Abstract
PurposeTo examine the involvement of the F11R/JAM-A protein in breast cancer metastasis, we utilized the F11R/JAM-A antagonistic peptide 4D (P4D) in experiments of transendothelial migration (TEM) of breast cancer cells.MethodsExperiments were conducted in the mouse 4T1 breast cancer model utilizing the human mammary epithelial cell and endothelial cell lines. The levels of soluble F11R/JAM-A (sJAM-A) in the murine plasmas were measured by ELISA. Levels of F11R/JAM-A mRNA and protein in cell lines were assessed by qRT-PCR and Western blot, respectively. Cell surface expression of F11R/JAM-A was demonstrated by flow cytometry. Functional tests included the TEM of breast cancer cells and adhesion of breast cancer cells to the endothelium. The endothelial permeability was studied by fluorescent tracer assay and by the Real-Time Cell Analysis (RTCA).ResultsThe tumor inducers Tβ4 and TGF-β1 reduced the levels of sJAM-A in murine plasma, and reduced the F11R/JAM-A protein levels in the human microvascular endothelial cell line HMEC-1. The adhesion and TEM measured between breast cancer cells and inflamed or Tβ4-treated endothelium were inhibited by P4D. The presence of P4D did not destabilize the pre-existing tight junctions in the endothelial monolayer. The barrier-protecting effect of P4D was stronger than that of forskolin, when a booster dose of P4D was applied to the inflamed endothelium.ConclusionsF11R/JAM-A protein can be considered as a novel target in the treatment of breast cancer metastasis. In vivo and clinical studies are needed to further investigate the effectiveness of F11R/JAM-A-derived peptide as a possible anti-metastatic drug.
Highlights
Breast cancer is the leading cause of cancer death among females worldwide, [1] including Poland [2]
We investigated how peptide 4D (P4D) influences the interactions between the breast cancer cells and endothelial cells in the mouse breast cancer model, and examined its effects on human cell lines treated with thymosin β4 (Tβ4), an inducer of metastasis [26], and linked with breast cancer [27,28,29]
Our studies on the murine 4T1 breast cancer model demonstrated that administration of Tβ4 and TGF-β1 decreased the soluble F11R/JAM-A (sJAM-A) levels in murine blood
Summary
Breast cancer is the leading cause of cancer death among females worldwide, [1] including Poland [2]. The formation of metastasis is initiated by the adhesion of tumor cells to the endothelium and the subsequent transendothelial migration (TEM) of cancer cells [4]. F11R/JAM-A molecules are thereby able to interact with leukocyte surface proteins, including F11R/JAM-A (by trans-homodimerization) and integrins, promoting leukocyte TEM [6, 14,15,16,17]. Further cell treatment involved the use of the inflammatory cytokines Both the formation of TJs and the interactions of cancer cells with the endothelium were blocked by P4D. We propose that P4D can be considered as the drug candidate for use in the prevention of breast cancer metastasis
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