Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties

Abstract

Treating metastasis has been challenging due to tumors complexity and heterogeneity. This complexity is partly related to the crosstalk between tumor and its microenvironment. Endothelial cells -the building blocks of tumor vasculature- have been shown to have additional roles in cancer progression than angiogenesis and supplying oxygen and nutrients. Here, we show an alternative role for endothelial cells in supporting breast cancer growth and spreading independent of their vascular functions. Using endothelial cells and breast cancer cell lines MDA-MB231 and MCF-7, we developed co-culture systems to study the influence of tumor endothelium on breast tumor development by both in vitro and in vivo approaches. Our results demonstrated that endothelial cells conferred survival advantage to tumor cells under complete starvation and enriched the CD44HighCD24Low/- stem cell population in tumor cells. Moreover, endothelial cells enhanced the pro-metastatic potential of breast cancer cells. The in vitro and in vivo results concordantly confirmed a role for endothelial Jagged1 to promote breast tumor through notch activation. Here, we propose a role for endothelial cells in enhancing breast cancer progression, stemness, and pro-metastatic traits through a perfusion-independent manner. Our findings may be beneficial in developing novel therapeutic approaches.

Nesting of colon and ovarian cancer cells in the endothelial niche is associated with alterations in glycan and lipid metabolism

“…Generally, increase in glucose metabolism and lactate production correlates with the increased proliferation rate of the cancer cells. Previously we reported that endothelial cells enhance proliferation capacity of cancer cells 4 days after co-culture was established12. Accordingly, the metabolic alterations identified in the first 48 hours might be solely associated with the cancer–endothelial-cells interactions and not with proliferation of cancer cells.…”

“…We previously established an in vitro model consisting of co-culture of cancer and endothelial cells111213. We selected endothelial cells E4 + EC previously created by transfection of the Primary Endothelial Cells (PECs) with the adenoviral E4ORF1 gene14.…”

Tumor endothelial cells accelerate tumor metastasis

“…described that TEC convert indolent tumor cells to more aggressive cells with greater tumorigenicity, extranodal invasion, and chemoresistance . Moreover, other groups have also demonstrated that the Notch signals in EC are involved in tumor progression and stem cell phenotype . Notch activation in EC promotes tumor cell migration and metastasis along with neutrophil infiltration …”

“…(42,43) Moreover, other groups have also demonstrated that the Notch signals in EC are involved in tumor progression and stem cell phenotype. (44)(45)(46)(47) Notch activation in EC promotes tumor cell migration and metastasis along with neutrophil infiltration. (48) In addition to the production of factors that simulate tumor cell progression, TEC also downregulate tumor suppressive factors.…”

Marinobufagenin inhibits glioma growth through sodium pump α1 subunit and ERK signaling‐mediated mitochondrial apoptotic pathway

“…They also found that MBG could downregulate certain genes involved in adhesion in the endothelial monolayers obtained from the human brain. Since tumor endothelial cells have been found to be associated with cancer progression and metastasis [26,27], the findings mentioned above could indicate a connection between MBG and glioma malignancy. Furthermore, it is known that MBG is involved in the inhibition of the sodium pump [28].…”