Research Report 2010 - MDC

A novel animal model to study the role of epigeneticmechanisms in immune escape andtumor progressionA: BALB/c-3T3 fibroblasts have been transformedby retroviral transduction of the humanherpervirus 8-encoded oncogenic chemokinereceptor vGPCR. B: vGPCR-transformed BALB/c-3T3 fibroblasts that are tumorigenic in BALB/cnude mice, but as expected fail to inducetumors in their immunocompetent BALB/ccounterparts. C: Tumor fragments obtainedfrom nude mice, which comprise stroma cells ofthe tumor microenvironment, grow progressivelyin immunocompetent BALB/c mice. D: vGPCRexpressingBALB/c cell lines have been establishedfrom grafted tumor fragments underpuromycin selection to get rid of any hostderivedcells. E: Unexpectedly, the tumor-derivedvGPCR-BALB/c cells gave rise to progressivelygrowing tumors in immunocompetent BALB/cmice (Thirunarayanan et al., Oncogene 14:523,2007). Ongoing experiments support ourhypothesis that the passage of vGPCR-3T3 cellstrough nude and immunocompetent miceleads to the induction of chromatin remodelingand epigenetic changes in the tumor-derivedcell lines resulting in immune escape and progressivetumorigenesis.associated with epigenetic changes in chromatin structurewe are performing genome-wide ChiP-on-Chipanalyses to define the landscape of activating/repressinghistone modifications during T FH cell differentiationin order to identify novel regulatory elementsthat may not be readily discernible throughexpression analysis and comparative genomics.The human herpesvirus 8 encoded chemokinereceptor vGPCR triggers progressive tumor -igenicity of fibroblasts in immuno competentBALB/c mice: A novel animal model to study therole of epigenetic mechanisms in immune escapeand tumor progressionThe human herpes virus 8 (HHV-8)-encoded G proteincoupledchemokine receptor (vGPCR) has been implicatedin the pathogenesis of Kaposi´s sarcoma (KS) particularlybecause of its high constitutive signaling activity.We have used retroviral transduction to generatevGPCR-expressing BALB/c-3T3 fibroblasts that aretumorigenic in nude mice, but as expected fail toinduce tumors in their immunocompetent counterparts.However, tumor fragments obtained from nudemice grow progressively in immunocompetent BALB/cmice. Unexpectedly, vGPCR-expressing cells establishedfrom grafted tumor fragments gave rise to tumors inimmunocompetent mice. These tumors exhibit a strikinghistological resemblance to KS including plumpspindle cell morphology, a high degree of vascularizationand brisk mitotic activity. Short interfering RNAdirected at vGPCR abrogated or significantly delayedtumorigenesis of tumor-derived cells in nude mice,demonstrating that the tumor development is specificallydriven by the vGPCR oncogene, but not by other118 Cancer Research