A functional genomics approach to Kaposi's sarcoma.
Kaposi's sarcoma (KS) is the most frequent malignancy afflicting acquired immune-deficiency syndrome (AIDS) patients. Tumor lesions are characterized by spindle cells of vascular origin and vascularization. Kaposi's sarcoma-associated herpes virus (KSHV) is consistently found in all forms of KS. Infection of dermal microvascular endothelial cells (DMVEC) with KSHV recapitulates spindle cell formation in vitro. We studied this transformation process by DNA microarray analysis comparing the RNA expression profiles of KSHV-infected and mock-infected DMVEC. Genes involved in tumorigenesis, angiogenesis, host defense, cell growth and differentiation, transcription, and metabolism were observed to change significantly upon infection with KSHV. One of the most consistently KSHV-induced genes was the receptor tyrosine kinase and proto-oncogene c-Kit. Inhibition of c-Kit activity with the pharmacological inhibitor of c-Kit signaling STI571 reversed the KSHV-induced morphological transformation of DMVEC. Moreover, overexpression studies showed that c-Kit was sufficient to induce spindle cell formation (Moses et al. J. Virol. 76(16): 8383-8399). These data demonstrate that microarrays are useful for the identification of pharmacological targets essential for KS tumorigenesis.
Moses
Ashlee V
AV
Vaccine and Gene Therapy Institute and Department of Molecular Microbiology and Immunology, Oregon Health Science University, Portland, Oregon 97239, USA.
Jarvis
Michael A
MA
Raggo
Camilo
C
Bell
Yolanda C
YC
Ruhl
Rebecca
R
Luukkonen
B G Mattias
BG
Griffith
Diana J
DJ
Wait
Cecily L
CL
Druker
Brian J
BJ
Heinrich
Michael C
MC
Nelson
Jay A
JA
Fruh
Klaus
K
D001549:Benzamides; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002472:Cell Transformation, Viral / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D023281:Genomics; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D000068877:Imatinib Mesylate; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D016372:RNA, Antisense / Q000235:genetics / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000235:genetics*; D014774:Virulence / Q000235:genetics
D001549:Benzamides; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D016372:RNA, Antisense; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit