Tumor-stroma interactions in hepatocellular carcinoma

Sammanfattning: Hepatocellular carcinoma (HCC), a highly deadly primary liver cancer with a rising global incidence and limited therapeutic options, is characterized by a vicious cross-talk between the tumor and its surrounding hepatic stroma. The stromal environment, consisting of hepatic stellate cells (HSC), endothelial cells, resident and infiltrating macrophages and other immune cells, platelets and extracellular matrix (ECM) components, actively contributes to creating an ideal niche for tumor proliferation and invasiveness. For instance, by secreting copious amounts of growth factors and ECM proteins, activated HSC directly stimulate tumor proliferation and promote fibrosis, neo-angiogenesis, inflammation and immunosuppression. In turn, tumor cell-derived factors induce the activated HSC phenotype, while also shaping other stromal components to benefit carcinogenesis. Infiltrating platelets are also known to have detrimental effects within a tumor microenvironment, and have been widely linked to stellate cell activation, inflammation and tumorigenesis in HCC. Another important hallmark of HCC development is endoplasmic reticulum (ER)-stress, a condition during which misfolded and unfolded proteins accumulate in the ER lumen and trigger a cellular survival strategy known as the unfolded protein response (UPR). Key mediators of the UPR have been shown to promote different facets of HCC progression, including tumor cell survival, fibrosis and inflammation. In the present studies, a chemically induced HCC mouse model, along with several 2D and 3D in vitro approaches, was used to study the role of tumor-stroma interactions in HCC development in order to identify new potential therapeutic targets that could benefit patients with liver cancer. It was thereby found that activated platelets promote disease progression by stimulating tumor growth, fibrosis and by altering the hepatic immune response. Additionally, the IRE1α-mediated UPR signaling branch was shown to play a key role in promoting hepatocarcinogenesis, fibrosis and in fueling the vicious cross-talk between stellate cells and tumor cells. Therefore, as stromal biology plays a key role in potentiating HCC progression, the malicious tumor-stroma interactions that shape the hepatic microenvironment also offer potential therapeutic targets for the treatment of liver cancer, thereby encouraging further research in the field.