Abstract
Hematogeneous metastasis can occur via a cascade of circulating tumor cell adhesion events to the endothelial lining of the vasculature, i.e. the metastatic cascade. Interestingly, the pro-inflammatory cytokines IL-6 and TNF-α, which play an important role in potentiating the inflammatory cascade, are significantly elevated in metastatic breast cancer (BCa) patients. Despite their high metastatic potential, human breast carcinoma cells MDA-MB-231 lack interactions with E-selectin functionalized surfaces under physiological shear stresses. We hypothesized that human plasma, 3-D tumor spheroid culture, and cytokine-supplemented culture media could induce a phenotypic switch that allows BCa cells to interact with E-selectin coated surfaces under physiological flow. Flow cytometry, immunofluorescence imaging, and flow-based cell adhesion assay were utilized to investigate the phenotypic changes of MDA-MB-231 cells with various treatments. Our results indicate that plasma, IL-6, and TNF-α promote breast cancer cell growth as aggregates and induce adhesive recruitment of BCa cells on E-selectin coated surfaces under flow. 3-D tumor spheroid culture exhibits the most significant increases in the interactions between BCa and E-selectin coated surfaces by upregulating CD44V4 and sLex expression. Furthermore, we show that IL-6 and TNF-α concentrations in blood may regulate the recruitment of BCa cells to the inflamed endothelium. Finally, we propose a mechanism that could explain the invasiveness of ‘triple-negative’ breast cancer cell line MDA-MB-231 via a positive feedback loop of IL-6 secretion and maintenance. Taken together, our results suggest that therapeutic approaches targeting cytokine receptors and adhesion molecules on cancer cells may potentially reduce metastatic load and improve current cancer treatments.
Highlights
Cancer mortality is predominantly caused by the dissemination of cancer cells from the primary tumor to distant organs where secondary sites are formed via a metastatic progression
When grown in 2-D monolayers with culture media, highly metastatic MDA-MB-231 breast cancer cells showed no adhesive interactions with E-selectin coated surfaces under flow conditions (Figure 1a) despite the expression of the E-selectin ligand CD44V4 and the binding moiety sialyl lewis x (sLex) (Figure 1b)
This is contradictory to its reported high metastatic potential from in vivo studies where MDA-MB-231 cells were found to efficiently metastasize to distant organs through the bloodstream [18], where selectin-mediated tethering and rolling events have been shown to play important roles, as reviewed in [19]
Summary
Cancer mortality is predominantly caused by the dissemination of cancer cells from the primary tumor to distant organs where secondary sites are formed via a metastatic progression. Circulating tumor cells (CTCs) can interact and adhere to the endothelial lining of the vasculature through a series of receptor-mediated events, commonly referred to as the metastatic adhesion cascade. This cascade mimics the leukocyte adhesion cascade (reviewed in [5]) where the initial contact between cancer cells and the endothelium is facilitated by a family of endothelial adhesion molecules called selectins [9,10]
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