Article

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature medicine (Impact Factor: 28.05). 12/2012; DOI: 10.1038/nm.3029
Source: PubMed

ABSTRACT Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.

Full-text

Available from: Joseph Michael Scandura, Jun 15, 2015
0 Followers
 · 
267 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.
    11/2014; 4:69. DOI:10.1186/2045-3701-4-69
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant DNA methylation is an important mechanism that contributes to oncogenesis. Yet, few algorithms exist that exploit this vast dataset to identify hypo- and hyper-methylated genes in cancer. We developed a novel computational algorithm called MethylMix to identify differentially methylated genes that are also predictive of transcription. We apply MethylMix to twelve individual cancer sites, and additionally combine all cancer sites in a pancancer analysis. We discover pancancer hypo- and hyper-methylated genes and identify novel methylation-driven subgroups with clinical implications. MethylMix analysis on combined cancer sites reveals ten pancancer clusters reflecting new similarities across malignantly transformed tissues.
    Genome Biology 01/2015; 16(1):17. DOI:10.1186/s13059-014-0579-8 · 10.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence demonstrates that SDF-1 and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nM, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nM. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nM and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small molecular inhibitor in pre-clinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin's lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinic studies for cancer. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Therapeutics 12/2014; DOI:10.1158/1535-7163.MCT-14-0850 · 6.11 Impact Factor