Malignant transformation of human cells by constitutive expression of platelet-derived growth factor-BB.
Platelet-derived growth factors (PDGFs) comprise a family of growth factors strongly implicated in human oncogenesis. A number of human tumors overexpress PDGF family members or have translocations activating PDGF receptors. Whereas the epidemiologic evidence implicating PDGF in human tumors is strong, malignant transformation of human cells by overexpression of PDGF has not been demonstrated. We have previously developed a human cell line by the sequential introduction of large T cells and telomerase, and we have demonstrated that these cells express functionally active PDGF receptor (PDGFR) beta. In order to determine whether growth factor-mediated transformation of human cells could occur, these cells were transduced with a retrovirus encoding PDGF-BB. Constitutive expression of PDGF-BB led to malignant transformation in nude mice. This is the first demonstration of constitutive signaling causing malignant transformation of human cells. Some of the changes that occur because of constitutive growth factor expression can be reversed by the clinically approved tyrosine kinase inhibitor Glivec, whereas other changes are not reversible by tyrosine kinase inhibitors. Our model allows the assessment of epigenetic changes that occur during human carcinogenesis. In addition, these studies provide insight into the clinical failure of tyrosine kinase inhibitors as monotherapy for advanced malignancy.
Govindarajan
Baskaran
B
Department of Dermatology, Emory University School of Medicine and Veterans Affairs Hospital, Atlanta, Georgia 30322, USA.
Shah
Asha
A
Cohen
Cynthia
C
Arnold
Rebecca S
RS
Schechner
Jeffrey
J
Chung
Jun
J
Mercurio
Arthur M
AM
Alani
Rhoda
R
Ryu
Byungwoo
B
Fan
Chun-Yang
CY
Cuezva
Jose M
JM
Martinez
Marta
M
Arbiser
Jack L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D000077214:Becaplermin; D001549:Benzamides; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D051798:Inhibitor of Differentiation Protein 1; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D020928:Mitogen-Activated Protein Kinases