Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis.
Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltrative skin tumors that presently are treated with surgery. DFSP and GCF tumors are genetically characterized by chromosomal rearrangements fusing the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. It has been shown that the resulting COL1A1/PDGF-B fusion protein is processed to mature PDGF-BB. Autocrine PDGF receptor stimulation has therefore been predicted to contribute to DFSP and GCF tumor development and growth. Here we demonstrate presence of activated PDGF receptors in primary cultures derived from six different DFSP and GCF tumors. Three of the primary cultures were further characterized; their in vitro growth displayed an increased sensitivity to treatment with the PDGF receptor tyrosine kinase inhibitor STI571, as compared with normal fibroblasts. Transplantable tumors, displaying a DFSP-like histology, were established from one of the DFSP primary cultures. Treatment of tumor-bearing severe combined immunodeficient mice with STI571 reduced tumor growth. The growth-inhibitory effects in vitro and in vivo occurred predominantly through induction of tumor cell apoptosis. Our study demonstrates growth-inhibitory effects of PDGF receptor antagonists on human DFSP- and GCF-derived tumor cells and demonstrates that autocrine PDGF receptor stimulation provides antiapoptotic signals contributing to the growth of these cells. These findings suggest targeting of PDGF receptors as a novel treatment strategy for DFSP and GCF.
Sjöblom
T
T
Ludwig Institute for Cancer Research, S-751 24 Uppsala, Sweden.
Shimizu
A
A
O'Brien
K P
KP
Pietras
K
K
Dal Cin
P
P
Buchdunger
E
E
Dumanski
J P
JP
Ostman
A
A
Heldin
C H
CH
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002675:Child, Preschool; D018223:Dermatofibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D005870:Giant Cell Tumors / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; C120892:COLIA1-PDGFB fusion protein, human; D006131:Growth Inhibitors; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta