IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways

Abstract

Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.

Multi-Omics Analyses Revealed GOLT1B as a Potential Prognostic Gene in Breast Cancer Probably Regulating the Immune Microenvironment

“…In patients with short survival time (< 5 years), the expression of JUN in breast cancer tissue is down-regulated and the risk of recurrence of breast cancer is increased (24). Furthermore, JUN mediates the functions of some important cytokines in breast cancer, such as IL-34, IL-33, and IL-1b (22,23,25). On the other hand, SIN3A is a transcriptional suppressor promoting osteolytic destruction in ERa-positive breast cancer (26).…”

Vasculogenic Mimicry in Breast Cancer: Clinical Relevance and Drivers

“…For example, the TNBC MDA-MB-231 and HCC1937 cells readily formed tubular-like structures in Matrigel [ 36 , 37 ]. In comparison, the ERα-positive cell line MCF-7 has been reported to be incapable of forming VM in this matrix [ 36 ]; however, in the presence of some VM drivers such as interleukin 1β, MCF-7 cells formed microvessel-like intersections and cords [ 38 ]. Further studies are needed to corroborate the effects of VM-drivers upon tubular-like structure formation in ER-positive breast cancer cells.…”

“…On this subject, it is known that TNBC MDA-MB-231 cells express IL-8 as well as its receptors CXCR1/CXCR2, and notably, it has been shown that IL-8 uptake increases during VM formation and that IL-8/CXCR2 signaling is necessary for tube formation, a process that correlates with increased IL-8 levels [ 58 ]. In a similar manner but using a different signalization pathway, IL-1β has shown to stimulate VM formation by MCF-7 and MDA-MB-231 cells [ 38 ]. Indeed, when these cells were incubated in the presence of IL-1β, they readily formed tube-like structures in Matrigel and expressed VM biomarkers, including VE-Cadherin, VEGF receptor-1, MMP-9, and MMP-2.…”

“…Indeed, when these cells were incubated in the presence of IL-1β, they readily formed tube-like structures in Matrigel and expressed VM biomarkers, including VE-Cadherin, VEGF receptor-1, MMP-9, and MMP-2. Of note, this effect was preserved under both normoxic and hypoxic conditions and involved the p38/MAPK and PI3K/Akt signaling pathways [ 38 ].…”

Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells

“…For instance, a study on more than 1,200 patients with BC showed a positive correlation between the increased VM positivity and larger tumor size, the propensity for metastasis, differentiation grade, and poor prognosis ( 14 ). Considering the characteristics of breast molecular subtypes and hormone-positive BC expression of VEGF ( 15 ), research has shown that cancer progression can be arrested or slowed down by targeting TGF-β1, MMP-2, and MMP-9 when irradiated by a proton beam ( 7 ). Additionally, the ERα-positive cell line MCF-7 has been reported to induce VM upon exposure to the VM mediator, interleukin 1β ( 7 ).…”