Murine Kupffer cells and hepatic natural killer cells regulate tumor growth in a quantitative model of colorectal liver metastases

Abstract

This investigation aimed to develop a biologically relevant murine model of colorectal liver metastases and determine if Kupffer cells (KC) and hepatic natural killer cells (hNKC) regulate tumor growth. The model involves the injection of murine colon adenocarcinoma 26 (MCA 26) tumor cells into the portal vein of female-specific pathogen-free BALB/c mice. Metastases developed in all animals, and the growth was limited entirely to the liver. To determine if KC and hNKC control the development of liver metastases, the in vivo function of these hepatic effector cells was modulated. Tumor growth was quantitated by the uptake of 125I into tumor DNA. Stimulation of the KC and hNKC produced a significant (P less than 0.01) dose-dependent decrease in 125I uptake in the liver in both treatment groups, which was associated with a significant improvement in survival (P less than 0.05). The in vivo cytotoxic function of the liver was inhibited with an intravenous injection of gadolinium chloride (for KC) or asialo GM1 antiserum (for hNKC). Inhibition of KC and hNKC cytotoxic function led to a significant (P less than 0.01) increase in 125I uptake in the liver and a significant decrease in survival (P less than 0.05).

Early Events of Hepatic Metastasis Formation in Mice: Role of Kupffer and NK-Cells in Natural and Interferon-γ-Stimulated Defense

“…To this end we established and refined the well-studied and predictable murine model for inducing hepatic metastasis with the C-26 colon carcinoma in syngeneic BALB/c mice [17,18]. Tumor cells were administered through the superior mesenteric vein, and metastatic parameters were assessed in untreated, immunostimulated (IFN-␥), and/or KCdepleted (GdCl 3 ) and/or NK-cell-depleted (anti-asGM 1 ) animals.…”

Utilization of Electron Probe Microanalysis in Gadolinium-Treated Mice

“…Recently, the technical aspects of microprobe analysis in toxicology have been reported (2, 9), yet we found that published applications of this procedure in toxicology studies are rather limited (21,23 (Fig. 1).…”

“…Inhibition of Kupffer cell phagocytosis by gadolinium has provided valuable information about the role of these cells and their reactive intermediates in tissue injury following endotoxemia (22), anaphylactic shock (16), intraabdominal sepsis (4), ischemic reperfusion injury (11), regulation of tumor growth (21), and graft prolongation (12).…”

Interactions between rat colon carcinoma cells and Kupffer cells during the onset of hepatic metastasis

“…12 However, most studies describing the in situ KC-tumor cell interactions focused on events occurring 2-3 weeks after tumor cell inoculation, 20,22,34,35 and only a few studies examined the early stages of hepatic metastases (Ͻ 24 hr). 36,37 Routine microscopic methods are not optimal for studying early hepatic metastasis because they require thin sections, low sampling volumes, complicated preparation methods and immunohistochemical procedures. 38 In contrast, confocal laser scanning microscopy (CLSM) enables the study of large sample volumes and sections 50 -100 m thick, facilitating investigation of rare cellular events such as the occurrence of tumor cells in the liver.…”