The normal hepatic sinusoid is formed or lined by four different cell types, each with its specific phenotypic characteristics, functions and topography. Endothelial cells constitute the closed lining or wall of the capillary. They contain small fenestrations to allow the free diffusion of substances, but not of particles like chylomicrons, between the blood and the hepatocyte surface. This filtering effect regulates the fat uptake by the liver. Sinusoidal endothelial cells also have a pronounced endocytotic capacity which makes them an important part of the reticuloendothelial system. They are also active in the secretion of bioactive factors and extracellular matrix components of the liver. Recently, a zonal heterogeneity of the endothelial lining has been reported with regard to its filtering capacity (fenestration) and binding capacity for lectins and cells. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytotic capacity. They are potent mediators of the inflammatory response by the secretion of a variety of bioactive factors and play an important part in the immune defense. A zonal heterogeneity has been established with regard to the endocytotic capacity and cytotoxic function. Pit cells are now known to represent a liver-associated population of large granular lymphocytes. They have the capacity to kill tumor cells and probably also play a role in the antiviral defense of the liver. In addition, pit cells may have a growth-regulatory function of the liver. They are known to be numerically more prominent in the periportal region, as is also the case for Kupffer cells. Fat-storing or Ito cells are present in the perisinusoidal space of Disse and are thought to represent the main hepatic source of extracellular matrix components. They are also the main site of vitamin-A storage. Fatstoring cells are more numerous in the periportal region than in the central region of the hepatic acinus. The periportal cells also store higher amounts of vitamin A. Sinusoidal cells may be considered to represent a functional unit at the border line between the hepatocytes or parenchymal cells and the blood. They participate in various liver functions and liver pathologies and our knowledge about this is growing. The heterogeneity of these cell types and possible cooperations between them and the hepatocytes may add to our understanding of liver functions.

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8⁺ PD1⁺ and CD8⁺ Siglec-7⁺/Siglec-9⁺ T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8⁺ T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

Insulin-like growth factor-1 (IGF-1) has been described as an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Angiogenesis correlates with development and prognosis of the MM disease. Vascular endothelial growth factor (VEGF) is one of the prominent factors involved in this process. The different functions of IGF-1 were investigated in the 5TMM mouse model with emphasis on proliferation, migration and VEGF secretion, and the signalling pathways involved. Western Blot analysis revealed that ERK1/2 and Akt (PKB) were activated after IGF-1 stimulation. The activation of ERK1/2 was reduced by the PI3K inhibitor Wortmannin, implying that the PI3K pathway is involved in its activation. Insulin-like growth factor-1 induced an increase in DNA synthesis in MM cells, which was mediated by a PI3K/Akt-MEK/ERK pathway. Insulin-like growth factor-1 enhanced F-actin assembly and this process was only PI3K mediated. Stimulation by IGF-1 of VEGF production was reduced by PD98059, indicating that only the MEK–ERK pathway is involved in IGF-1-stimulated VEGF production. In conclusion, IGF-1 mediates its multiple effects on MM cells through different signal transduction pathways. In the future, we can study the potential in vivo effects of IGF-1 inhibition on tumour growth and angiogenesis in MM.