PO-290 Oncostatin M signalling mediates the crosstalk between cancer cells and tumour microenvironment and promotes breast cancer progression

AbstractCancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression1,2. However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.

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Sympathetic activity in breast cancer and metastasis: partners in crime

Bone Research ◽

10.1038/s41413-021-00137-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Francisco Conceição ◽

Daniela M. Sousa ◽

Joana Paredes ◽

Meriem Lamghari

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Bone Remodeling ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Sympathetic Innervation ◽

Breast Cancer Progression ◽

Vicious Cycle ◽

Native Bone ◽

Cancer Management

AbstractThe vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

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The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression

Endocrinology ◽

10.1210/endocr/bqab095 ◽

2021 ◽

Author(s):

Amy E Baek ◽

Natalia Krawczynska ◽

Anasuya Das Gupta ◽

Svyatoslav Victorovich Dvoretskiy ◽

Sixian You ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Myeloid Cells ◽

Breast Cancer Progression ◽

Label Free ◽

Tumor Growth And Metastasis ◽

Promote Breast Cancer

Abstract Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite, 27-hydroxycholesterol (27HC), as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and a liver x receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells, with neutrophils (PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that include exosomes. The resulting EVs had a size distribution that was skewed slightly larger, compared to EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across three different subtypes: primary murine PMNs, RAW264.7 monocytic cells and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in two different syngeneic models, demonstrating the potential role of 27HC induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their pro-tumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

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Abstract P2-02-10: Progesterone receptor membrane component-1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells: Potential mechanism contributing to breast cancer progression

10.1158/1538-7445.sabcs18-p2-02-10 ◽

2019 ◽

Author(s):

M Ludescher ◽

N Stamm ◽

D Niederacher ◽

E Ruckhäberle ◽

T Fehm ◽

...

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Cholesterol Synthesis ◽

Cholesterol Metabolism ◽

Breast Cancer Progression ◽

Potential Mechanism ◽

Membrane Component

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LncRNA NEAT1 accelerates breast cancer progression through regulating miR-410-3p/ CCND1 axis

Cancer Biomarkers ◽

10.3233/cbm-190721 ◽

2020 ◽

Vol 29 (2) ◽

pp. 277-290

Author(s):

Xuan Liu ◽

Weirong Yao ◽

Haiwei Xiong ◽

Qiang Li ◽

Yingliang Li

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Breast Cancer Progression ◽

Cell Counting ◽

Luciferase Reporter ◽

Cancer Tissues

BACKGROUND: Breast cancer is the most common malignant tumor and usually occurs in women. Studies have shown that lncRNA nuclear enriched abundant transcript 1 (NEAT1) contributes to breast cancer progression. This study intends to further investigate the molecular mechanism of NEAT1 in breast cancer. METHODS: The expression levels of NEAT1, miR-410-3p and Cyclin D1 (CCND1) were detected by quantitative real-time PCR (qRT-PCR) in breast cancer tissues and cells. Kaplan-Meier analysis and the log-rank test were performed to determine the relationship between NEAT1 and overall survival. Cell Counting Kit-8 (CCK-8) assay analyzed cell proliferation. Transwell assay was performed to examine cell migration and invasion. The protein levels of CCND1 and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Vimentin) were measured by western blot. The target relationship was predicted by bioinformatics analysis, and confirmed by luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Xenograft analysis was used to evaluate the tumor growth in vivo. RESULTS: NEAT1 and CCND1 were upregulated, while miR-410-3p was down-regulated in breast cancer tissues and cells. Higher NEAT1 expression level was associated with lower survival rate of breast cancer patients. Knockdown of miR-410-3p restored silenced NEAT1-mediated the inhibition of on proliferation, migration, invasion and EMT of breast cancer cells. In addition, NEAT1 regulated CCND1 expression by sponging miR-410-3p in breast cancer cells. NEAT1 knockdown blocked the tumor growth in vivo. CONCLUSION: NEAT1 induced breast cancer progression by regulating the miR-410-3p/CCND1 axis, indicating that NEAT1 may be a potential therapeutic target in breast cancer.

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The long non‐coding RNA DANCR regulates the inflammatory phenotype of breast cancer cells and promotes breast cancer progression via EZH2‐dependent suppression of SOCS3 transcription

Molecular Oncology ◽

10.1002/1878-0261.12622 ◽

2020 ◽

Vol 14 (2) ◽

pp. 309-328 ◽

Cited By ~ 11

Author(s):

Ke‐Jing Zhang ◽

Xiao‐Lang Tan ◽

Lei Guo

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Breast Cancer Progression ◽

Non Coding Rna ◽

Inflammatory Phenotype ◽

Long Non Coding Rna

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Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment

International Journal of Oncology ◽

10.3892/ijo.2017.3883 ◽

2017 ◽

Vol 50 (4) ◽

pp. 1191-1200 ◽

Cited By ~ 16

Author(s):

Vasilios Panagopoulos ◽

Damien A. Leach ◽

Irene Zinonos ◽

Vladimir Ponomarev ◽

Giovanni Licari ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Tumour Microenvironment ◽

Breast Cancer Progression ◽

Promote Breast Cancer

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Mesenchymal stromal cell activation by breast cancer secretomes in bioengineered 3D microenvironments

Life Science Alliance ◽

10.26508/lsa.201900304 ◽

2019 ◽

Vol 2 (3) ◽

pp. e201900304 ◽

Cited By ~ 6

Author(s):

Ulrich Blache ◽

Edward R Horton ◽

Tian Xia ◽

Erwin M Schoof ◽

Lene H Blicher ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Breast Cancer Cells ◽

Cell Activation ◽

Tumour Microenvironment ◽

Paracrine Signalling ◽

Organ Specific ◽

Mcf 7

Mesenchymal stromal cells (MSCs) are key contributors of the tumour microenvironment and are known to promote cancer progression through reciprocal communication with cancer cells, but how they become activated is not fully understood. Here, we investigate how breast cancer cells from different stages of the metastatic cascade convert MSCs into tumour-associated MSCs (TA-MSCs) using unbiased, global approaches. Using mass spectrometry, we compared the secretomes of MCF-7 cells, invasive MDA-MB-231 cells, and sublines isolated from bone, lung, and brain metastases and identified ECM and exosome components associated with invasion and organ-specific metastasis. Next, we used synthetic hydrogels to investigate how these different secretomes activate MSCs in bioengineered 3D microenvironments. Using kinase activity profiling and RNA sequencing, we found that only MDA-MB-231 breast cancer secretomes convert MSCs into TA-MSCs, resulting in an immunomodulatory phenotype that was particularly prominent in response to bone-tropic cancer cells. We have investigated paracrine signalling from breast cancer cells to TA-MSCs in 3D, which may highlight new potential targets for anticancer therapy approaches aimed at targeting tumour stroma.

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Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/β-Catenin Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21176357 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6357

Author(s):

Hui Shi ◽

Luping Zhao ◽

Xinlin Guo ◽

Runping Fang ◽

Hui Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Nuclear Translocation ◽

Breast Cancer Progression ◽

Gm Csf ◽

Stat3 Phosphorylation

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.

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