Human Kupffer cells are cytotoxic against human colon adenocarcinoma

Abstract

11/6/20928activity against human colon tumor cell lines. Hopefully, through an understanding of the cytotoxic mechanisms of human KC, strategies to stimulate human KC to prevent or eradicate hepatic metastases can be developed rationally.T h e aim of this investigation is to determine if (1) human KC are cytotoxic against human colon carcinoma in vitro, (2) this cytotoxic activity can be stimulated, and (3) human KC mediate cytotoxicity through the secretion of T N F . MATERIAL AND METHODSIsolation of human KC. At the time of resection for colon cancer in six patients, a small (2 X 2 cm) wedge biopsy specimen of the liver was obtained. The specimen was placed in an enzyme solution (0.05% collagenase and deoxyribonuclease) and incubated in a shaking water bath at 37" C for 35 minutes. The cell suspension in Dulbecco's phosphate-buffered saline solution (DPBS) was placed on a 30% metrizamide gradient and centrifuged for 20 minutes (1400 g at 4" C). The KC were taken from the metrizamide-DPBS interface, washed, and placed in a 96-microwell plate at various effector concentrations (0.5 X lo', 1.0 X lo', and 2.5 X lo5 KC/well). The KC adhered for 2 hours and were washed twice with DPBS. This technique produced a suspension of >95% KC as determined by (1) macrophage morphology in a Wright-Giemsa-stained 400 SURGERY

Characterization of the Host Proinflammatory Response to Tumor Cells during the Initial Stages of Liver Metastasis

“…In vitro studies provided compelling evidence that activated Kupffer cells play a role in tumor surveillance in the liver and can exert cytotoxic or cytostatic effects on various tumor cells including human colon adenocarcinoma cells. 33 These tumoricidal effects could be induced by various mediators including cytokines. 34,35 In one of these studies, the tumoricidal effect of Kupffer cells on colon adenocarcinoma MCA26 cells in vitro was in fact linked to their ability to produce IL-1␣ and TNF-␣.…”

Activation of human Kupffer cells by thymostimulin (TP-1) to produce cytotoxicity against human hepatocellular cancer

“…Murine Kupffer cells activated by interferon-gamma, LPS, or macrophage colony-stimulating factor release TNF and IL-1, and these monokines produce cytotoxicity in vitro and in vivo against murine colorectal adenocarcinoma cells (27,28). Similarly, human Kupffer cells produce cytotoxicity in vitro against metastatic human colon adenocarcinoma cells through the release of TNF-a (29). TP-1 treatments in patients with HCC may produce tumor regression in part by activating hepatic Kupffer cells to release cytotoxic monokines.…”

An electron microscopy study of Kupffer cells in livers of mice having Friend erythroleukemia hepatic metastases

“…Previous studies demonstrated that Kupffer cells and other macrophages can be activated to a tumoricidal state by administering biological response modifiers (BRMs) such as lipopolysaccharide [11][12][13]20], gamma interferon [11,12,21,22] and muramyl peptides [6,7,20,23,24] resulting in reduced tumor load and increased survival time. The close proximity of Kupffer cells to liver metastases makes them an attractive target for immunomodulatory therapy to stimulate macrophage defense [7,10,12].…”

“…The close proximity of Kupffer cells to liver metastases makes them an attractive target for immunomodulatory therapy to stimulate macrophage defense [7,10,12]. Presently liposomes and microparticles are being tested as colloidal carriers to deliver BRMs to macrophages [7,10,23].…”

“…Within the hepatic sinusoids reside the largest single population of active macrophages, the Kupffer cells, which are important effector cells in host defense against metastatic tumors [6][7][8][9][10][11][12]. Kupffer cells in hepatic sinusoids are not only tumoricidal [6,7,[13][14][15], but can directly phagocytose tumor cells [1,16].…”