Abstract
BackgroundThyroid 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.MethodsIn 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.ResultsConditioned 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.ConclusionOur 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.
Highlights
Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development
Our observations suggest that estrogen is a mediator of angiogenesis as it that might activate the formation of a paracrine loop between endothelial cells and thyroid cancer cells, which is targeted by DIM
Estrogen treated thyroid cancer cells enhance migration of endothelial cells In order to investigate the pro-angiogenic effects of estrogen in TPD, we first evaluated Human Umblical Vein Endothelial Cells (HUVECs) migratory function using a modified Boyden chamber technique
Summary
As with other types of cancer, is dependent on angiogenesis for its continued growth and development. Common characteristics observed during this increased vascularity are enhanced endothelial cell proliferation, blood capillary enlargement, and the sprouting of new blood vessels from preexisting capillaries [2]. All of these phenotypic changes that occur are all aimed at sustaining thyroid. Cancer cells are proposed to mediate angiogenesis by secreting such growth factors that will bind to the respective receptors present on the endothelial cells resulting in endothelial cell migration, proliferation and tubulogenesis These growth factors are termed as proangiogenic factors and include transforming growth factor-α (TGF-α), angiogenin, vascular permeability growth factor (VPF) and vascular endothelial growth factor (VEGF) [6]. VEGF has been repeatedly shown as a significant component involved in regulation of thyroid angiogenesis with disturbances in intrathyroid VEGF expression leading to several thyroid pathologies, including tumor and goiter [1,13]
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