Suppression of Liver Tumor Growth and Metastasis by Adiponectin in Nude Mice through Inhibition of Tumor Angiogenesis and Downregulation of Rho Kinase/IFN-Inducible Protein 10/Matrix Metalloproteinase 9 Signaling

Abstract

Purpose: We aimed to investigate the effects of adiponectin on liver cancer growth and metastasis and explore the underlying mechanisms.Experimental Design: An orthotopic liver tumor nude mice model with distant metastatic potential was applied. Either Ad-adiponectin (1 × 10 8 ; treatment group) or Ad-luciferase (control group) was injected via portal vein after tumor implantation. Tumor growth and metastasis were monitored by Xenogen In vivo Imaging System. Hepatic stellate cell activation by α-smooth muscle actin staining, microvessel density by CD34 staining, macrophage infiltration in tumor tissue, and cell signaling leading to invasion, migration [Rho kinase (ROCK), IFN-inducible protein 10 (IP10), and matrix metalloproteinase 9], and angiogenesis [vascular endothelial growth factor (VEGF) and angiopoietin 1] were also compared. Tumor-nontumor margin was examined under electron microscopy. Direct effects of adiponectin on liver cancer cells and endothelial cells were further investigated by a series of functional studies.Results: Tumor growth was significantly inhibited by adiponectin treatment, accompanied by a lower incidence of lung metastasis. Hepatic stellate cell activation and macrophage infiltration in the liver tumors were suppressed by adiponectin treatment, along with decreased microvessel density. The treatment group had less Ki-67-positive tumor cells and downregulated protein expression of ROCK1, proline-rich tyrosine kinase 2, and VEGF. Tumor vascular endothelial cell damage was found in the treatment group under electron microscopy. In vitro functional study showed that adiponectin not only downregulated the ROCK/IP10/VEGF signaling pathway but also inhibited the formation of lamellipodia, which contribute to cell migration.Conclusion: Adiponectin treatment significantly inhibited liver tumor growth and metastasis by suppression of tumor angiogenesis and downregulation of the ROCK/IP10/matrix metalloproteinase 9 pathway. Clin Cancer Res; 16(3); 967-77. ©2010 AACR.Although surgical procedures such as liver resection and liver transplantation are first-line treatments for liver cancer, tumor recurrence and metastasis remain to be major problems affecting long-term disease-free survival. Therefore, development of novel adjuvant therapies targeting liver cancer growth, recurrence, and metastasis without obvious toxicity to the liver itself is essential.Adiponectin, a fat-derived hormone, has been shown to have a correlation with tumor development and prognosis (1, 2). Lower circulating levels of adiponectin have been found to be an independent predictor of colorectal cancer recurrence (3). Adiponectin can suppress hepatic stellate cell activation that plays an important role in angiogenesis. Hypoadiponectinemia accelerated liver tumor formation in a nonalcoholic steatohepatitis mouse model (4). It has been found that recombinant adiponectin not only significantly attenuated liver steatosis but also improved liver function by amelioration of inflammation (5) and rescued the marginal liver...

PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells

“…SIRT1, as a master regulator of cellular metabolism, might provide a crucial link between metabolic homeostasis and inhibition of cancer metastasis, by either preventing a hypoxic and/or inflammatory response downstream of the metabolic disorder, or by promoting the synthesis and release of humoral factors that have anti-metastatic properties. Indeed, several known targets of SIRT1, such as adiponectin, whose dysfunction contributes to metabolic syndrome, have been implicated in cancer metastasis (Man et al, 2010). To support this notion are the observations that calorie restriction (CR), a well-studied process known to activate SIRT1, offers some beneficial effects in combating cancer (Bonorden et al, 2009;Lee and Longo, 2011;van Ginhoven et al, 2010).…”

Plasma Levels of Adiponectin and Primary Liver Cancer Risk in Middle-Aged Japanese Adults with Hepatitis Virus Infection: A Nested Case–Control Study

“…However, this study did not include hepatitis virus infection status as a matching variable and treated anti-HCV as a confounding factor. Although in vitro and in vivo studies have indicated that adiponectin exerts antitumor effects against hepatocelluar carcinoma by inducing apoptosis or suppressing tumor angiogenesis (12,13), it is not unusual for the results of epidemiologic studies to contradict those of experimental studies. In addition, the insulin-sensitizing properties of adiponectin do not explain the connection with liver cancer.…”

“…These results also suggested that elevated levels of adiponectin would be associated with a reduced risk of primary liver cancer linked with obesity, and that hyperadiponectinemia might suppress liver tumorigenesis (11). Indeed, experimental studies indicated that adiponectin treatment increased apoptosis of hepatocelluar carcinoma, the most common form of primary liver cancer, and inhibited its proliferation (12,13). However, it has been pointed out that hyperadiponectinemia reflects the progression of liver disease leading to the development of liver cancer, as the liver is the main organ of adiponectin metabolism (9,11).…”

Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway

“…It is also possible that fenofibrate differentially regulates pathological and physiological angiogenesis, as has been proposed for the effects of statins on vascularization (32). Similarly, adiponectin enhances angiogenic responses in mouse ischemic hindlimb and rabbit cornea angiogenesis assays (18,25,33), whereas adiponectin suppresses tumor angiogenesis in vivo (6,20). Of importance, it is established that activation of AMPK/eNOS signaling confers a proangiogenic phenotype in ischemic hindlimb (18,22,23,26,33).…”