Platelets as Key Factors in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix, and a variety of immune cells interact in highly complex and intertwined signaling pathways. A key factor in these cross-talks are platelets, whose role in cancer has gained growing evidence in recent years. Platelets have been reported to promote HCC cell proliferation and invasion, but their involvement goes beyond the direct effect on tumor cells, as they are known to play a role in pro-fibrinogenic signaling and the hepatic immune response, as well as in mediating interactions between these factors in the stroma. Anti-platelet therapy has been shown to ameliorate liver injury and improve the disease outcome. However, platelets have also been shown to play a crucial role in liver regeneration after organ damage. Therefore, the timing and microenvironmental setting need to be kept in mind when assessing the potential effect and therapeutic value of platelets in the disease progression, while further studies are needed for understanding the role of platelets in patients with HCC.

Keywords: fibrosis; hemostasis; hepatic stellate cells; hepatocellular carcinoma; macrophages; platelets; tumor-stroma interactions.

Figure 1

The interaction between platelets and different cells in the tumor and stromal compartments of hepatocellular carcinoma (HCC). Upon activation, platelets release α-granules and dense granules containing inflammatory cytokines, chemokines, and growth factors, such as platelet-derived growth factor beta (PDGFβ), serotonin, endothelial growth factor (EGF), insulin-like growth factor I (IGF-1) transforming growth factor beta (TGFβ), tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 4 (CXCL4), vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF). Platelets promote HCC cell proliferation, invasion, and chemoresistance, by releasing cytokines (serotonin, HGF, VEGF-A TGFβ, IGF-1, TNFα, EGF, and IL-6) and by adhering to tumor cells, allowing them to avoid immunodetection. Their involvement goes beyond the direct effect on tumor cells, as they also affect the different cells in the stromal compartment, which creates an environment that stimulates tumor growth, invasion, and metastasis. Platelets release factors (mainly TGFβ, PDGFβ, serotonin, and CXCL4) that activate stellate cells, turning them in extracellular matrix (ECM) producing myofibroblasts which support tumor growth and aid metastasis. By secreting pro-angiogenic factors (VEGF-A and FGF) and by interacting with endothelial cells via CD40L and P-selectin, they contribute to the angiogenic switch, which increases the tumoral blood supply and facilitates vascular invasion. Platelets also play an important role in changing the hepatic immune cell population, as the release of microparticles containing serotonin, CXCL4, TGFβ, and PDGFβ promotes a shift from anti-tumoral macrophages to pro-tumoral macrophages, which are potent drivers of carcinogenesis. In addition, both the direct contact and release of TGFβ can decrease the cytotoxic potential of natural killer (NK) cells, causing an immunosuppressive environment that benefits tumor growth.

Figure 2

Overview of different anti-platelet therapies currently tested in preclinical and clinical studies for hepatocellular carcinoma (HCC) and other types of cancer. Aspirin irreversibly inhibits cyclooxygenase-1 on platelets, which is involved in the metabolism of arachidonic acid through TXA2 synthase activity. It has generated significant interest as a potential chemopreventive agent, mainly due to the finding that a low-dose of aspirin decreases the risk of colorectal cancer [99] and HCC [100]. Clopidogrel, on the other hand, is a purinergic P2Y₁₂ receptor inhibitor. Clopidogrel restrains the binding of adenosine diphosphate (ADP) to its receptor and attenuates the activation and aggregation of platelets. Combining aspirin and clopidogrel has been shown to ameliorate the progression of HCC in vivo [14,15,78]. The effect is synergistic, through their distinct binding sites on platelets. Inhibition of platelets can also be achieved by targeting isomers of phosphodiesterases (PDE2, PDE3, and PDE5) which have different cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) selectivity. These drugs have been shown to induce apoptosis and cell cycle arrest in a broad spectrum of tumor cells and are known to stimulate liver regeneration after hepatectomy [101].