Essential role of stromally induced hedgehog signaling in B-cell malignancies.
Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.
Dierks
Christine
C
Kinase Biology/In-vivo Oncology, Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. chdierks@yahoo.de
Grbic
Jovana
J
Zirlik
Katja
K
Beigi
Ronak
R
Englund
Nathan P
NP
Guo
Gui-Rong
GR
Veelken
Hendrik
H
Engelhardt
Monika
M
Mertelsmann
Roland
R
Kelleher
Joseph F
JF
Schultz
Peter
P
Warmuth
Markus
M
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D008024:Ligands; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C052617:Bcl2 protein, mouse; C000541:cyclopamine