title: Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype.
abstract: Tumor dormancy has important implications for early detection and treatment of cancer. Lack of experimental models and limited clinical accessibility constitute major obstacles to the molecular characterization of dormant tumors. We have developed models in which human tumors remain dormant for a prolonged period of time (>120 days) until they switch to rapid growth and become strongly angiogenic. These angiogenic tumors retain their ability to grow fast once injected in new mice. We hypothesized that dormant tumors undergo a stable genetic reprogramming during their switch to the fast-growing phenotype. Genome-wide transcriptional analysis was done to dissect the molecular mechanisms underlying the switch of dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors. A consensus expression signature distinguishing all four dormant versus switched fast-growing tumors was generated. In alignment with our phenotypic observation, the angiogenesis process was the most significantly affected functional gene category. The switch of dormant tumors was associated with down-regulation of angiogenesis inhibitor thrombospondin and decreased sensitivity of angiogenic tumors to angiostatin. The conversion of dormant tumors to exponentially growing tumors was also correlated with regulation and activation of pathways not hitherto linked to tumor dormancy process, such as endothelial cell-specific molecule-1, 5'-ecto-nucleotidase, tissue inhibitor of metalloproteinase-3, epidermal growth factor receptor, insulin-like growth factor receptor, and phosphatidylinositol 3-kinase signaling. Further, novel dormancy-specific biomarkers such as H2BK and Eph receptor A5 (EphA5) were discovered. EphA5 plasma levels in mice and mRNA levels in tumor specimens of glioma patients correlated with diseases stage. These data will be instrumental in identifying novel early cancer biomarkers and could provide a rationale for development of dormancy-promoting tumor therapy strategies.
authors.affiliation: Center of Cancer Systems Biology, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA. Nava.Almog@Tufts.edu
authors.forename: Nava
authors.initials: N
authors.lastname: Almog
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
authors.forename: Raktima
authors.initials: R
authors.lastname: Raychowdhury
authors.forename: Christian
authors.initials: C
authors.lastname: Schwager
authors.forename: Ralf
authors.initials: R
authors.lastname: Erber
authors.forename: Sarah
authors.initials: S
authors.lastname: Short
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
mesh_terms: D000091082:Angiomotins; D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D036123:Receptor, EphA5 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D014335:Tropomyosin / Q000378:metabolism
chemical_list: C423985:AMOT protein, human; D000091082:Angiomotins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D014335:Tropomyosin; D036123:Receptor, EphA5