What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

Abstract

Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science Core Collection) to identify preclinical reports, and in three clinical registers (ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union (EU) Clinical Trials Register) to identify clinical trials, from 2008 to 2019. Sixty-seven preclinical studies and 11 clinical trials were recognized as eligible. Although preclinical studies identified specific key ILs which promote breast cancer bone metastases, which have pro-metastatic effects (e.g., IL-6, IL-8, IL-1β, IL-11), and whose inhibition also shows potential preclinical therapeutic effects, the clinical trials focused principally on ILs (IL-2 and IL-12), which have an anti-metastatic effect and a potential to generate a localized and systemic antitumor response. However, these clinical trials are yet to post any results or conclusions. This inconsistency indicates that further studies are necessary to further develop the understanding of cellular and molecular relations, as well as signaling pathways, both up-and downstream of ILs, which could represent a novel strategy to treat tumors that are resistant to standard care therapies for patients affected by breast cancer bone disease.An initial literature search found 905 references, of which 151 articles were recognized using the PubMed database, 481 articles were recognized using Scopus, and 273 articles were found in the Web of Science Core Collection. Subsequently, the resulting references were submitted to a public reference manager (Mendeley 1.17.11) to eliminate duplicate articles, obtaining 666 articles. From the 666 articles obtained, after exclusion, 116 full-text articles were evaluated, of which 67 met the inclusion criteria. The 560 studies excluded from this review were excluded because they were meeting reports, reviews, book chapters, and case reports, and/or because they reported IL roles in primary breast tumor, as well as in lung, liver, and pulmonary metastasis, leukemia, osteosarcoma, ovarian tumor, melanoma, prostate cancer, autoimmune arthritis related to breast cancer, and other pathological conditions; however, they did not reveal the favorable development of bone metastases from breast cancer. In addition, we excluded studies where IL profiling was derived from breast cancer metastatic patients that were not grouped/analyzed based on the site of metastasis, and where breast cancer bone metastases were evaluated, but no IL roles/functions were examined. Finally, we also eliminated studies where responses to specific therapy (not IL-based) for breast cancer bone metastasis were analyzed, studies that evaluated the contributions of the sensory signaling pathways to neuropathic pain induced by breast cancer bone metastases, and studies on chronic s...

The IL1β-IL1R signaling is involved in the stimulatory effects triggered by hypoxia in breast cancer cells and cancer-associated fibroblasts (CAFs)

“…1 a. The “Cytokine-cytokine receptor interaction” transduction pathway, including IL1B, IL1A, IL1R, IL6, IL6ST, IL7R, IL1RAP, INHBA, OSMR and TGFBR2 that are strongly associated with breast cancer progression [ 35 – 41 ], was found significantly correlated with HIF-1α. Next, we performed gene set enrichment analysis (GSEA) in order to explore the “Cytokine-cytokine receptor interaction” expression profile according to the high and low HIF-1α phenotypes of both TCGA and METABRIC cohorts of TNBC patients.…”

Notch-Inflammation Networks in Regulation of Breast Cancer Progression

“…To follow up on the conventional categorization of M1 “classically activated” and M2 “alternatively activated” macrophages, very often tumor-associated macrophages (TAMs) are considered as M2-polarized cells that promote tumor cell proliferation, angiogenesis, immune suppression and other key tumor-supporting events [ 70 , 71 , 72 ]. In parallel, M1 macrophages are generally regarded as anti-tumor cells that constitute a major source for pro-inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) [ 70 , 73 ]; whereas these cytokines can promote anti-tumor activities at certain stages of the malignancy process, they are also often linked to chronic inflammation and to pro-metastatic effects in BC and other malignancies as well [ 45 , 74 , 75 , 76 , 77 , 78 , 79 ]. In this context, it is important to note that actually, macrophage types are not dichotomic but rather these cells demonstrate a very high level of plasticity that leads to a continuum of phenotypes and activities [ 80 , 81 ].…”

“…Many of these factors were linked to a less favorable disease course in cancer, and play causative roles in promoting tumor progression. Specifically, pro-inflammatory cytokines and inflammatory chemokines were reported to have a strong tumor-supporting impact on cancer development and metastasis, as illustrated by many studies of BC and other cancer types as well (e.g., [ 45 , 74 , 75 , 76 , 77 , 78 , 79 , 91 , 92 , 93 , 94 , 95 , 96 ]).…”

“…In parallel, different studies indicated that the pro-inflammatory mediators TNFα and IL-1β, as well as the inflammatory chemokines CXCL8 (IL-8), CCL2 (MCP-1) and CCL5 (RANTES)—that are major contributors to BC progression [ 45 , 74 , 75 , 76 , 77 , 78 , 79 , 93 , 94 , 95 , 96 ]—were connected to Notch activities in BC. For example, evidence from our studies indicated that co-culturing of TNBC cells with mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the presence of TNFα or IL-1β stimulation has given rise to contact-dependent increase in CXCL8, CCL2 and CCL5 levels in the co-cultures.…”

“…With these findings in mind, it is interesting to note that another pro-inflammatory cytokine, IL-6 has been highly implicated in tumor-promoting processes [ 79 , 91 , 92 ] and in Notch-related pathways in BC. Here, two main lines of evidence were obtained: the first is that Notch pathway activities have given rise to tumor-promoting functions in BC via IL-6 and STAT3 activation ( Figure 1 (B1)), and the second is that IL-6 stimulation/STAT3 activation has led through Notch family members to pro-metastatic activities in BC ( Figure 1 (B2)).…”