br Introduction br Alpha fetoprotein AFP is known as an
Alpha-fetoprotein (AFP) is known as an embryonal serum glyco-protein that is normally synthesized from fetal hepatocytes and yolk sac UNC 1999 during the gestational period . In adulthood, AFP is commonly regarded as a characteristic tumor biomarker for screening and super-vising hepatocellular carcinoma or yolk sac tumors. Nevertheless, sev-eral studies have uncovered that some other types of malignant solid tumors, such as tumors of the stomach, ovary, gallbladder, lung, and pancreas can also secrete AFP, with gastric cancer being the most common . Gastric cancer with a high serum AFP level is defined as alpha-fetoprotein-producing gastric cancer (AFPGC) . The incidence of AFPGC is merely 1.3–15.0% worldwide . In most studies, the patients with AFPGC have been found to have aggressive characteristics and a high incidence of synchronous and metachronous liver and lymph node metastasis, even undergoing radical surgery; accordingly, the survival rates of AFPGC indicate an extremely poor prognosis compared that of with common gastric cancer . Although surgical treatment or systemic chemotherapy is conducted to treat this malignancy in the clinic, the benefit to patients with AFPGC is still controversial , therefore, the molecular mechanism and standardized treatment pro-cess of AFPGC remain unclear. Therefore, it is essential to identify ef-fective predictive biomarkers to understand the mechanism and
improve the current treatment for this more malignant subtype of gastric cancer.
Angiogenesis is a sophisticated biologic process involving en-dotheliocyte multiplication, migration, invasion, and neovasculariza-tion. Furthermore, angiogenesis is necessary for various physiologic processes, such as body growth and tissue reproduction. To date, Angiogenesis has been identified as one of the hallmarks of tumor de-velopment . The new vascularization infiltrates the tumor and sup-plies it with oxygen and nutrients that assist in tumor growth beyond a certain size. New tumoral vessels that exhibit abnormally high pro-liferation and the migration of these new tumoral vessels usually result in a poorly functioning vasculature. The loose connections between endothelial cells and cells surrounding tumoral blood vessels are con-ducive to tumor cells entering the circulation through the blood vessel wall, thereby promoting metastasis and spreading to secondary sites. Thus, antiangiogenic therapy has become one of the most important anticancer therapies. Antiangiogenic therapy has obvious advantages over systemic chemotherapy, which usually leads to rapid mutation and treatment resistance.
Neovascularization of a tumor relies on the production of specific angiogenic molecules; both host and tumor cells transfer from an an-giogenic balance to a proangiogenic phenotype . To date, many angiogenic growth factors that have been identified as critical
E-mail address: [email protected] (T. Liu). 1 These authors contribute to this work equally.
dominators of the proliferation, apoptosis, and mobility of endothelial cells, including vascular endothelial growth factor (VEGF) and angio-poietin. So far, a new family of genes whose molecular structure is si-milar to that of angiopoietins, has been reported and subsequently denominated “angiopoietin-like gene family”.
Angiopoietin-like proteins (ANGPTLs) contain a set of eight secreted glycoproteins, from ANGPTL1 to ANGPTL8, and are similar to angio-poietin proteins; they have a specific structure: a C-terminal fibrinogen-like domain (FLD) and an N-terminal coiled-coil domain (CCD). Nevertheless, in contrast with angiopoietins, angiopoietin-like proteins do not bind to Tie 1 and Tie 2 receptors . Interestingly, ANGPTLs are widely expressed in numerous organs such as the heart, vascular system, and have small intestine and hematopoietic system and have multibiological properties involved in angiogenesis , inflammation and lipid metabolism . Emerging evidence has shown that some ANGPTLs (including ANGPTL2 [12,13], ANGPTL3, ANGPTL4 , and ANGPTL7(15)) are critical factors in tumor growth, migration, devel-opment, and drug resistance. Initially known as angiopoietin-related growth factor, ANGPTL6 has been reported to be a proangiogenic molecule , although it also plays an important role in regulating energy metabolism . More recently, overexpression of ANGPTL6 through the downregulation of miRNA-128 was related to tumor pro-liferation of glioblastoma undiﬀerentiated cells . The intrahepatic ANGPTL6 and the interaction between tumoral α6 integrin and E-cadherin drive homing and colonization by colorectal cancer cells . However, the role of ANGPTL6 in gastric cancer, especially AFPGC, remains elusive.