Stem-like tumor cells involved in heterogeneous vasculogenesis in breast cancer

Abstract

Sorafenib, a small-molecule tyrosine kinase inhibitor with antiangiogenic activity, has been used in liver cancer and kidney cancer treatments. However, clinical trials with sorafenib for breast cancer were stopped in phase III due to limited efficacy. The existence of heterogeneous vasculatures involving tumor cells, such as vessel-like structures formed by vasculogenic mimicry and mosaic vessels, and their resistance to antiangiogenic therapy are thought to be a possible reason for failure of sorafenib therapy. Nevertheless, the features and mechanism of vasculogenesis by tumor cells remain unclear. In the present study, we found that breast cancer stem-like cells (BCSLCs, ALDH1+ cells) were involved in vasculogenic mimicry and mosaic vessel formation in triple-negative breast cancer tissues. Further, only ALDH1+ BCSLCs sorted from MDA-MB-231 could exhibit the tube formation and angiogenesis ability. Sorafenib could inhibit vascularization from endothelial cells rather than that from ALDH1+ cells. α-SMA was identified as a key molecule in vascular formation of BCSLCs. Mechanistically, HIF-1α enhanced the mRNA and protein levels of α-SMA by binding to the HRE element in the promoter directly and meanwhile increased the BCSLCs population. Interestingly, pigment epithelium-derived factor (PEDF), an endogenous angiogenesis inhibitor, could inhibit both endothelial cell-derived and tumor cell-derived angiogenesis by downregulating HIF-1α in breast cancer. Our finding clarified the possible reason for the poor outcome of anti-angiogenesis therapy and PEDF may have the therapeutic potential.

Ultrasound-Targeted Microbubble Destruction Enhances Inhibitory Effect of Apatinib on Angiogenesis in Triple Negative Breast Carcinoma Xenografts

“…Simple antiangiogenic therapy inhibits blood vessel formation alone and has no influence on the growth of tumor cells. Under this condition, the tumor cells may experience recoding to counteract with ischemia and hypoxia and then transform into tumor stem cells highly expressing VEGFR2, which is involved in the formation of heterogeneous vasculatures, reducing the antitumor effect of antiangiogenic drugs [33]. In the present study, the VM structure was not detected, and only three mosaic blood vessels were identified in the UTMD group.…”

Pigment Epithelium-Derived Factor and Sex Hormone-Responsive Cancers

“…Oestrogen regulates PEDF in the endometrium [20], ovarian surface epithelial cells [18] and granulosa cells [19]. There has only been one report indicating that PEDF expression is under the regulatory control of oestrogen in BC cells [24], but this study did not utilise a microenvironment containing other forms of oestrogen-E1 and E1S.…”

“…PEDF may prevent BC cell EMT by regulating nuclear factor-kappa B (NF-κB) and extracellular signal regulated kinase (ERK)/Akt signalling to decrease the expression of EMT markers vimentin, Snail, fibronectin, and matrix metalloproteinases (MMPs), and increase E-cadherin expression, an important cell adhesion molecule [25,26]. The ability of PEDF to potently inhibit tumour angiogenesis is another important anti-tumour mechanism, whereby PEDF reduces BC growth and improves survival potentially by downregulating pro-angiogenic hypoxia inducible factor (HIF)-α/α-smooth muscle actin signalling in BC cells [24]. These findings show decreased PEDF expression promotes a pro-angiogenic, pro-metastatic tumour microenvironment (TME) essential for facilitating BC growth and progression.…”

Beyond the Liver: Liver-Eye Communication in Clinical and Experimental Aspects

“…Its possible mechanism of action is related to inflammation-related pathways. A study has found that PEDF can inhibit angiogenesis from endothelial cells and tumor cells by downregulating HIF-1α in breast cancer (Mao et al, 2020). Notably, PEDF is up-regulated in the liver of cirrhotic humans and bile duct-ligated rats, and the adenovirus-mediated gene transfer in bile duct-ligated rats exogenously overexpresses PEDF, which inhibits liver angiogenesis, fibrogenesis and reduces portal pressure (Mejias et al, 2015).…”