-Original-

Reexpression of Reduced VEGF Activity in Liver Metastases of Experimental Pancreatic Cancer

Munehisa Fukuhara¹, Eiji Uchida¹, Takashi Tajiri¹, Takayuki Aimoto¹, Zenya Naito² and Toshiyuki Ishiwata²

¹Surgery for Organ Function and Biological Regulation, Nippon Medical School Graduate School of Medicine
²Integrative Pathology, Nippon Medical School Graduate School of Medicine

Purpose: Vascular endothelial growth factor (VEGF) is thought to play a crucial role in the process of cancer growth and metastasis. In this study, the expression of VEGF in liver metastases of pancreatic cancer was investigated using an established hamster model.
Methods: Pancreatic cancer cells (PGHAM-1, 1×10⁶) derived from N-nitrosobis (2-oxopropyl) amine (BOP)-induced pancreatic tumors in Syrian golden hamsters were transplanted into the pancreas of female hamsters. All hamsters were sacrificed at 21 days after transplantation and used for the histopathological examination of pancreatic and metastatic lesions (primary transplantation model). The metastatic liver tumors were minced with scissors and 1 mm³ tumors were retransplanted into the pancreas of a second hamster. All hamsters were sacrificed 21 days after retransplantation, and the pancreatic tumors were removed (back transplantation model). Immunohistochemical analyses using antibody against VEGF were performed for all pancreatic and liver tumors. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to examine the expression of VEGF mRNA in the tumors. In addition, we investigated the proliferation of each tumor using Ag-NOR staining.
Results: In the primary transplantation models, VEGF expression in the pancreatic tumors was positive, but that in the liver metastases was only weakly positive or negative. On the other hand, VEGF expression in the pancreatic tumors that had developed from the retransplantation of the liver tumors (back transplantation model) was strongly positive. VEGF mRNA was expressed in the pancreatic tumors of both primary and back transplantation models. In the metastatic liver tumors of the primary transplantation model, VEGF mRNA was expressed in all cases, although the immunohistochemical staining pattern was weakly positive or negative. Similarly, in the metastatic liver tumor of the back transplantation model, VEGF mRNA was expressed in all cases, although the immunohistochemical staining pattern was weakly positive or negative. No significant differences in Ag-NOR scores were found between the models.
Conclusion: Our results suggest that VEGF expression usually occurs in PGHAM-1 cells but that VEGF expression is reduced during the process of liver metastasis and revived by retransplantation. Thus, the interrelationship between cancer cells and the organ environment might play an important role in VEGF expression.

J Nippon Med Sch 2005; 72: 155-164

Keywords
vascular endothelial growth factor (VEGF), liver metastasis, experimental pancreatic cancer, pancreatic cancer cell line (PGHAM-1)

Correspondence to
Munehisa Fukuhara, First Department of Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
m-fuku@nms.ac.jp

Received, September 21, 2004
Accepted, December 24, 2004