Liver macrophage-mediated cytotoxicity toward mastocytoma cells involves phagocytosis of tumor targets

Gardner, Carol R.; Wasserman, Arthur J.; Laskin, Debra L.

doi:10.1002/hep.1840140219

Cited by 24 publications

(8 citation statements)

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“…This is an in situ confirmation of previous in vitro findings concerning tumor cell binding prior to cytoxocity and phagocytosis. 14 -16 The presence of a single large DiO-filled phagosome in KCs indicates whole tumor cell phagocytosis and degradation in vivo, in concordance with the literature, 7,15,35,52 and parallel to the lysosomal localization of fluorescein in KCs 24 hr after injection of fluorescein-labeled colon cancer cells. 53 Lysosomal degradation of the ingested tumor cells was demonstrated by the subsequent appearance of smaller DiO-filled vacuoles resembling lysosomes at the electron microscopy level and the complete disappearance of the phagosome after 24 hr.…”

Section: Discussionsupporting

confidence: 74%

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

Timmers

Vekemans

Vermijlen³

et al. 2004

Intl Journal of Cancer

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Liver sinusoids harbor populations of 2 important types of immunocompetent cells, Kupffer cells (KCsColon cancer is one of the most common cancers in the Western world. 1 Metastases to the liver, a common event in cancer patients, is an important cause of death, and the rate of metastasis generally determines survival time. 2,3 The growth and development of metastasis involve a cascade of tumor-host cell interactions.The first vascular bed encountered by blood-borne tumor cells from the gastrointestinal tract is in the liver, in the sinusoids of which they encounter 2 immunocompetent cells, Kupffer cells (KCs) and natural killer (NK) cells. 4,5 KCs represent the largest macrophage population in the body. 5 They move along sinusoids, scavenge degenerated cells, macromolecules and microorganisms and function as antigen-presenting cells. 4,6,7 By virtue of these capacities and their privileged location within the circulation, KCs form the first line of defense against disseminating colorectal tumor cells. 8 Their role in controlling hepatic metastasis in vivo has been demonstrated by their capacity to kill tumor cells in vitro. 9 -13 It has been shown that binding to tumor cells is necessary for effective killing in vitro, 14 -16 which is accomplished by a variety of mechanisms, including phagocytosis and the release of proteinases, tumor necrosis factor and oxygen metabolites. 4,17,18 The role of KCs in controlling metastasis has been demonstrated at late stages of metastasis (3 weeks); metastasis is enhanced by selectively eliminating KCs and reduced by stimulating them. 8,19 -22 Whether or not this effect can also be observed during the early stages of metastasis has not been reported yet.Liver 32 and the receptor-mediated pathway (members of the TNF family). 33 Both KCs and liver NK cells belong to the innate immune system and are often observed in close contact with each other. 24,27 It is supposed that these cells affect the growth of liver metastases only if they interact with incoming tumor cells shortly after their arrival in the liver (ϳ 24 hr) because later on the natural host defenses may be incapable of limiting metastasis due to the rapid proliferation of the cancer cell population, angiogenesis and weakened host defenses. 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. 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...

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Section: Discussionsupporting

confidence: 74%

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

Timmers

Vekemans

Vermijlen³

et al. 2004

Intl Journal of Cancer

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“…The importance of Kupffer cells in mediating metastases via their cytotoxic effects have been defined previously [21][22][23][24][25][26]. Gardener has identified tumor cell binding as an important early event in Kupffer cell killing of tumor cells [27] and recent work by Meterissian and Thomas (unpublished data) has demonstrated a putative tumor cell binding protein on Kupffer cells. HCRC cell binding to Kupffer cells is increased significantly after KI-8110 treatment of Clone A, CX-1, and CCL-235 cell lines.…”

Section: Discussionmentioning

confidence: 96%

“…Kupffer cells use numerous mechanisms to mediate tumor cell cytotoxicity including the release of tumor necrosis factor (TNF-o 0 [26], extracellular cytolysis and phagocytosis. Gardner et al used electron microscopy to show that the initial event in phagocytosis and cytotoxicity is tumor cell binding [27]. Electron microscopy has also been used to study the binding characteristics of both hepatocytes and Kupffer cells to a variety of tumor cell targets.…”

Section: Introductionmentioning

confidence: 97%

Desialylation of metastatic human colorectal carcinoma cells facilitates binding to Kupffer cells

et al. 1994

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Cell surface hypersialylation of human colorectal carcinoma (HCRC) cells correlates with increased metastatic potential after intrasplenic injection, while desialylation with various agents has been shown to inhibit hepatic metastases. In this study we examined the effects of desialylation of HCRC cell lines with a novel intracellular inhibitor of the CMP-sialic acid transport protein (KI-8110). HCRC cells, which are poorly differentiated and poorly metastatic in nude mice (Clone A and MIP-101) were compared to well-differentiated, highly metastatic cells (CX-1 and CCL-235). KI-8110 treatment has previously been shown to reduce sialic acid levels in each of these cell lines and to reduce hepatic metastases in CX-1 and CCL-235 cell lines. This study attempts to identify a mechanism by which desialylation inhibits hepatic metastases. After KI-8110 treatment, in vitro adhesion assays were performed with each cell line to examine binding to Kupffer cells and the extracellular matrix protein fibronectin. Binding of Clone A, CX-1, and CCL-235 to Kupffer cells was significantly increased after KI-8110 treatment. Desialylation had no significant effect on binding of HCRC cell lines to fibronectin. While the metastatic cascade involves many complex interactions, the cytotoxic effects of Kupffer cells in the hepatic sinusoid are known to be an important mechanism of host defense against tumor cells. Cell surface sialic acids may well mask Kupffer cell binding to HCRC cells, preventing their cytotoxic effects and enhancing the metastatic potential of circulating tumor cells.

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“…Interestingly, CRC cells become vulnerable to macrophage tumouricidal activity during endothelial adhesion and extravasation [129,130] . Specifically, KCs may recruit inflammatory cells, they may arrest CRC cells and inhibit their growth acting in a cytostatic way, and they may bind and eliminate them in a cytotoxic way [130] ; the latter occurs by several mechanisms: phagocytic release of TNF, secretion of proteases and production of oxygen metabolites [131][132][133] . Rat experiments demonstrated that in the early stages of CRC liver metastasis, KCs exerted tumouricidal activity in conjunction with NK cells.…”

Section: Kupffer Cellsmentioning

confidence: 99%

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

Paschos

Majeed

Bird

2014

WJG

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Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting. Paschos KA, Majeed AW, Bird NC. Natural history of hepatic metastases from colorectal cancer -pathobiological pathways with clinical significance.

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Liver macrophage-mediated cytotoxicity toward mastocytoma cells involves phagocytosis of tumor targets

Cited by 24 publications

References 24 publications

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

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

Desialylation of metastatic human colorectal carcinoma cells facilitates binding to Kupffer cells

Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance

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