Our lab focusses on the interaction between different cells in the tumour environment and the tumour cells in hepatocellular carcinoma. Hepatocellular carcinoma is a primary liver cancer that develops in a background of liver diseases, meaning that it usually develops in a sick, fibrotic liver. This creates an environment that is favourable for tumour growth. In our lab, we try to identify the mechanisms that are responsible for creating a favourable tumour environment. And we will try to prevent or slow down the development of liver cancer, specifically by focusing on the tumour environment.
Interaction between stellate cells and tumour cells
Every year 500.000 patients are diagnosed with hepatocellular carcinoma (HCC), making it one of the most common cancers worldwide. There are limited therapeutic options, resulting in an average survival of 4 months after diagnosis. HCC typically arises in the context of liver cirrhosis which is caused by chronic liver damage. One of the key players in the progression of cirrhosis to HCC is the hepatic stellate cell, which is activated during liver damage and differentiates towards a contractile myofibroblast-like cell. Activated stellate cells play an essential role in the onset and progression of HCC and blocking their activation has been proposed as a potential therapy for patients with HCC (Figure 1). We focus on the interaction between stellate cells and tumor cells, with the overall aim to find new therapeutic strategies for patients with HCC.
Platelets in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in a background of chronic liver disease. It is characterized by a prolonged inflammatory process which induces a micro-environment that favours tumour growth and is a major factor in its complex molecular pathogenesis. This environment includes hepatic stellate cells, macrophages or Kupffer cells, endothelial cells, extracellular matrix (ECM) and a variety of immune cells. The dynamic cross-talk between these factors is believed to promote tumour initiation, proliferation and metastasis.
The liver plays a central role in coagulation and fibrinolysis but is also closely intertwined with the function and number of blood platelets. Platelets enter the injured liver and interact with hepatic sinusoidal endothelial cells, leading to platelet activation. This results in the release of a range of up to 300 bioactive proteins (including growth factors and chemokines). Platelets have been reported to interact with different cell types in the tumour micro-environment, including stellate cells, inflammatory cells, cancer cells and macrophages, thereby contributing to a more aggressive and metastatic tumour phenotype. We investigate the influence of platelets on different hepatic cell populations, including stellate cells, cancer cells and macrophages. Specifically, we look at how platelets alter the immune cell population and we study the functional effects on phagocytosis, tumor growth and metastasis.
The P2Y12 receptor in different hepatic cell populations
P2Y12 belongs to the G-protein coupled purinergic receptors and is a chemoreceptor for ADP. While the function of P2Y12 on platelets has been described extensively, we investigate the role of these receptors on different cell types in the liver. Hypoxia or inflammation, activates the release of extracellular nucleotides such as ATP and UTP which interact with cell surface P2Y-receptors to induce a broad range of physiological responses, which could be relevant in the pathogenesis of liver cirrhosis and hepatocellular carcinoma.
The effect of extracellular matrix on tumour stem cell properties
Activated hepatic stellate cells cause an excessive deposition of ECM in chronically damaged livers. ECM proteins as well as their proteolytic fragments play a crucial role in tumour growth, metastasis, and tumour neo-angiogenesis. While the effect of ECM on angiogenesis has been investigated extensively, less is known about the direct effects of ECM proteins and their degradation products on tumour growth. Interestingly, increasing evidence shows that the ECM is an essential component of the stem cell niche and that it can directly regulate stem cell differentiation, although the molecular details of how this is achieved have only just started to emerge. Liver progenitor cells (LPCs) reside in the canals of herring and are bipotential stem cells with the capacity to develop towards hepatocytes or cholangiocytes. HCC lesions often express LPC or cancer stem cell (CSC) markers and the LPC/CSC´s capacity to maintain uncontrolled proliferation and differentiation makes them specifically interesting since they could potentially give rise to several satellite tumour nodules after they acquire the potential to invade.
In our lab we study the direct effects of the deposition of ECM by activated stellate cells on tumour growth, mainly focusing on proliferation, migration and progenitor cell differentiation in HCC.