Phenotypic Switch in Blood: Effects of Pro-Inflammatory Cytokines on Breast Cancer Cell Aggregation and Adhesion

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.

Circulating tumor cell clusters: What we know and what we expect (Review)

“…Interactions between Thomsen-Friedenreich glycoantigen and galectin-3 also take part in breast cancer cell aggregation (53). In addition, some pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α could also promote tumor cell growth as clusters and induce adhesive recruitment in the circulation system (54). For patients of metastatic stage, the existence of CTC clusters from metastases is possible and makes things more complicated.…”

“…In addition, cytokines such as interleukin-6 and tumor necrosis factor-α can induce a positive feedback loop, leading to the aggregation of subsequent tumor cells and adhesion of tumor cells to endothelium (54). Alternatively, intravascular metastatic formation has also been proposed in certain cases in order to better understand tumor metastasis (49,53,77).…”

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

“…Deregulation of cell aggregation in metastatic cells is reported to result from loss of functional E-cadherin accompanied by a gain of expression of N-cadherin (6), differential adhesion to the extracellular matrix (7), or a response to inflammatory cytokines (8). A few studies also suggest that cell aggregation correlates inversely with tension in the cytoskeleton (9).…”

Modern concepts of factors for gastric cancer progression

“…Большинство работ свидетельствуют о том, что выраженная воспалительная инфильтрация стромы опухоли является фактором, способствующим прогрессии злока-чественных новообразований [48,49]. Полагают, что влияние воспалительной инфильтрации стромы опухоли и окружающих тканей на опухолевую прогрессию может быть связано с актива-цией ангиогенеза [50][51][52], повышением экспрессии селектинов и интегринов [27,53], разрушением соединительнотканного ма-трикса и базальных мембран эпителиев протеолитическими фер-ментами [51,54].…”