Hepatic colorectal cancer metastases: imaging initial steps of formation in mice

To prospectively use optical imaging to study the cell-specific mechanisms of entrapment and subsequent growth of two human colon cancer cell lines differing in their propensity to form hepatic metastases.

In this Animal Care Committee-approved study, intravital optical imaging was performed in exteriorized livers of three groups of mice after intrasplenic inoculation of human colon cancer cells. Group 1 mice (control group; n=12) received a cell-maintaining solution only. Groups 2 and 3 (n=12 in each) were administered poorly (MIP-101 colon cancer cells) or highly (CX-1 colon cancer cells) metastatic cells. Imaging was performed on postinoculation days 0, 1, 3, and 6 to document sites and mechanisms of tumor cell entrapment and presence and sites of endothelial cell activation and of tumor cell interactions with systemic macrophages and Kupffer cells. Fluorescence intensity of Kupffer cells was compared by using the Mann-Whitney test. Immunohistochemistry served as the reference standard for all in vivo observations.

Whereas both MIP-101 and CX-1 colon cancer cells adhered to periportal Kupffer cells, the CX-1 cells resulted in Kupffer cell activation, evidenced in vivo by increased visible peroxidase activity (P<.05). Only CX-1 cells were associated with subsequent downstream endothelial cell activation, evidenced by in vivo expression of E-selectin. By day 6, regression of periportal MIP-101 tumor growth correlated with ingrowth of systemic macrophages, while CX-1 tumor growth, originating in the outflow venous regions, correlated with translobular migration and ingrowth of activated Kupffer cells.

Formation of hepatic colon cancer metastases is cancer cell-type specific, with cell lines differing in their mechanisms and intrahepatic locations of initial entrapment and Kupffer cell activation and subsequent growth.