Prevention of Hepatic and Peritoneal Metastases by the Angiogenesis Inhibitor FR‐118487 after Removal of Growing Tumor in Mice

Abstract

We established a mouse "primary tumor resection model" in which a transplanted tumor was resected after an orthotopic transplantation of colorectal cancer tissue to estimate the therapeutic effect of an angiogenesis inhibitor on metastasis. The angiogenesis inhibitor FR-118487 is a member of the fumagillin family. Here, 1 mg/kg/day of FR-118487 was subcutaneously administered to nude mice for 1 week, 2 weeks, or 4 weeks through an osmotic pump. Liver metastasis developed in 7 of 9 control mice, 2 of 6 mice that underwent the tumor resection 2 weeks after transplantation (early resection), and in all 7 of the mice that underwent the tumor resection 4 weeks after transplantation (late resection). In the short treatment trial, the FR-118487 administration immediately after the early resection completely inhibited both hepatic and peritoneal metastases, whereas its administration after the late resection had no effect on liver metastasis. In the prolonged treatment trial, inhibitory effects of prolonged treatment with FR-118487 on both hepatic and peritoneal metastases after the late resection were clearly demonstrated. The mice of the resection-alone group all died within 106 days after tumor inoculation, due to metastases of colon carcinoma. In contrast, half of the mice that underwent resection and then received antiangiogenic therapy were alive at the end of the observation period (160 days after transplantation). In conclusion, the combination of surgery and subsequent antiangiogenic therapy may be useful to prevent the distant metastasis of colorectal cancer and to improve the prognosis of patients with colorectal cancer. Key words: Hepatic metastasis -Metastasis after surgery -Human colon cancer -Angiogenesis inhibitor -Tumor removalHepatic metastasis is the most common cause of death after surgery for patients with colorectal cancer, and methodologies to prevent liver metastasis after surgery have been sought to improve the prognosis of these patients. There are no reports of a liver metastasis model after the resection of a primary colorectal tumor, to our knowledge. We established such a metastatic model, which well reflected the clinical situation, in which hepatic metastases developed after the removal of transplanted orthotopicallygrowing colorectal tumor. Accordingly, the results obtained in this model are thought to be of relevance to the clinical situation. With this model, therapeutic effects of antiangiogenic therapy followed by surgery on human colon cancer have been investigated.Tumor neovascularization is part of the complicated process of tumor metastasis, 1) and is crucial to the occurrence of hepatic metastasis.2) Since a small focus of tumor cells cannot grow indefinitely at a secondary site without the induction of angiogenesis, it is speculated that the inhibition of angiogenesis could provide a potent form of therapy for the hepatic metastasis of colonic cancer.3) Many studies have demonstrated the essential role of angiogenesis in the aggressive growth of solid tumors and their metastases.

Experimental microcomputed tomography study of the 3D microangioarchitecture of tumors

“…Arteries (arrow) and veins (asterisk) can be discriminated in the 3D images (c, d) [26,27,28,29,30,31]. There have been several reports on angiogenesis [25,26,27,28,29,30,31,32,33]. Folkman et al [32,33] defined angiogenesis as the formation of new blood vessels produced by the proliferation and migration of vascular endothelial cells in old blood vessels, a biological reaction which occurs under various physiological and pathological conditions.…”

“…Images of VX2 tumors obtained by a, b soft X-ray irradiation, c micro-CT, and d rotational micro-CT. Neovascularization and tortuous vessels, not found in normal rabbits, are present in the transplantation area seen on the micro-CT images. Arteries (arrow) and veins (asterisk) can be discriminated in the 3D images (c, d) [26,27,28,29,30,31]. There have been several reports on angiogenesis [25,26,27,28,29,30,31,32,33].…”

Lysophosphatidic Acid (LPA)-Induced Vascular Endothelial Growth Factor (VEGF) by Mesothelial Cells and Quantification of Host-Derived VEGF in Malignant Ascites

“…Many in vivo studies have shown that VEGF also plays important roles in the development of peritoneal metastasis [3][4][5][6][7]. In accordance, malignant ascites in ovarian or gastrointestinal cancer patients contains elevated levels of VEGF [8 -11].…”

TSU68 Prevents Liver Metastasis of Colon Cancer Xenografts by Modulating the Premetastatic Niche

“…After 5 wk of drug administration, mice were sacrificed and tumors were removed and weighed. Metastatic foci on the liver surface were counted macroscopically and were confirmed microscopically, as reported previously (28,29).…”