Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice

Abstract

NK4, a 4-kringle fragment of hepatocyte growth factor (HGF), is an HGF antagonist that also acts as an angiogenesis inhibitor. NK4 strongly inhibits the infiltration, metastasis, and tumor growth of pancreatic cancer. The aim of our study was to evaluate the antitumor effect of adenovirus-mediated NK4 gene transfer to the liver on hepatic metastasis of pancreatic cancer in vivo. We constructed recombinant adenoviral NK4 (Ad-NK4), which encodes a secreted form of human NK4. Intrasplenic injection of Ad-NK4 induced high and relatively maintained expression of NK4 protein in the liver and suppressed the number and growth of metastatic foci in the liver in a nude mouse model. Microscopically, central necrosis was found even in small metastatic foci in Ad-NK4 treated mice. Immunohistochemical analysis of metastatic tumors showed a remarkable decrease in microvessel density and an increase in the number of apoptotic tumor cells after treatment with Ad-NK4. These results indicate that intraportal injection of Ad-NK4 may be a useful therapeutic modality for the clinical control of hepatic metastasis in pancreatic cancer. ' 2005 Wiley-Liss, Inc.Key words: gene therapy; NK4; HGF antagonist; angiogenesis inhibitor; pancreatic cancer; hepatic metastasis; recombinant adenovirus Pancreatic cancer remains one of the most malignant neoplasms. The disease is diagnosed frequently at an advanced stage, and only 3% of patients survive 5 years. 1 Pancreatic cancer has a high rate of local and systemic recurrence, including liver metastasis, peritoneal dissemination and retroperitoneal recurrence. 2 There is no effective treatment for this disease. Radical resection has only a limited effect for the disease, 3 but even after curative resection of the primary tumor, liver metastasis occurs frequently and constitutes a major course of this disease. 2,4 Generally, micrometastasis to the liver seems to have already occurred in most patients when pancreatic cancer is diagnosed. 5 Pancreatic cancer is highly resistant to the chemotherapy and radiation protocols available currently. Even gemcitabine, which has become the standard drug used for metastatic disease, does not improve median survival. One factor underlying the aggressive local and early systemic tumor growth may be rapid tumor neoangiogenesis, which results in an abundant blood supply. Tumor-induced neoangiogenesis is a common phenomenon during growth, particularly in tumors larger than 1-2 mm in diameter. 6,7 We showed previously that pancreatic cancer cells frequently overexpress c-Met/hepatocyte growth factor (HGF) receptor and that HGF plays important roles in the mitogenic, motogenic and morphogenic activities of these cells. We also identified and prepared NK4 as an antagonist of HGF. 8,9 NK4 is composed of the N-terminal hairpin and 4 kringle domains of HGF. NK4 binds c-Met/HGF receptor but does not induce tyrosine phosphorylation of c-Met. NK4 is a potent antiangiogenic agent and antagonizes not only HGF-induced angiogenesis but also that of other angiogenic factors suc...

Progress of antibody-based inhibitors of the HGF–cMET axis in cancer therapy

“…19 In preclinical studies, adenoviruses expressing the NK4 gene have demonstrated antitumor effects in numerous types of tumors including mesothelioma and pancreatic cancer. 65, 66 A phase I clinical study of gene therapy using the NK4 -expressing adenoviral vector in patients with mesothelioma is ongoing. 67 …”

Radiation Enhances Adenoviral Gene Therapy in Pancreatic Cancer via Activation of Cytomegalovirus Promoter and Increased Adenovirus Uptake

“…Therefore, molecular therapies for pancreatic cancer are promising new approaches to treat this often fatal disease. Investigators have used adenovirus-mediated gene transfer to treat pancreatic cancer and reported that adenovirus-mediated gene therapy inhibited progression of pancreatic cancer in vivo and in vitro (17,18). However, clinical trials revealed that it is difficult to eradicate pancreatic tumors with adenovirusmediated gene therapy alone (19,20).…”

Inhibitory effect of 4‐methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice

“…Pancreatic cancer remains one of the most malignant neoplasms because the disease is diagnosed frequently at an advanced stage, and only 3% of patients survive 5 years 1, 2, 3, 4. One of the pathological characteristics of this carcinoma is its early invasion of surrounding tissues and metastasis.…”

“…Pancreatic cancer has various modes of spread, such as hepatic metastasis, peritoneal dissemination, retroperitoneal recurrence, lymph node metastasis and local and distant metastasis from an early stage 5. Recently, the standard drug for treatment of progressive pancreatic cancer has been gemcitabine,6 but this does not improve survival time because pancreatic cancer is highly resistant to chemotherapy 1. Therefore, more effective therapy for progressive pancreatic cancer is needed.…”