Expression of angiopoietin-like 4 in human gastric cancer: ANGPTL4 promotes venous invasion

Abstract

Abstract. There is strong evidence that the angiopoietin family is involved in the regulation of tumour progression, cellular growth and differentiation. Recently, it has been reported that angiopoietin-like 4 (ANGPTL4) in cancer cell promotes the metastatic process by increasing vascular permeability. To elucidate ANGPTL4 expression and its association with clinicopathological factors and prognosis in human gastric adenocarcinomas, we examined 103 cases of surgicallyresected human gastric adenocarcinoma by immunohistochemistry. Among 103 cases of adenocarcinoma, 38 cases (36.9%) showed positive staining in the cytoplasm of the carcinoma cells for ANGPTL4. Histologically, papillary and mucinous adenocarcinomas showed relatively high expression of ANGPTL4 (60 and 60%, respectively). The expression of ANGPTL4 was correlated with the depth of tumour invasion (p<0.005), lymph node metastasis (p<0.001), venous invasion (p<0.00005) and TNM stage (p<0.001) in the total carcinoma. In univariate survival analysis, ANGPTL4 expression was not associated with the overall survival. RT-PCR or Western blot analysis showed the expression of mRNA or protein of ANGPTL4 in all four surgically-resected samples and all four cell lines of human gastric adenocarcinoma. ANGPTL4 expression was correlated with several clinicopathological factors, especially venous invasion. These findings suggest that the ANGPTL4 is one of the factors involved in the progression of human gastric cancer. IntroductionGastric cancer is one of the most common cancer types in the world today, in spite of the fact that its incidence has shown a gradual decline in many countries (1). The occurrence and progression of cancer are considered to be a series of genetic events affecting the structure and/or expression of a number of oncogenes, tumour suppressors and growth factors (2,3). The deep invasive carcinomas, such as gastric cancer, have higher rates of lymph duct and venous invasions and lymph node metastasis (4). However, the mechanisms of invasion and metastasis of gastric carcinoma are not fully understood.The molecular mechanisms in tumour progression, local invasion and the formation of tumour metastases represent a major challenge in cancer research. Metastasis of tumour cells is the primary cause of death in patients with cancer (5). To metastasize, tumour cells undergo a multistep progression through a series of sequential and selective events (6). The metastatic process consists of tumour cell detachment, local invasion, motility, angiogenesis, vessel invasion, survival in the circulation, adhesion to endothelial cells, extravasation and regrowth in different organs (7). In each step, causative molecules have been identified; these include cell-adhesion molecules, various growth factors, matrix degradation enzymes and motility factors, of which most of these can be regarded as prognostic factors (7).There is strong evidence that the angiopoietin family is involved in the regulation of tumour progression, cellular growth and differentiation (8-10). A...

Mechanisms involved in biological behavior changes associated with Angptl4 expression in colon cancer cell lines

“…It is consistently expressed in ischemic tissues and in the perinecrotic areas of different human tumors as a direct or indirect target gene of hypoxia (10), and may be involved in tumor progression. There have been several reports concerning Angptl4 protein or gene expression in cancer tissues (11)(12)(13), and in breast cancer, Angptl4 induction by TGF-β via the Smad signaling pathway primes lung metastases (14). Yet, the role of Angptl4 in CRC remains unclear.…”

Expression of angiopoietin-like 4 (ANGPTL4) in human colorectal cancer: ANGPTL4 promotes venous invasion and distant metastasis

“…the cancer cells with venous invasion showed strong immunopositivity for Angptl4 proteins in the cytoplasm. In our previous study, the expression of Angptl4 in gastric cancer was correlated with lymphovascular infiltration (33). one report proposed that ANGPTL4 up-regulates the infiltration of cancer cells into the capillary adjacent to the tumour due to acute disruptions of the endothelial cell-cell junctions caused by Angptl4 (15).…”

Emerging Roles of Angiopoietin-like 4 in Human Cancer

“…TGF-b upregulates ANGPTL4 in breast tumor cells and disrupts the endothelial cell-cell junctions, leading to enhanced vascular leakiness and transendothelial migration of the tumor cells. Furthermore, clinical studies have correlated ANGPTL4 expression with venous and lymphatic invasion in human gastric and CRCs, which further emphasizes the role of ANGPTL4 in tumor metastasis (47)(48)(49). ANGPTL4 was found to promote transendothelial migration and metastasis of hepatocellular carcinoma cells through the upregulation of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells and the activation of the VCAM-1/integrin b1-signaling axis (27).…”

“…Presently, the lack of structural information on ANGPTL4 limits our ability to fully explain this phenomenon. Unfortunately, numerous studies that have attempted to decipher the role of ANGPTL4 in cancer have failed to address the posttranslational modifications and proteolytic processing of ANGPTL4, which clearly have a significant influence on the functions of ANGPTL4 (10,30,37,(47)(48)(49). For example, the expression of either the nANGPTL4 or the cANGPTL4 truncation in transgenic mice remains unknown (43).…”