Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis.
Non-invasive therapies for the treatment of hepatocellular carcinoma (HCC) would be of great benefit to public health. To this end, we have developed a platelet-derived growth factor-C (PDGF-C) transgenic (Tg) mouse model, which mimics many aspects of human liver carcinogenesis. Specifically, overexpression of PDGF-C results in liver fibrosis, which is preceded by activation and proliferation of hepatic stellate cells, and is followed by the development of dysplastic lesions and angiogenesis, and progression to HCCs by 8 months of age. Here, we show that PDGF-C overexpression induces the proliferation of endothelial-like cells that are present in tumors and adjacent non-neoplastic parenchyma. The protein tyrosine kinase inhibitor, imatinib (Gleevec), decreases the proliferation of non-parenchymal cells (NPC) in vitro and in vivo, with concomitant inhibition of Akt. In vivo treatment with imatinib also blocks the expression of CD34 in PDGF-C Tg mice. Decreased NPC proliferation and CD34 expression correlated with lower levels of active ERK1/2 and total levels of PDGF receptor alpha (PDGFRalpha). In summary, the small molecule inhibitor imatinib attenuates stromal cell proliferation in PDGF-C-induced HCC, which coincides with decreased expression of both CD34 and PDGFRalpha, and activated Akt. Our findings suggest that imatinib may be efficacious in the treatment of hepatocarcinogenesis, particularly when neovascularization is present.
Campbell
Jean S
JS
Department of Pathology, University of Washington School of Medicine, Box 357705, Seattle, WA 98195, USA. campjs@u.washington.edu
Johnson
Melissa M
MM
Bauer
Renay L
RL
Hudkins
Kelly L
KL
Gilbertson
Debra G
DG
Riehle
Kimberly J
KJ
Yeh
Matthew M
MM
Alpers
Charles E
CE
Fausto
Nelson
N
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000068877:Imatinib Mesylate; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D008222:Lymphokines; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C411423:platelet-derived growth factor C; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3