Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis

Abstract

E-selectin is a cytokine-inducible endothelial cell adhesion receptor which is involved in the process of leukocyte rolling, the first in a cascade of interactions leading to leukocyte transmigration. Several studies have implicated this receptor in carcinoma cell adhesion to the endothelium, an interaction thought to be required for tumor extravasation during metastasis. To study the role of this receptor in the process of metastasis, we utilized a murine carcinoma line H-59 which is highly metastatic to the liver in vivo. When adhesion of H-59 cells to primary cultures of murine hepatic endothelial cells was measured, it was found that the tumor cells had a low basal level of adhesion to the sinusoidal endothelial cells, which could be significantly and specifically augmented by pre-activation of the endothelial cells with rTNFa. This incremental increase in adhesion to the activated endothelium could be completely and specifically abolished by a neutralizing monoclonal antibody to murine E-selectin (MAb 9A9). Similar results were obtained with 2 highly metastatic human colorectal carcinoma lines, HM 7 and CX-1, but not with a second murine subline, M-27, which is poorly metastatic to the liver. To assess the role of E-selectin in metastasis to the liver in vivo, the effect of MAb 9A9 on experimental liver metastasis was evaluated using the syngeneic H-59 model. We show here that this antibody caused a marked, specific and Fc-independent inhibition of experimental liver metastasis, reducing the median number of metastases by 97% relative to the control groups. Our results provide evidence that endothelial E-selectin is a mediator of carcinoma metastasis to the liver. Int. J. Cancer 71:612-619, 1997.r 1997 Wiley-Liss, Inc.The ability of disseminating cancer cells to establish metastases in secondary organs is regulated by a combination of factors, including access to the organ microvasculature (hemodynamic factors) and specific host-tumor cell interactions (Radinsky and Fidler, 1992). The attachment of circulating tumor cells to the vascular endothelium of the target organ is thought to be one key step in the metastatic cascade. The evidence suggests that this attachment precedes and is required for tumor cell extravasation and subsequent invasion into the target organ parenchyma (Brodt, 1996). Organ-specific receptors have been identified on the luminal surface of the microvascular endothelium which are specifically recognized by tumor cell ligands, thereby facilitating tumor cell arrest and transmigration into the extravascular space (Pauli et al., 1992). Studies of leukocyte transmigration have suggested that the specificity of the interaction between a circulating leukocyte and the microvascular endothelium may be determined by the outcome of a series of sequential receptor-ligand interactions rather than the complementarity of a single receptor-ligand system (Springer, 1994). It appears likely that the process of tumor extravasation is also mediated through a series of adhesive interactions (reviewed in B...

Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms

“…6 Intravital microscopy was used to quantify tumor cell (H-59 and M-27) adhesion to liver sinusoidal endothelium in vivo, in real time (Fig. 1a).…”

“…6,33 It was, therefore, of interest to investigate whether selectin ligands containing sialyl-Lewis x (sLe x ) moieties on the sur-face of the tumor cells played a role in the early attachment of these tumor cells to sinusoidal endothelial cells. H-59 cells were treated with a monoclonal anti-sLe x antibody before injection into the mice.…”

“…Interactions between endothelial selectins and tumor cell selectin ligands have been implicated in the metastatic process. [5][6][7][8] Selectins are a family of transmembrane glycoproteins possessing an extracellular lectin domain that binds to carbohydrate moieties present on their ligands. 9 The three known selectins that function as cell adhesion molecules are expressed on the surface of endothelial cells (E-selectin and P-selectin), platelets (P-selectin) and leukocytes (L-selectin).…”

“…Functional inhibition of E-selectin has been shown to prevent adhesion of tumor cells to endothelial monolayers in vitro, and attenuate the development of metastases in vivo. 6,10,11 In addition, L-selectin knockout mice were shown to develop fewer lung metastases following intravenous injection of colon carcinoma cells, implying that leukocyte selectin expression, and thus leukocyte-cancer cell interactions, may also play a role in the development of metastasis. 12 The ligands recognized by selectins are fucosylated and sialylated carbohydrate antigens such as sialyl Lewis-a (sLe a ) and sialyl Lewis-x (sLe x ), which are present on mucin-like glycoproteins.…”

Cimetidine in colorectal cancer – are the effects immunological or adhesion-mediated?

“…In this way neutrophils can be recruited to sites of inflammation. However, sL X and sL A are known to also be expressed on a number of different tumour cell types and for many years this interaction has been implicated in the pathogenesis of cancer metastasis (Brodt et al, 1997;Dennis et al, 1982;Kitayama et al, 2000). SL X expression is increased in human hepatic colorectal metastases compared to the primary tumour (Hoff et al, 1989) and expression has been shown to correlate with poor survival of colorectal cancer patients (for example, in stage III patients 5 year survival was 42% in the sL X positive group vs 81% in patients with tumours negative for sL X in one study) (Nakamori et al, 1993).…”