In vivo and in vitro interactions between human colon carcinoma cells and hepatic stellate cells

Stromal reaction is important for the growth of cancer both in primary and metastatic sites. To demonstrate this reaction during the hepatic metastasi s of human colon carcinoma, we histologically investigated alterations to t he distribution and phenotype of hepatic stellate cells (HSCs), the only me senchymal cells in the liver parenchyma, using a nude mouse model. Intraspl enically injected colon carcinoma LM-H3 cells migrated into the space of Di sse and underwent proliferation, in close association with hepatocytes and HSCs, at 2 days. At 14 days, HSCs were accumulated around the tumor mass an d expressed alpha -smooth muscle actin, a marker for HSC activation. We nex t investigated in vitro the growth factors involved in the interactions bet ween LM-H3 cells and HSCs. Conditioned medium of rat HSCs which underwent c ulture-induced activation contained platelet-derived growth factor (PDGF)-A B, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta , and could augment LM-H3-cell proliferation and migration. Neutralizing an tibodies against PDGF-AA and PDGF-BB and those against PDGF-BB and HGF inhi bited proliferation and migration, respectively, of LM-HS cells, whereas an tibody against TGF-beta had no effect. LM-H3 cells expressed PDGF receptors -alpha and -beta and c-met. Conditioned medium of LM-H3 cells contained PDG F-AB, and could enhance HSC proliferation and migration. This augmenting ef fect was suppressed by treatment with anti-PDGF-AB antibody. The present st udy has demonstrated that bidirectional interactions involving PDGF and HGF take place in vitro between colon carcinoma cells and HSCs, raising the po ssibility that similar interactions might be involved in the stromal reacti on during hepatic metastasis.