title: Molecular target based combinational therapeutic approaches in thyroid cancer.
abstract: BACKGROUND
  Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer.
  
  
  METHODS
  In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3'-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations.
  
  
  RESULTS
  Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3'-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs.
  
  
  CONCLUSIONS
  Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3'-diindolylmethane is a promising naturally occurring anti-estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer.
authors.affiliation: Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, 10595, USA.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Rajoria
authors.forename: Robert
authors.initials: R
authors.lastname: Suriano
authors.forename: Andrea L
authors.initials: AL
authors.lastname: George
authors.forename: Ameet
authors.initials: A
authors.lastname: Kamat
authors.forename: Stimson P
authors.initials: SP
authors.lastname: Schantz
authors.forename: Jan
authors.initials: J
authors.lastname: Geliebter
authors.forename: Raj K
authors.initials: RK
authors.lastname: Tiwari
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D004967:Estrogens; D007211:Indoles; D042461:Vascular Endothelial Growth Factor A; D000077267:Fulvestrant; D004958:Estradiol; C016392:3,3'-diindolylmethane