Angiogenesis is the process of vascular network development and plays a crucial role in
cancer growth, progression, and
metastasis. Phthalates are a class of
environmental pollutants that have detrimental effects on human health and are reported to increase
cancer risk. However, the interplay between
phthalate exposure and angiogenesis has not been investigated thoroughly. In this study, we investigated the effect of prolonged di (2-ethylhexyl)
phthalate (
DEHP) treatment on the angiogenic potential of
triple-negative breast cancer. MDA-MB-231 cells were exposed to physiological concentrations of
DEHP for more than three months. Prolonged
DEHP exposure induced angiogenesis in
breast cancer cells.
Endoglin (ENG)/CD105 is a
membrane glycoprotein and an auxiliary receptor of the TGFβ receptor complex. In endothelial cells, ENG is highly expressed and it is a prerequisite for developmental angiogenesis. A literature review highlights
endoglin as a well-known mesenchymal stem cell marker responsible for vascular development and angiogenesis. NGS analysis showed that
endoglin overexpression in
DEHP-exposed MDA-MB-231 cells correlated with
tumor development and growth. An in vivo zebrafish xenograft assay showed that VEGFA induced sprouting of the subintestinal vein (SIV) in embryos injected with
DEHP-exposed cells.
Endoglin knockdown reduced SIV sprouting and VEGFA expression in zebrafish embryos. An in vitro HUVEC tube formation assay showed that
endoglin depletion reversed
DEHP-induced
VEGF-mediated HUVEC tube formation in coculture.
DEHP-induced
endoglin activated TGFβ/SMAD3/
VEGF and
MAPK/p38 signaling in MDA-MB-231 cells. A
cytokine angiogenesis antibody array showed induced expression of the inflammatory
cytokines IL1α, IL1β,
IL6, and
IL8, along with GMCSF and
VEGF.
Endoglin knockdown reversed
DEHP-induced activation of the TGFβ/SMAD3/
VEGF signaling axis,
MAPK/p38 signaling, and
cytokine regulation, limiting angiogenesis potential both in vivo and in vitro. Targeting
endoglin might serve as a potential alternative treatment to control angiogenesis, leading to
metastasis and limiting
cancer progression.