tetrathiomolybdate and Liver-Neoplasms

The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma.. A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry.. The median concentration of copper in serum was 401.70, 469.40, and 665.35 μg/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 μg/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2.. The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of combination therapy.

Topics: Animals; Copper; Liver Neoplasms; Mice; Vascular Endothelial Growth Factor A

Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ∼800 000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 was significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlate with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestalled tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Chelating Agents; Copper; Copper Transporter 1; Copper-Transporting ATPases; Homeostasis; Humans; Liver Neoplasms; Molybdenum; SLC31 Proteins