Expression of growth factors in colorectal carcinoma liver metastatic patients after partial hepatectomy: implications for a functional role in cell proliferation during liver regeneration

Abstract

Liver has a remarkable ability to replace lost cell mass. Surgical resection of hepatic lobes triggers hepatocyte replication. Normally hepatocytes have a quiescent, highly differentiated phenotype and rarely divide in adult humans [1,2]. However, their capacity to replicate is readily activated after liver resection or after toxic injury. A number of studies have demonstrated the involvement of specific cytokines and growth factors in liver regeneration. The intact liver is relatively unresponsive to exogenous factors but partial hepatectomy provides some critical element that makes hepatocytes competent to fully respond to these substances [3,4]. Many growth factors play important roles in liver regeneration, most notably hepatocyte growth factor (HGF) and transforming growth factor a (TGF-alpha) [5,6]. HGF is an important multifunctional cytokine involved in liver repair after an injury. It acts as a motogen, a morphogen and a mitogen. Mesenchymal cells are responsible for the production of HGF whereas epithelial cells of various organs and tissues including the liver normally express HGF receptor cMET. In the liver HGF is produced by nonparenchymal cells especially perisinusoidal cells (PC), Kupffer cells (KC) and endothelial cells (EC). The expression of HGF mRNA during liver regeneration is also seen in mesenchymal cells in the lung and spleen and level of HGF increases in the blood after partial hepatectomy [7-9]. In contrast to HGF, which stimulates hepatocyte replication by a paracrine mechanism, TGF-alpha is an autocrine growth factor that is produced by hepatocytes and acts on these cells through binding the epidermal growth factor receptor (EGF-R) [10]. It is not known whether HGF and TGF-alpha have identical or complementary functions in hepatocyte replication. Human liver regeneration is known to be influenced by the size of resection and also by the condition of the liver. Vascular complications and ischemic injury in hepatectomized patients could result in adequate regeneration, leading to hepatic insufficiency [11]. Moreover, regeneration of human liver is influenced by coexisting liver diseases. Clinical experience has shown that resection of diseased liver sometimes results in postoperative liver failure due to limited hepatic functional reserve. While considerable interest has been focused on the tumor recurrence in liver cancer patients who underwent partial hepatectomy (PH) no data have been reported regarding the regenerating process after PH in liver tumor-bearing patients. The growth factors released by cancer cells may possibly regulate the growth of other cells in paracrine manner. The aim of the present study was initiated to determine the hepatocyte proliferation in relation to the expression of HGF and TGF-alpha in blood and liver tissue of patients with benign and malignant liver tumors after liver resection.