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Tumoricidal Function of Hepatic Natural Killer Cells

The liver is a major site for the formation and metastasis of tumors. Malignant liver tumors fall into two classes: Primary and Metastatic. While the former originate in the liver itself, the latter, commonly known as 'liver metastases' are cancerous tumors that originate at sites remote from the liver and spread to the liver via the bloodstream. As filtration of blood is one of the main functions of the liver, cancer cells from other parts of the body have easy access to the liver which provides a fertile platform for the tumor, not only because of its rich, dual blood supply but also because of humoral factors that promote cell growth. It therefore becomes essential to control the dissemination and growth of metastatic tumors...

Tumoricidal Function of Hepatic Natural Killer Cells

Pathway Summary

The liver is a major site for the formation and metastasis of tumors. Malignant liver tumors fall into two classes: Primary and Metastatic. While the former originate in the liver itself, the latter, commonly known as 'liver metastases' are cancerous tumors that originate at sites remote from the liver and spread to the liver via the bloodstream. As filtration of blood is one of the main functions of the liver, cancer cells from other parts of the body have easy access to the liver which provides a fertile platform for the tumor, not only because of its rich, dual blood supply but also because of humoral factors that promote cell growth. It therefore becomes essential to control the dissemination and growth of metastatic tumors. This is achieved by the function of hepatic NK cells, which have the ability to mediate spontaneous cytotoxicity against the primary and secondary tumor cells. The liver is a complex organ composed of hepatic parenchymal cells, hepatocytes, sinusoidal endothelial cells (SEC), Kupffer cells and several subsets of resident lymphocytes, including NK Cells/Pit cells and T cells. When a tumor cell enters the liver, it is mechanically trapped and adheres to SEC. Hepatic NK cells also adhere to SEC and are thus in a strategic position to kill arriving tumor cells. NK cells adhere to tumor cells via adhesion molecules such as LFA1 which are recognized by their receptor ICAM1 expressed on the tumor cell surface.Several mechanisms contribute to the anti-tumor effects of effector NK cells. The two most potent of these are: 1) Triggering of the Fas-mediated death pathway by the ligation of FasL on NK cells to cell surface Fas on target tumor cells, and 2) The perforin-granzyme cell death pathway which mediates apoptosis of the target tumor cell. FasL on NK cells binds Fas on the target cell leading to activation of caspase 8, followed eventually by apoptosis. Soluble Fas (sFas) produced by hepatocytes blocks FasL on NK cells, preventing possible harmful effects on the FasL-sensitive SEC and hepatocytes.Perforin and granzymes, of which granzyme B is the most potent, reside in granules present in the cytosol of hepatic NK cells. Perforin and granzyme B along with Serglycin (SRGN) as a scaffold form a complex and are released by granule exocytosis in the space formed between the NK cell-tumor conjugate. The complex is taken up into the tumor cell by endocytosis through the receptor M6PR. Perforin then releases granzyme B that is sequestered in an endosome into the cytosol. This initiates a number of pathways including proteolytic activation of the caspase cascade by direct activation of caspase 3, indirectly through caspase 8 or through a mitochondria-dependent pathway via cleavage of BID, its translocation to the mitochondria and the activation of caspase 9 culminating in apoptosis. On the other hand, CytoC release causes mitochondrial dysfunction which leads to the release of factors such as AIF and EndoG which mediate DNA damage. Granzyme B also causes direct activation of DFF40/CAD which leads to proteolysis of the inhibitor ICAD and DNA damage to the tumor cell. Damage of liver cells other than the tumor cells that might be caused by leakage of granzyme B and perforin is prevented by the very efficient endocytic uptake of the granzyme B-SRGN-perforin complex by the HAR expressed on SEC. SECs and NK cells themselves are protected from the action of granzyme B by strong expression of the endogenous granzyme B inhibitor PI9.

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