Circulating interleukin‐6 predicts survival in patients with metastatic breast cancer

Salgado, Roberto; Junius, S.; Benoy, Ina; Dam, Peter van; Vermeulen, Peter B.; Marck, Eric Van; Huget, P.; Dirix, Luc

doi:10.1002/ijc.10833

Cited by 384 publications

(313 citation statements)

References 58 publications

(58 reference statements)

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“…This is in concordance with the observations in patient biopsies, where these cytokines were expressed at elevated levels in basal‐like tumors compared to the luminal tumors. As these cytokines are associated with poor prognosis and cancer progression (Benoy et al ., 2004; Lv et al ., 2013; Salgado et al ., 2003), their abundance in basal‐like tumors may be linked to the aggressive behavior of this subtype. In the current study, we pursued this idea by studying the ability of BCC‐secreted factors to engage tumor‐supportive macrophages.…”

Section: Discussionmentioning

confidence: 99%

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

et al. 2018

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The tumor microenvironment (TME) may influence both cancer progression and therapeutic response. In breast cancer, particularly in the aggressive triple‐negative/basal‐like subgroup, patient outcome is strongly associated with the tumor's inflammatory profile. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the TME, shown to be linked to poor prognosis and therapeutic resistance. In this study, we investigated the effect of the metastasis‐ and inflammation‐associated microenvironmental factor S100A4 on breast cancer cells (BCCs) of different subtypes and explored their further interactions with myeloid cells. We demonstrated that extracellular S100A4 activates BCCs, particularly the basal‐like subtype, to elevate secretion of pro‐inflammatory cytokines. The secreted factors promoted conversion of monocytes to TAM‐like cells that exhibited protumorigenic activities: stimulated epithelial–mesenchymal transition, proliferation, chemoresistance, and motility in cancer cells. In conclusion, we have shown that extracellular S100A4 instigates a tumor‐supportive microenvironment, involving a network of cytokines and TAM‐like cells, which was particularly characteristic for basal‐like BCCs and potentiated their aggressive properties. The S100A4–BCC–TAM interaction cascade could be an important contributor to the aggressive behavior of this subtype and should be further explored for therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

et al. 2018

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“…When the mice were treated with the anti-inflammatory drug dexamethasone, 53 The inflammatory cytokine IL-6 is elevated during several tumorigenic processes in correlation with tumor grade and poor survival. 54,55 IL-6 induces EMT in breast cancer cells, 56 which could be a consequence of continuous signal transducer and activator of transcription 3 (STAT3) activation that leads to the downregulation of crucial EMT-regulatory microRNAs. 57 An interesting report illustrates how tumor-derived IL-6 and IL-8 (CXCL8) attract circulating tumor cells (CTCs) to the original tumors (termed as 'tumor self-seeding') and influence tumor progression and metastasis through the selection of the most aggressive cancer cells.…”

Section: Inflammation and Metastasismentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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“…This is as far as the analogy goes, because far from being the end-state non-functional bridging tissue which forms across skin wounds, cancerassociated stroma secretes a plethora of factors such as IL-6 which promote the growth and invasion of the underlying tumor (reviewed in [18]). Increased concentration (>4 pg/ml) of IL-6 in the serum of breast cancer patients is an indicator of overall poor prognosis, predicting liver metastases and pleural effusion, and lack of response to chemo-endocrine therapy [19][20][21]. IL-6 serum levels were increased in 27% of breast cancer patients [22] and a correlation in breast cancer patients between highly elevated IL-6 serum levels and tumor progression has been reported [23].…”

Section: Cancer-associated Fibroblasts As a Potential Source Of Il-6 mentioning

confidence: 99%

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancerassociated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic Microenvironment (2012) 5:83-93 DOI 10.1007 groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

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Circulating interleukin‐6 predicts survival in patients with metastatic breast cancer

Cited by 384 publications

References 58 publications

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

Inflammation and skeletal metastasis

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

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