Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma.
The pathogenesis of Hodgkin lymphoma (HL) is still largely unknown. Based on a search for footprints of pathogenetic mechanisms in global RNA expression data of Hodgkin/Reed-Sternberg (HRS) cell lines, we analyzed the expression and activation of 6 receptor tyrosine kinases (RTKs) in classic HL. Immunohistochemistry revealed that the RTKs platelet-derived growth factor receptor A (PDGFRA), DDR2, EPHB1, RON, TRKB, and TRKA were each expressed in HRS cells in 30% to 75% of patients. These RTKs were not expressed in normal B cells, the origin of HRS cells, or in most B-cell non-Hodgkin lymphoma (NHL). In the majority of patients at least one RTK was expressed, and in most patients several RTKs were coexpressed, most prominently in Hodgkin lymphoma of the nodular sclerosis subtype. Phosphotyrosine-specific antibodies revealed exemplarily the activation of PDGFRA and TRKA/B and an elevation of cellular phosphotyrosine content. Immunohistochemistry for RTK ligands indicated that DDR2 and TRKA are likely activated in a paracrine fashion, whereas PDGFRA and EPHB1 seem to be activated by autocrine loops. Activating mutations were not detected in cDNA encoding the RTKs in HRS cell lines. These findings show the unprecedented coexpression of multiple RTKs in a tumor and indicate that aberrant RTK signaling is an important factor in HL pathogenesis and that it may be a novel therapeutic target.
Renné
Christoph
C
Department of Pathology, University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
Willenbrock
Klaus
K
Küppers
Ralf
R
Hansmann
Martin-Leo
ML
Bräuninger
Andreas
A
D019898:Autocrine Communication; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006689:Hodgkin Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D019899:Paracrine Communication; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases