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 metastasis of human colon carcinoma, we histologically investigated alterations to the distribution and phenotype of hepatic stellate cells (HSCs), the only mesenchymal cells in the liver parenchyma, using a nude mouse model. Intrasplenically injected colon carcinoma LM-H3 cells migrated into the space of Disse and underwent proliferation, in close association with hepatocytes and HSCs, at 2 days. At 14 days, HSCs were accumulated around the tumor mass and expressed alpha-smooth muscle actin, a marker for HSC activation. We next investigated in vitro the growth factors involved in the interactions between LM-H3 cells and HSCs. Conditioned medium of rat HSCs which underwent culture-induced activation contained platelet-derived growth factor (PDGF)-AB, hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta, and could augment LM-H3-cell proliferation and migration. Neutralizing antibodies against PDGF-AA and PDGF-BB and those against PDGF-BB and HGF inhibited proliferation and migration, respectively, of LM-H3 cells, whereas antibody 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 PDGF-AB, and could enhance HSC proliferation and migration. This augmenting effect was suppressed by treatment with anti-PDGF-AB antibody. The present study has demonstrated that bidirectional interactions involving PDGF and HGF take place in vitro between colon carcinoma cells and HSCs, raising the possibility that similar interactions might be involved in the stromal reaction during hepatic metastasis.
Shimizu
S
S
Department of Surgery, Osaka City University Medical School, Abeno-ku, Osaka 545-8585, Japan. n-yamada@med.osaka-cu.ac.jp
Yamada
N
N
Sawada
T
T
Ikeda
K
K
Kawada
N
N
Seki
S
S
Kaneda
K
K
Hirakawa
K
K
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology / Q000556:secondary / Q000648:ultrastructure; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D017077:Culture Media, Conditioned; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary* / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor