Estrogen enhances tumor growth and angiogenesis indirectly via mediation of bone marrow‑derived cells as well as directly through stimulation of tumor and endothelial cells

Abstract

Estradiol (E2) is a prime culprit for enhancing the progression of female hormone‑related cancers. Bone marrow‑derived cells (BMDCs) have been found to play a pivotal role in tumor growth. Estrogen receptors (ERs) are also found on certain subtypes of BMDCs, in addition to endothelial cells (ECs) and certain tumor cells. However, the role of BMDCs in E2‑induced tumor biology is still unclear. Thus, the effects of E2 on ER‑negative 4T1 breast cancer growth, the mobilization and recruitment of BMDCs, and interactions among BMDCs, ECs, and 4T1 cells were investigated. The results showed that E2 potentiated 4T1 tumor growth and angiogenesis in mice subjected to sham operation, ovariectomy (OVX), or OVX and E2 replacement treatment. E2 supplementation in mice with OVX upregulated the transcription of stromal cell‑derived factor‑1 (SDF‑1) mRNA in tumor tissues and enhanced the recruitment of BMDCs into tumor tissues in vivo. E2 deficiency significantly decreased proangiogenic CXCR4+, β3+, Sca‑1+ and CXCR4+β3+ BMDCs circulating in the peripheral blood. Cell‑based system analyses showed that E2 augmented the transcription of β3 mRNA in ECs, increased the adhesion of BMDCs to ECs. In addition, E2 enhanced the BMDC‑induced EC proliferation and migration, the BMDC‑induced 4T1 proliferation and the 4T1‑stimulated EC proliferation in addition to enhancing the proliferation of tumor cells and the migration of ECs in vitro. Therefore, E2 enhanced the growth of breast tumors by stimulating tumor cells and ECs directly, as well as by increasing proangiogenic BMDC mobilization and recruitment leading to augmentation of the tumor and EC functions indirectly by cell proliferation assay. These findings reveal a separate mechanism via which E2 promotes the growth of female hormone‑dependent tumors, which may be useful in explorations of new therapies for related cancers.

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“…Previous studies have confirmed that 17β-estradiol (E2) can participate in hormone-dependent tumor proliferation and metastasis through a variety of mechanisms [ 39 , 40 ]. The biological role of E2, in addition to directly binding to ER to mediate genomic effects, can also rapidly induce extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation to trigger intracellular non-genomic effect [ 41 , 42 ].…”

17-β Estradiol up-regulates energy metabolic pathways, cellular proliferation and tumor invasiveness in ER+ breast cancer spheroids

“…The substantial majority of studies showing the effect of E2 on cancer cell proliferation ( 45 , 46 ), survival, angiogenesis ( 47 ), migration, invasion ( 48 ) or metastasis ( 17 ) have been performed in bi-dimensional cell cultures. Although bi-dimensional models have been helpful for understanding the biochemistry and physiology of cancer cells, such information has been difficult to translate into treatment and early detection or biomarker identification of actual tumors, because bi-dimensional cultures does not reflect the physiological behavior of tumor cells in situ .…”

Predictors of Tumour Growth and Autonomous Cortisol Secretion Development during Follow-Up in Non-Functioning Adrenal Incidentalomas

“…To our knowledge, no other previous clinical study has identified female sex as a risk factor for tumour growth. However, as in other tumours, oestradiol enhances the progression and migration of endothelial cells in adrenal tumours [ 26 ]. In fact, the proliferation rate in steroidogenic cells of female rats is 6.3-fold higher than in male rats [ 27 , 28 ].…”