Abstract
BackgroundThe global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion.MethodsBiomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17β-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined.ResultsBoth embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17β-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMPs. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice.ConclusionsThe similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present studies offer the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.
Highlights
The global epidemiological studies reported lower cancer risk after long-term use of contraceptives
The differences between the two cell lines were that RL95-2 expressed high levels of ICAM-1, and intermediate levels of E-selectin, whereas, human umbilical vein endothelial cells (HUVECs) expressed intermediate levels of ICAM-1, L-selectin and VCAM-1
Effects of sex hormones and abortifacients on expressions of cell adhesion molecules Since integrin α3, α5, α6, β1 and αvβ3, and ICAM-1 were highly expressed on both endometrial cells RL95-2 and HUVECs, we investigated if sex hormones and abortifacients could affect the expression of these molecules on the two kinds of seeding cell lines
Summary
The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Before GLOBOCAN estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths worldwide occurred in 2020 for 36 Cancers in 185 countries [2], Lancet Oncology in 2015 published a large epidemiological study [3] that indicated that long-term administration of oral contraceptives prevented the risks of ovarian cancer and endometrial cancer. The most important finding of the study is that the longer the women had used oral contraceptives, the greater the reduction in ovarian cancer risk. This reduction in cancer risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat weakened over time: the proportional risk reductions per 5 years of use were 29% for use that had ceased less than 10 years previously, 19% for use that had ceased 10–19 years previously, and 15% for use that had ceased 20–29 years previously
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