnosis and target for HCC therapeutics.

Abstract No. 486 - Association of intra-procedural use of tumor feeding vessel tracking software with local tumor progression in hepatocellular carcinoma patients treated with hepatic arterial embolization

Abstract No. 486 - Association of intra-procedural use of tumor feeding vessel tracking software with local tumor progression in hepatocellular carcinoma patients treated with hepatic arterial embolization

Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.

e14690 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.

Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: Analyzing patterns of progression in 285 patients

Although most cancers are considered predominantly systemic processes, this may not hold true for hepatocellular carcinoma (HCC). The literature regarding patterns of progression of HCC (local versus systemic) has been relatively sparse. Our objectives were to: (1) analyze patterns of progression in HCC patients presenting with intrahepatic disease from initial treatment until death, and (2) identify clinically relevant risk factors for the development of metastases. Over a 9-year period, 285 patients treated with transarterial locoregional therapies underwent scheduled imaging follow-up from treatment until death and were categorized by pattern of progression: (i) intrahepatic (increased tumor enhancement/size, development/progression of vascular invasion, new hepatic lesions) progression or (ii) extrahepatic (adrenal/bone/lung/lymph node) metastases. Uni/multivariate analyses assessing the risk factors for the development of metastases were performed. The median time from last scan to death was 2.4 months (interquartile range: 1.3-4.8 months). The time to development of metastases, vascular invasion, and/or new lesions was 13.8 months (confidence interval: 11.3-17.7 months). Of the 209 patients followed until death, only 50 developed extrahepatic metastases (24%). Multivariate analyses identified age <65 years (P = 0.038), alpha-fetoprotein >200 ng/mL (P = 0.04), and vascular invasion (P = 0.017) as significant predictors of metastases development. Knowledge of the risk factors associated with the development of metastases may help guide assessment of patient prognosis. Because 76% of patients presenting with local disease treated with locoregional therapies die without developing extrahepatic metastases, the notion of HCC as a systemic disease, as detected by imaging, may be reconsidered.

Regulatory T cells are associated with post-cryoablation prognosis in patients with hepatitis B virus-related hepatocellular carcinoma

We carried out this study to evaluate the association between regulatory T cells (Treg) and prognosis and progression after cryoablation in patients with hepatitis-B virus-related hepatocellular carcinoma. Peripheral Treg frequency in 111 patients with hepatocellular carcinoma (HCC) was detected by flow cytometry. Treg frequency and function were re-examined during patient follow up. A possible association between Treg and α-fetoprotein (AFP) was also analyzed, and the distribution of resident CD4(+) and CD8(+) T cells and FoxP3(+) T cells in the liver tissue of patients with HCC was examined by immunohistochemistry. Treg frequency significantly increased with disease progression. Our longitudinal study showed that Treg frequency had significantly decreased in 17 patients with HCC regression following cryoablation, but the frequency had dramatically increased in 14 patients with HCC recurrence or progression. Furthermore, AFP levels varied in a way comparable with Treg frequency in patients with elevated AFP recorded before therapy. Significantly increased suppressive effects of Treg on proliferation and cytokine secretion of CD8(+) and CD4(+) T cells were observed during follow up in patients with tumor progression, but not in patients with tumor response. Moreover, the numbers of CD8(+), CD4(+), and FoxP3(+) cells infiltrating the tumors around the cryotherapeutic zones were significantly decreased after argon-helium cryoablation, and this was associated with a reduction in the FoxP3/CD8 ratio. Importantly,increased quantities of circulating CD4(+)CD25(+)FoxP3(+) Treg and tumor infiltrating FoxP3(+) cells before cryoablation were associated with high recurrence or risk of progression in HCC patients after cryoablation. Treg variation is associated with tumor regression or progression in HCC following cryoablation and may be used as a marker to estimate HCC progression.

Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)?

The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies.

Increased Regulatory T Cells Correlate With CD8 T-Cell Impairment and Poor Survival in Hepatocellular Carcinoma Patients

Recent studies have suggested that CD4(+)CD25(+) regulatory T cells (Treg) are increased and linked to compromised immune responses in patients with hepatocellular carcinoma (HCC). This study attempted to further characterize CD4(+)CD25(+) forkhead/winged helix transcription factor (FoxP3)(+) Treg in blood, tumor, and nontumor liver tissues of HCC patients, and to understand how the Treg affects immune responses and contributes to disease progression. A total of 123 HCC patients with chronic hepatitis B virus (HBV) infection, 21 HBV-related liver cirrhosis (LC) patients, and 47 normal controls were enrolled randomly. Flow cytometric, immunohistochemical, and immunosuppressive assays were used for analyses of properties of Treg. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating CD4(+)CD25(+)FoxP3(+) Treg frequency was increased significantly and correlated with disease progression in HCC patients. An abundant accumulation of Treg concurrent with significantly reduced infiltration of CD8(+) T cells was found in tumor regions compared with nontumor regions. Expression of granzyme A, granzyme B, and perforin was decreased dramatically in tumor-infiltrating CD8(+) T cells. Furthermore, Treg of HCC patients inhibited proliferation, activation, degranulation, and production of granzyme A, granzyme B, and perforin of CD8(+) T cells induced by anti-CD3/CD28 antibodies. Importantly, an increased quantity of circulating Treg was associated with high mortality and reduced survival time of HCC patients. Increased CD4(+)CD25(+)FoxP3(+) Treg may impair the effector function of CD8(+) T cells, promote disease progression, and represent both a potential prognostic marker and a therapeutic target for HBV-related HCC individuals.

Determination of the optimal model for end-stage liver disease score in patients with small hepatocellular carcinoma undergoing loco-regional therapy

The model for end-stage liver disease (MELD) has been a prevailing system to prioritize cirrhotic patients awaiting liver transplantation. An "exceptional" MELD score of 20 and 24 points is assigned for stage T1 and T2 patients with small hepatocellular carcinoma (HCC), respectively. However, this strategy is based on scarce data and the optimal score for these patients remains uncertain. We investigated 238 patients with small HCC who were candidates for liver transplantation and underwent arterial chemoembolization or percutaneous injection therapy using acetic acid or ethanol. Tumor stage (P = .001) and Child-Turcotte-Pugh (CTP) class (P < .001) were independent risk factors predicting tumor progression or death in survival analysis. The risk of disease progression in HCC patients stratified by tumor stage was mapped and equated with the risk of mortality of 456 cirrhotic patients without HCC. The 6- and 12-month rates of disease progression were 4% and 6%, respectively, for stage T1 HCC patients (n = 50; mean MELD: 9.5). These rates were close to and no higher than the mortality rate in MELD category 8-12 at the corresponding time period (7.1% and 11.3%, respectively; n = 141). For stage T2 patients (n = 188; mean MELD: 9.3), the corresponding rates were 5.3% and 13.8%, respectively, which were close to and no higher than the mortality rate in MELD category 10-14 (9.0% and 13.9%, respectively, n = 166). In conclusion, the risk of disease progression is quite low for selected HCC patients undergoing loco-regional therapy. A lower MELD score may be suggested to be equivalent to the risk of short- and mid-term mortality in the cirrhosis group.