Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Breast Cancer Res. 2019 Apr 29;21(1):54. doi: 10.1186/s13058-019-1136-x.
Highly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment (TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-β (IFN-β). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-β induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome.
Using transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-β. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation.
There are three major findings from our study. First, exposure of purified, non-CSC to IFN-β prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-β mRNA expression and autocrine/paracrine IFN-β signaling. Restoring IFN-β signaling to OSM-driven CSC re-engages IFN-β-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-β to treat OSM-driven tumors significantly suppresses tumor growth.
Our findings suggest that the levels of IFN-β and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-β signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-β expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-β signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.
高度侵袭性、转移性和治疗耐药的三阴性乳腺癌（TNBC）通常富含癌症干细胞（CSC）。乳腺肿瘤微环境（TME）中的细胞因子通过调节肿瘤细胞分化程序来影响 CSC 状态。两种常见的乳腺 TME 细胞因子是白细胞介素-6 家族成员之一的肿瘤坏死因子-α（OSM）和干扰素-β（IFN-β）。OSM 可驱动 TNBC 细胞去分化为高度侵袭性的 CSC 状态。相反，IFN-β 诱导 TNBC 分化，从而抑制 CSC 特性。在这里，我们评估这些乳腺 TME 细胞因子如何影响 CSC 可塑性和临床结果。
我们使用转化的人乳腺上皮细胞（HMEC）和 TNBC 细胞模型，评估了暴露于 OSM 和/或 IFN-β 后 CSC 标志物和特性。CSC 标志物包括 CD24、CD44 和 SNAIL；CSC 特性包括肿瘤球形成、迁移能力和肿瘤起始。
我们的研究有三个主要发现。首先，暴露于纯化的非 CSC 的 IFN-β可防止 OSM 介导的 CD44 和 SNAIL 表达，并抑制肿瘤球形成和迁移能力。其次，在 OSM 诱导的去分化过程中，OSM 抑制内源性 IFN-β mRNA 表达和自分泌/旁分泌 IFN-β 信号。恢复 IFN-β 信号至 OSM 驱动的 CSC 重新激活 IFN-β 介导的分化，通过抑制 OSM/STAT3/SMAD3 介导的 SNAIL 表达、肿瘤起始和生长来抑制 OSM 驱动的 CSC 重新激活。最后，IFN-β 治疗 OSM 驱动的肿瘤的治疗用途可显著抑制肿瘤生长。
我们的研究结果表明，TNBC 中的 IFN-β 和 OSM 水平决定了具有 CSC 表型的细胞的丰度。事实上，具有高 IFN-β 信号的 TNBC 具有抑制 CSC 特性和更好的临床结果。相反，具有高 OSM 信号的 TNBC 具有更差的临床结果。同样，由于 OSM 抑制 IFN-β 的表达和信号，我们的研究表明，限制 OSM 信号或激活 IFN-β 信号的策略将使负责 TNBC 侵袭性的去分化程序脱钩。
