Role of Periostin in Hepatocellular Carcinoma: The Importance of Tumor Microenvironment

The contribution of the tumor microenvironment in cancer progression is becoming widely recognized. The tumor microenvironment consists not only of cellular components such as immune cells, fibroblasts, and endothelial cells as well as the malignant tumor cells themselves, but also includes noncellular component such as the extracellular matrix (ECM). The ECM is a complex meshwork made up of both proteins and proteoglycans with covalently attached sugar chains, glycosaminoglycans. Although primary role of ECM may be to provide structural support of an organ, it is also crucial in modulating cell functions by playing a role as a reservoir for growth factors or signaling molecules. ECM signaling may involve in proliferation, migration and invasion of cancerous cells. In addition collagen fibers of ECM can build migration tracks for tumor cells. At the same time, ECM may work as a barrier, hindering the penetration of immune cells or drugs into the tumor sites. Periostin, also known as osteoblast-specific factor 2, is initially identified as a cell adhesion protein in mouse osteoblast cell line. It is a secreted N-glycoprotein and is reported to interact with other ECM proteins such as collagen I, fibronectin, and tenascin C. Meanwhile, several recent studies demonstrated enhanced expression of periostin in breast, colon, lung, and pancreas cancer. Moreover, high serum periostin level was detected in patients with advanced lung and breast cancer accompanied by metastasis of the disease. Jang et al. reported that high periostin expression was related with decreased survival and increased recurrence in hepatocellular carcinoma (HCC). They suggested that pathological overexpression of periostin, in combination with existence of microvascular invasion could be a useful prognostic marker for HCC. Although existence of microvascular invasion is widely accepted as an important predictor recurrence after the curative treatment, usefulness of serum and pathologic periostin expression in HCC still needs some validations. However, the results from the study by Jang et al. are in accordance with the previous studies. A study which included 56 HCC patients reported that elevated serum periostin levels indicated decreased diseasefree survival (DFS) and overall survival (OS). Another study that evaluated pathological expression of periostin in 71 HCC patients also showed that high periostin expression was associated with compromised DFS as well as OS. Periostin, ECM protein, seems to contribute in liver fibrosis. Periostin expression was significantly upregulated in carbon tetrachloride and bile duct ligation induced liver cirrhosis. On the other hands, periostin deficient mice demonstrated attenuated liver fibrosis. In addition, periostin downregulation resulted in ameliorated hepatic stellate activation and proliferation, which might be directly related with liver fibrosis. Liver fibrosis and cirrhosis are one of the most important risk factors for HCC occurrence. HCC is very frequently accompanied by underlying liver fibrosis and cirrhosis and there is increased chance that expression of periostin in HCC might be associated with underling liver condition. The study by Jang et al. did not comment on the existence of liver cirrhosis in the recruited patients that were tested for histological periostin expression in HCC. However, previous study by Lv et al. reported increased serum periostin level in patient with liver cirrhosis compared with that of the healthy volunteers. The study also compared serum periostin levels between patients