Signaling pathways in liver cancer: pathogenesis and targeted therapy.

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

S100A6 drives lymphatic metastasis of liver cancer via activation of the RAGE/NF-kB/VEGF-D pathway.

Patients diagnosed with lymph node (LN) metastatic liver cancer face an exceedingly grim prognosis. In-depth analysis of LN metastatic patients' characteristics and tumor cells' interactions with human lymphatic endothelial cells (HLECs), can provide important biological and therapeutic insights. Here we identify at the single-cell level that S100A6 expression differs between primary tumor and their LN metastasis. Of particular significance, we uncovered the disparity in S100A6 expression between tumors and normal tissues is greater in intrahepatic cholangiocarcinoma (ICC) patients, frequently accompanied by LN metastases, than that in hepatocellular carcinoma (HCC), with rare occurrence of LN metastasis. Furthermore, in the infrequent instances of LN metastasis in HCC, heightened S100A6 expression was observed, suggesting a critical role of S100A6 in the process of LN metastasis. Subsequent experiments further uncovered that S100A6 secreted from tumor cells promotes lymphangiogenesis by upregulating the expression and secretion of vascular endothelial growth factor-D (VEGF-D) in HLECs through the RAGE/NF-kB/VEGF-D pathway while overexpression of S100A6 in tumor cells also augmented their migration and invasion. Taken together, these data reveal the dual effects of S100A6 in promoting LN metastasis in liver cancer, thus highlighting its potential as a promising therapeutic target.