Ou et al., pp. 1208-1214 Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), one of the most common malignant tumors in Asia. It has a very high mortality rate due to the high incidence of metastasis. HBx, a small regulatory protein necessary for infection, is the only viral gene product consistently present in hepatic tumor cells. While previous work has mainly centered on its potential role in tumor development, in their study, Ou et al. focus on HBx' role during metastasis. The clinical data revealed HBx expression in 80.1 % of samples collected from 136 patients with HCC. HBx expression correlated with elevated levels of membrane-type 1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinsase-2 (MMP-2). The primary function of MT1-MMP and MMP-2 is the degradation of the extracellular matrix, including the basement membrane. Being able to move through the extracellular matrix is indispensable for tumor cells if they are to successfully break away from the primary tumor and settle in distant locations. A closer look revealed that HBx is able to induce the expression of MT1-MMP in Chang liver cells, which in turn activates the expression of MMP-2. Freed from the constraints posed by the extracellular matrix, HBx expressing Chang cells showed improved wound repair and migration. Together with the strong correlation between MMP expression and the poor prognosis of HCC patients, the high prevalence of HBx expression assigns HBx a potentially important function during invasion and metastasis. Ngo et al., pp. 1261-1267 Tissue factor (TF), the only nonplasma protein in the clotting cascade, is the primary molecule that initiates coagulation. In the last decade, however, TF has been found to be involved in a variety of other physiologic processes. TF expression is indispensable for normal embryonic development, plays a significant role in inflammatory processes and is tightly associated with oncogenic processes. Tumor metastasis, for example, appears to be closely tied to tissue factor overexpression; metastatic cells may express up to 1000-fold more tissue factor than their nonmalignant counterparts. In addition, it promotes tumor growth and tumor angiogenesis, suggesting TF as a promising target for specific cancer therapy. To put this hypothesis to the test, Ngo et al. assessed the capability of CNTO 859, a humanized monoclonal antibody directed against human TF, to inhibit the spread of human MDA-MB-231 breast cancer cells to the lungs of SCID Beige mice. The inhibition of metastasis was essentially complete, with a 99.9 % reduction in the number of lung lesions in treated mice. Therapeutic doses of CNTO 859 also reduced tumor incidence and the growth of xenografted human breast cancer cells. Although other inhibitors of coagulation have been shown to inhibit metastasis in tail vein models, this is the first time that a function-blocking human antibody has been shown to do so. Before therapeutic anti-TF antibodies can be taken to the clinic, further studies will be necessary to uncover potential adverse side effects and to elucidate the mechanism behind the powerful inhibition of metastasis. Spanjaard, et al., pp. 1304-1310 Melanoma is the deadliest form of skin cancer, resulting from the malignant transformation of cells called melanocytes. Once the transformation has occurred, melanocytes are notoriously difficult to kill and the best bet is still early detection and excision. Since no treatment can substantially enhance patient survival once metastasis has occurred, scientists have been scrambling for biomarkers and novel therapeutic targets, albeit with limited success. Particularly difficult to come by have been tumor-specific cell surface proteins, which prevented the development of therapeutic antibodies that have proven successful in other solid tumors in recent years. TROY, a novel melanoma biomarker discovered by Spanjaard et al. and belonging to the tumor necrosis factor receptor superfamily, may be the long awaited chink in the armor of melanoma cells. Identified during a genetic in vitro screen, TROY, also known as TAJ or TNFRSF19, is widely expressed during embryogenesis and later switched off with the exception of certain brain areas and hair follicles. The protein displays all the hallmarks of an excellent biomarker: It is expressed in all primary and metastatic melanoma cells and tissue samples but not in melanocytes found in normal skin biopsies and other types of skin cancer. Slashing expression levels with siRNA significantly decreased replication levels of melanoma cells, suggesting that TROY functions as a growth-promoting signaling molecule. This makes TROY a rare and promising target for tumor-specific immunotherapies or small molecule inhibitors.
Read full abstract
Jun 16, 2013
Yuri Miyazawa + 5
Open Access
