Role of Kupffer cells in arresting circulating tumor cells and controlling metastatic growth in the liver

Abstract

Metastasis to the liver is a common event in clinicaloncology. Blood-borne tumor cells (TCs) arriving to the coined the term metastasis in 1829 in his treatise ''Reliver sinusoids run into a special vascular bed. The lining cherches du Cancer,'' the metastatic cascade has been of liver sinusoids is shared by Kupffer cells (KCs) and exhaustively studied.1,2 Metastases originate from a seendothelial cells. KCs, liver-fixed macrophages, are re-lective population of cells within the great biological sponsible for detection and removal of ''non-self'' parti-heterogeneity of the tumor.3 They must invade the vascles. To investigate their role in arresting blood-borne cular wall to be dislodged into the circulation and surTCs and controlling tumor growth, we injected a synge-vive in the blood stream until they arrest at the distant neic colon carcinoma cell line into a mesenteric vein of vascular bed of the target organ by adherence or metwo groups of rats; one group was without Kupffer cells chanical trapping. Then, they have to proliferate to iniand the other normal controls. We removed the liver of tiate a metastatic colony. these animals at different time intervals and performedLiver metastasis is a common event in cancer paimmunohistochemical analysis with monoclonal antitients. This is of particular relevance for neoplasias of bodies (MoAbs) against our tumor cell line, three macrophage subpopulations, natural killer cells, and B and T the gastrointestinal tract, because the liver is the first lymphocytes. Additionally, we showed in vitro spontane-vascular bed to be encountered by blood-borne tumor ous cytotoxicity of KCs against our tumor cell line. Re-cells (TCs) through the portal system. 4 The lumen of sults suggest that KCs play a relevant role in arresting liver sinusoids differ from the ordinary capillaries in circulating TCs at the liver sinusoid, although it is lim-that, besides endothelial cells, the stellate cells of von ited to a small number of malignant cells. They also seem Kupffer are lining the sinusoid wall.5 Kupffer cells to play a major role in clearing neoplastic cells from the (KCs) represent one of the largest populations of the liver parenchyma, in controlling tumor growth in the mononuclear phagocyte system in the body. Their privery early stages of metastatic development, and in mod-mary function is to discriminate between ''self'' and ulating the host immune response to cancer cells. (HEPA-''non-self'' particles, playing a prominent role as anti-

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

“…Our results show that there is a high density of KCs in the liver (10 4 KCs/mm 3 ), comparable to what has been reported, 48 and located mainly in the periportal areas as described by others. 22,49 Moreover, our results suggest that the reported recruitment-based increase in the number of macrophages after 3 days 36 may start as early as 1 day after arrival of cancer cells in the liver. There was a rapid response by macrophages to the newly arrived cancer cells, which were observed lying against and protruding through the endothelial lining as described in a model for mouse mammary carcinoma metastasis.…”

“…Synergism between KCs and NK cells in the elimination of tumor cells has been postulated in vivo 34 and illustrated in vitro. 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.…”

Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice

“…These cells show spontaneous cytotoxic activity against tumor cells in vitro. 48 Kupffer cells might also arrest circulating tumor cells and control their growth in the very early stage of metastatic development and thereby be involved in controlling hepatocarcinogenesis and HCC progression. 49,50 In the present study, Kupffer cells would capture antigen of liver tumor in an early stage of liver tumor development in C3H/HeNCrj mice.…”

Macrophage profile in primary versus secondary liver tumors

“…In the studies of TAMs involvement in the development of hepatic metastases (HM), the most numerous were related to the colorectal cancer (CRC)-associated metastases [17][18][19][20][21]. Similarly to HCC, macrophages in HM can act against metastatic cells in a direct cytotoxic way or by secretion of TNF and proteases [22], however, TAMs can also support survival and differentiation of malignant cells via secretion of growth factors [23] or metalloproteinases [24].…”