Angiogenesis and Tumor Proliferation/Metastasis of Human Colorectal Cancer Cell Line SW620 Transfected with Endocrine Glands-Derived-Vascular Endothelial Growth Factor, As a New Angiogenic Factor

Abstract

Endocrine glands-derived-vascular endothelial growth factor (EG-VEGF) was recently cloned as a new angiogenic factor that selectively acts on the endothelium of endocrine gland cells. We evaluated the involvement of EG-VEGF in colorectal cancer. The expression of EG-VEGF was confirmed in all of the colorectal cancer cell lines. (On the other hand, the expression of EG-VEGF mRNA was not detected in colorectal normal mucosae.) Stable EG-VEGF infectors of colorectal cancer cell line SW620 were produced, EG-VEGF transfectants were implanted into cecum and s.c., and cell proliferation was evaluated. Angiogenesis was evaluated by dorsal air sac method. Liver metastasis was evaluated after the implantation of EG-VEGF transfectants into the mouse spleen. Tumor proliferation (cecum, s.c.) was significantly higher in the EG-VEGF transfectants than in the control cells. The small vessels were significantly increased in EG-VEGF transfectants as compared with those in control cells. Also, liver metastatic ratio was higher in the EG-VEGF transfectants than in the control cells. In this study, EG-VEGF, a new angiogenic factor, may lead to angiogenesis, promoting cell proliferation and liver metastasis in colorectal cancers. When the EG-VEGF gene-overexpressing colorectal cancer cell line that had been treated with phosphorothioate antisense EG-VEGF oligonucleotides was injected s.c. into mice, angiogenesis and tumor growth were inhibited. Although the novel angiogenesis factor EG-VEGF was not expressed in the normal colorectal mucosa, it was expressed in colorectal cancer cells, which indicates that it is a cancerspecific and possibly tissue-specific angiogenesis factor in the large intestine, and which suggests that it can be targeted by a novel antiangiogenesis therapy.

Implications of Endocrine Gland–Derived Vascular Endothelial Growth Factor/Prokineticin-1 Signaling in Human Neuroblastoma Progression

“…EG-VEGF/Prok-1 induces angiogenesis and promotes cell proliferation and liver metastasis in colorectal cancers. Antisense EG-VEGF/Prok-1, on the other hand, successfully inhibited EG-VEGF/Prok-1 -induced angiogenesis and tumor growth in mice (26). Together, these results suggest that EG-VEGF/Prok-1 promotes neuroblastoma progression not only by inducing proliferation, migration/invasion, and vascularization, but also by inhibiting the apoptosis of neuroblastoma cells.…”

“…EG-VEGF/Prok-1 is also a potent angiogenic factor, and it may therefore also promote vascularization in the development and metastasis of neuroblastoma (3,25). Other than the receptors, elevated EG-VEGF/ Prok-1 expressions have also been implicated in colorectal (26) and prostate cancers (27). EG-VEGF/Prok-1 induces angiogenesis and promotes cell proliferation and liver metastasis in colorectal cancers.…”

Pancreatic Islet and Stellate Cells Are the Main Sources of Endocrine Gland-Derived Vascular Endothelial Growth Factor/Prokineticin-1 in Pancreatic Cancer

“…Studies in endocrine glandrelated cancers, such as ovarian carcinoma [11] , Leydig cell tumor [29] and prostate cancer [30] , demonstrate that PK1 could be involved in carcinogenesis via regulation of angiogenesis. In addition, PK1 expression was found to be upregulated in colon cancer cell lines that express estrogen receptor ␤ , promoting cell proliferation and liver metastasis in colorectal cancers [31] . In the present study, we demonstrate absence of PK1 in normal ductal cells and cancer cells of pancreatic tissues.…”

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

“…For example, mice implanted with colorectal cancer cell line SW620 stably expressing PK1/EG-VEGF had an increase of angiogenesis and of colorectal cancer metastasis [28] . In ovarian carcinoma, PK1/EG-VEGF was evenly detected in benign, low malignant potential neoplasms or stage Ⅰ ovarian cancer [29] , and no expression was observed in endometrial carcinoma [30] .…”