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Posts Tagged ‘Dormant Tumors to Fast-Growing Angiogenic Phenotype: The Role of the Transcriptional Switch’


Dormant Tumors to Fast-Growing Angiogenic Phenotype: The Role of the Transcriptional Switch

Reporter: Aviva Lev-Ari, PhD, RN

 

 

 

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One of the visionary ideas of the late Dr. Judah Folkman was to treat cancer based on discovery of ultra-early biomarkers long before tumors become symptomatic or determination of their anatomical location is feasible. This idea was based on the hypothesis that most tumors remain dormant as microscopic lesions for a long period of time, until they gain the ability to recruit vessels in a process called tumor angiogenesis. Dormant tumors that switch to the angiogenic phenotype grow exponentially and ultimately become clinically apparent, which is referred to as the disease state of cancer. A major limitation in investigating the tumor dormancy process is the lack of suitable experimental models and the limited clinical accessibility of dormant tumors. In this report, Almog and colleagues identified the molecular determinants of tumor dormancy by characterizing the consensus transcriptome signature of dormant versus fast-growing experimental human osteosarcoma, liposarcoma, breast carcinoma, and glioblastoma multiforme tumor models. Differential regulation and activation of several signaling pathways not previously associated with the dormancy process are also reported and validated based on protein expression and activation levels. The molecular signature of tumor dormancy was further used to test the feasibility of selected proteins as blood (plasma)-based biomarkers in mice and in human specimens. The enhanced sensitivity of dormant tumors to angiostatin, compared with that of fast-growing angiogenic tumors, was correlated with selective uptake of angiostatin (green) in angiomotin (red)-positive dormant osteosarcoma cells (blue, cell nucleus). This work may provide molecular instructions for discovery of ultra-early tumor biomarkers and possible therapeutic targets for the blockage of early tumor development. For details, see the article by Almog and colleagues on page 836 of this issue.

 

SOURCE

http://cancerres.aacrjournals.org/content/69/3.cover-expansion

Transcriptional Switch of Dormant Tumors to Fast-Growing Angiogenic Phenotype

  1. Nava Almog1,2,
  2. Lili Ma1,
  3. Raktima Raychowdhury1,
  4. Christian Schwager3,
  5. Ralf Erber4,
  6. Sarah Short2,
  7. Lynn Hlatky1,
  8. Peter Vajkoczy4,
  9. Peter E. Huber1,3,
  10. Judah Folkman2, and
  11. Amir Abdollahi1,2,3

+Author Affiliations


  1. 1Center of Cancer Systems Biology, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine; 2Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; 3Department of Radiation Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg Medical School, Heidelberg, Germany; and 4Department of Neurosurgery, Charité-Universitaetsmedizin Berlin, Berlin, Germany
  1. Requests for reprints:
    Amir Abdollahi, Center of Cancer Systems Biology, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, 736 Cambridge Street CBR1, Boston, MA 02135. Phone: 617-779-6569; Fax: 617-562-7142; E-mail: Amir.Abdollahi@Tufts.edu or Nava Almog, E-mail: Nava.Almog@Tufts.edu.

Cancer Res February 1, 2009 69; 836

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. [Cancer Res 2009;69(3):836–44]

Footnotes

  • Note: J. Folkman died on January 14, 2008.

 

SOURCE

http://cancerres.aacrjournals.org/content/69/3/836

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