Hepatocyte-derived soluble factors regulate proliferation and autocrine growth factor expression in colon cancer cell lines of varying liver-colonizing capability.
We investigated the role of hepatocyte-derived soluble growth factors on cell proliferation and expression of growth factors and their receptors in four colon cancer cell lines of varying liver-colonizing ability. Cocultures of hepatocytes and colon cells and cultures of colon cells with hepatocyte-conditioned medium resulted in growth inhibition of both weakly and strongly metastatic cell lines. Growth inhibition was accompanied by a reduced expression of erb-B2 in the colon cells after 4 days in the presence of hepatocytes. In LS174T and LiM6 cells, there was a dramatic reduction in heregulin-alpha levels in the presence of hepatocytes. Interestingly, after 2 days in culture, hepatocyte-derived soluble factors increased the mRNA levels for the EGF family members amphiregulin and cripto. These studies show an inhibitory effect of hepatocyte-derived soluble factors on the proliferation of colon cell lines, mediated in part by changes in the expression of autocrine growth factors and receptors of the EGF and heregulin family.
Zvibel
I
I
Liver Metastasis Research Group, Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Israel. isab@tasmc.health.gov.il
Brill
S
S
Papa
M
M
Halpern
Z
Z
D066258:Amphiregulin; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D058851:GPI-Linked Proteins; D006023:Glycoproteins / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000556:secondary*; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins / Q000096:biosynthesis; D020890:Neuregulin-1 / Q000096:biosynthesis; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D066258:Amphiregulin; D017077:Culture Media, Conditioned; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C587848:AREG protein, human; C587850:Areg protein, rat; C070636:TDGF1 protein, human; C117463:heregulin alpha