Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin

Abstract

In highly aggressive tumors, cancer cells may form channel-like structures through a process known as vasculogenic mimicry (VM). VM is generally associated with metastasis, mesenchymal phenotype, and treatment resistance. VM can be driven by antiangiogenic treatments and/or tumor microenvironment-derived factors, including those from the endothelium. Curcumin, a turmeric product, inhibits VM in some tumors, while calcitriol, the most active vitamin D metabolite, exerts potent antineoplastic effects. However, the effect of these natural products on VM in breast cancer remains unknown. Herein, we studied the effect of both compounds on triple-negative breast cancer (TNBC) VM-capacity in a co-culture model. The process of endothelial cell-induced VM in two human TNBC cell lines was robustly inhibited by calcitriol and partially by curcumin. Calcitriol promoted TNBC cells’ morphological change from spindle-like to cobblestone-shape, while curcumin diminished VM 3D-structure. Notably, the treatments dephosphorylated several active kinases, especially those involved in the PI3K/Akt pathway. In summary, calcitriol and curcumin disrupted endothelium-induced VM in TNBC cells partially by PI3K/Akt inactivation and mesenchymal phenotype inhibition. Our results support the possible use of these natural compounds as adjuvants for VM inactivation in patients with malignant tumors inherently capable of forming VM, or those with antiangiogenic therapy, warranting further in vivo studies.

The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells

“…Finally, knowing that PI3K–Akt is involved in VM activation [ 10 ], we pharmacologically inhibited this signaling pathway with LY294002 and found that VM was suppressed, further suggesting that the FGFR/PI3K–Akt axis was a main regulator of VM in our CCs. Other works have previously shown that FGFR or PI3K/Akt inhibition can impair both angiogenesis and VM in different types of cancer, and that the pan-FGFR inhibitor PD173074 impaired VM in cultured TNBC cells [ 38 , 71 , 76 , 77 , 78 ]; however, to our knowledge, this is the first report of VM inhibition in breast cancer by AZD4547 and LY294002, warranting future clinical studies.…”

“…Previously, we and others have shown the paracrine contribution of ECs in tumor cell behavior, including TNBC VM formation [ 10 , 12 , 25 , 26 ]. In this study, our aim was to gain further insight into the contribution of cellular components of the tumor microenvironment in TNBC VM induction, focusing on identifying the participation of ECs and SCs in this process.…”

“…Herein, we characterized a simple CC model to study VM in vitro that considers the interplay between cancer and endothelial cellular components, mimicking the in vivo tumor microenvironment more accurately. The CCs allow exploring the physical interaction between TNBC cells and ECs, which are known to stimulate VM in breast cancer through paracrine signaling [ 10 , 25 ], while at the same time consider the mixture of VM-driving factors produced by their mutual communication. Numerous studies have previously reported models of tumor cells-ECs interaction; however, they were used to address angiogenesis, ECs proliferation, or cross-talk between cancer cells and ECs, but not VM formation [ 13 , 39 , 40 , 41 , 42 ].…”

“…However, little is known about the participation of ECs and stromal cells (SCs) in the microenvironmental changes and reprogramming of cancer cells that enable them for VM formation. Moreover, even if previous studies have shown the ability of ECs to induce VM in breast cancer [ 10 , 11 , 12 , 13 ], there is limited information so far on the factors provided by these cells that are capable of inducing VM and the mechanisms involved. Therefore, in this study, we aimed to explore the capacity of ECs and SCs to induce VM in two different TNBC cell lines using an in vitro co-culture model that allows us to study their close interaction.…”

Advance in vasculogenic mimicry in ovarian cancer (Review)

“…In addition, the study of biomimetic mechanisms and associated inhibitors in OC remains a difficult research area. Certain anti-angiogenic mimetic drugs that have been applied to other tumors, including flavonoids ( 97 ), curcumin ( 98 ), doxycycline ( 20 ), thalidomide ( 60 ), and so on, need to be tested for their pharmaco-toxicological and pharmacokinetic properties before they can be formally applied in a clinical setting; therefore, there remains a long way to go before they can be applied for the treatment of OC angiogenic mimicry ( 99 ). Thus, there remains a long way to go before these agents can be used in therapeutic strategies for the treatment of OC angiogenic mimicry.…”