Interactions between colon cancer cells and hepatocytes in rats in relation to metastasis

Abstract

Adhesion of cancer cells to endothelium is considered an essential step in metastasis. However, we have shown in a previous study that when rat colon cancer cells are administered to the vena portae, they get stuck mechanically in liver sinusoids. Then, endothelial cells retract rapidly and cancer cells bind to hepatocytes. We investigated the molecular nature of these interactions between colon cancer cells and hepatocytes. Cancer cells in coculture with hepatocytes became rapidly activated with distinct morphological changes. Cancer cells formed long cytoplasmic protrusions towards hepatocytes in their close vicinity and these protrusions attached to microvilli of hepatocytes. Then, adhering membrane areas were formed by both cell types. Integrin subunits αv, α6 and β1 but not αL, β2, β3 and CD44 and CD44v6 were expressed on the cancer cells. In conclusion, colon cancer cells show an active behaviour to bind to hepatocytes, likely involving the integrin subunits av, a6 and B1, indicating that early events in colon cancer metastasis in liver are distinctly different than assumed thus far.

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

“…A recent study suggested that the adhesion of CC531s colon cancer cells to hepatocytes correlates with increased expression levels of the integrin subunits ␣ v , ␣ 6 , and ␤ 1 . However, the requirement for these integrin subunits for directly facilitating interactions between colon cancer cells and hepatocytes was not established (31). Such results are in keeping with previous studies suggesting that breast cancer cell adhesion to hepatocytes involves integrin-mediated adhesion to hepatocytes (19).…”

“…Previous studies have suggested that integrins may play an important role in cancer cell interactions with hepatocytes (17)(18)(19)31). Our previous studies suggested that claudin-2 can influence breast cancer cell adhesion to extracellular matrices, such as type IV collagen and fibronectin, in an integrin-dependent fashion (45).…”

“…In this respect, claudin-2 is known to be expressed at high levels in hepatocytes (47). Recent data have demonstrated that colorectal cancer cells lodge in the liver due to mechanical restriction and that endothelial cells retract to permit the direct interaction of cancer cells with hepatocytes (31,32). The number of breast cancer cells that adhered to a monolayer of primary hepatocytes was quantified.…”

“…Subsequent in vitro studies revealed that breast cancer cells form electron-dense structures at points of contact between hepatocytes, which are reminiscent of tight-junctional complexes (37). The importance of cancer cell-hepatocyte interactions has been reinforced by the observation that colorectal cancer cells also interact directly with hepatocytes during liver metastasis (31,32). However, the mechanisms underlying these heterotypic cell-cell interactions are largely unexplored.…”

Functional blocking of specific integrins inhibit colonic cancer migration

“…Extravasation was traditionally proposed to follow cancer cell adhesion [6,11,12,20]. However, recent work by Mook et al [21,22] has shown that colorectal cells proliferate intravascularly and bind to the hepatocytes exposed by rapid retraction of the endothelial cells. Intravascular proliferation of metastatic cells has been described widely [23][24][25] and questions where extravasation occurs as rapidly as previously thought.…”