Abstract
Macrophage-associated cytokines play an important role in cancer metastasis; however, the functions of interleukins (IL) 6 and 10 in breast cancer (BC) progression and metastasis are not clear. In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration (± IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC (n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-231 migration with IL-10 treatment was observed (P = 0.03). BC cells were more adhesive to blood vs lymphatic EC, however, IL-6/IL-10 had no effect on adhesion patterns. High expression of IL-6/IL-10 was associated with clinicopathological criteria (e.g. hormone receptor status, all P < 0.05), improved disease-free survival (DFS; P < 0.05) and improved BC-specific survival (BCSS; only IL-6, P = 0.017). However, neither IL-6 nor IL-10 expression were independent prognostic factors from multivariate analysis. In BC subgroups, IL-6 and IL-10 were good prognosticators in terms of DFS in non-basal, non-triple-negative (non-TN), ER-positive, PgR-positive (only IL-10), and Her-2-negative (only IL-6) BC (all P < 0.05). IL-6 was associated with improved BCSS in non-basal, ER-positive and non-TN BC (all P < 0.05).
Highlights
The presence of lymph node (LN) metastasis in breast cancer (BC) is associated with poor overall survival with recent studies showing that lymphatic vessel invasion (LI) rather than blood vessel invasion (BI) is the predominant form of lymphovascular invasion (LVI) in early stage invasive BC [1, 2]
A dose-dependent decrease in MDA-MB-231 migration was seen with increasing concentrations of IL-10, with a weak but significant difference seen at 15 ng/mL in comparison to control (P = 0.03)
The current study aimed to investigate the potential role(s) that IL-6 and IL-10 may play in the metastatic process in vitro and examine IL-6 and IL-10 expression in BC tissues to determine their association with clinicopathological parameters and prognostic significance
Summary
The presence of lymph node (LN) metastasis in breast cancer (BC) is associated with poor overall survival with recent studies showing that lymphatic vessel invasion (LI) rather than blood vessel invasion (BI) is the predominant form of lymphovascular invasion (LVI) in early stage invasive BC [1, 2]. Macrophages represent a significant population of the inflammatory infiltrate and are linked to BC malignancy [4]. They can polarise into M1s, a pro-inflammatory anti-tumour type, or M2s, an anti-inflammatory form. The presence of inflammatory cytokines in the tumour milieu influences a number of processes at different stages of tumour progression, including initiation, proliferation, promotion, tumour cell conversion, angiogenesis, invasion, inhibition of apoptosis, immune surveillance, drug resistance and metastasis [5]. Little is known, about the roles of the macrophage-associated cytokines Interleukin-6 (IL-6) and interleukin-10 (IL-10) in the regulation of LVI, and LN metastasis or even their expression in breast tumours
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