Effect of PlGF-inhibition on survival in mice with hepatocellular carcinoma

Background: Inhibition of angiogenesis is currently hot topic in the search for an effective treatment for hepatocellular carcinoma (HCC). Up till recently, the focus was mainly on VEGF, an important regulator in the pathologic and physiologic angiogenesis. Although promising results are seen by inhibiting the VEGF-pathway, patients often suffer from major side effects. Placental growth factor (PlGF) is a VEGF analogue only involved in pathologic angiogenesis and its inhibition has the potential to restrain tumour growth, without affecting healthy organs. Therefore, we assessed whether administration of PlGF-antibodies could serve as a potential therapy for HCC in mice. Methods: 5-week-old male mice (sv129) received intraperitoneal (ip) injections once per week with N-nitrosodiethylamine (35 mg/kg bodyweight) or saline , which gives rise to HCC after 25W in WT. PlGF-knock-out mice (PlGF-/-) received weekly ip DEN-injections and were compared with their WT counterparts. At 26W, WT mice were treated with twice a week with murine monoclonal PlGF-antibodies (20 mg/kg anti-PlGF) or IgG for 5W and 10W. Results: By 25 weeks of DEN treatment, 29% of the WT mice but none of the PlGF-/- mice had succumbed to the disease (p = 0,056). Also, treatment of DEN-injected HCC mice from 25 weeks for 5 weeks with 5D11D4 (ThromboGenics N.V.) or IgG showed a significant difference in mortality. While 45% died in the control IgG group, only 23% mortality was observed in the anti-PlGF group (N=48; P < 0.05). Also, the liver/body weight ratio was 0.057 ± 0.003 in the control group versus 0.042 ± 0.004 in the 5D11D4 group (N=19; P < 0,05). After 10W treatment 90% died in the control IgG group, while only 41 % mortality was observed in the anti-PlGF group (N = 11, P < 0,05). No mortality was observed in mice injected with saline instead of DEN, followed by 5 wks of treatment with anti-PlGF or IgG. The liver/body weight ratio was 0.038 ± 0.001 in the saline and IgG group versus 0.041 ± 0.002 in the anti-PlGF group (N=12, P = 0,27). Figure 1: left: Mean survival of IgG and aPlGF treated mice ; right: mean survival of PlGF knock out mice and WT’s during DEN-induction Conclusion: Our study showed that administration of 20 mg/kg anti-PlGF twice a week, has a positive effect on survival in mice with HCC. The liver/bodyweight ratio of anti-PlGF treated mice was significantly lower than in the control IgG group, showing a specific effect on liver tumours. Treatment of anti-PlGF in healthy mice did not induce negative side effects. Therefore, treatment with PlGF antibodies might serve as a promising systemic treatment in hepatocellular carcinoma patients

The roles of transforming growth factor-β, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours

Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis

Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The increasing incidence of hepatocellular carcinoma in Western countries has led to an expanding interest of scientific research in this field. Therefore, a vast need of experimental models that mimic the natural pathogenesis of hepatocellular carcinoma (HCC) in a short time period is present. The goal of our study was (1) to develop an efficient mouse model for HCC research, in which tumours develop in a natural background of fibrosis and (2) to assess the time-dependent angiogenic changes in the pathogenesis of HCC.</p> <p>Methods</p> <p>Weekly intraperitoneal injections with the hepatocarcinogenic compound N-nitrosodiethylamine was applied as induction method and samples were taken at several time points to assess the angiogenic changes during the progression of HCC.</p> <p>Results</p> <p>The N-nitrosodiethylamine-induced mouse model provides well vascularised orthotopic tumours after 25 weeks. It is a representative model for human HCC and can serve as an excellent platform for the development of new therapeutic targets.</p

Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study:idarubicin dose selection, tissue response and survival

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31

Targeting ER stress in the hepatic tumor microenvironment

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer