IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer

AbstractBreast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.

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The α2β1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: A preclinical study

Cancer Letters ◽

10.1016/j.canlet.2014.12.032 ◽

2015 ◽

Vol 358 (1) ◽

pp. 67-75 ◽

Cited By ~ 11

Author(s):

Nadia Rucci ◽

Mattia Capulli ◽

Ole K. Olstad ◽

Patrik Önnerfjord ◽

Viveka Tillgren ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastases ◽

Tumour Growth ◽

Primary Tumour ◽

Preclinical Study ◽

Binding Domain ◽

Primary Tumour Growth

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Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling

Nature Communications ◽

10.1038/s41467-019-12807-0 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 13

Author(s):

Rachel Eyre ◽

Denis G. Alférez ◽

Angélica Santiago-Gómez ◽

Kath Spence ◽

James C. McConnell ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Bone Metastasis ◽

Bone Metastases ◽

Colony Formation ◽

Breast Cancer Cells ◽

Wnt Signalling ◽

Early Event ◽

Metastatic Lesions ◽

Breast Cancer Bone Metastasis

Abstract Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however cells may lie dormant for many years before bone metastases develop. Treatment for bone metastases is not curative, therefore new adjuvant therapies which prevent the colonisation of disseminated cells into metastatic lesions are required. There is evidence that cancer stem cells (CSCs) within breast tumours are capable of metastasis, but the mechanism by which these colonise bone is unknown. Here, we establish that bone marrow-derived IL1β stimulates breast cancer cell colonisation in the bone by inducing intracellular NFkB and CREB signalling in breast cancer cells, leading to autocrine Wnt signalling and CSC colony formation. Importantly, we show that inhibition of this pathway prevents both CSC colony formation in the bone environment, and bone metastasis. These findings establish that targeting IL1β-NFKB/CREB-Wnt signalling should be considered for adjuvant therapy to prevent breast cancer bone metastasis.

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PTHrP(12-48) for the diagnosis of breast cancer bone metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21039 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21039-e21039

Author(s):

Charity L. Washam ◽

Stephanie D. Byrum ◽

Kim Leitzel ◽

Ali M. Suhail ◽

Allan Lipton ◽

...

Keyword(s):

Breast Cancer ◽

Logistic Regression ◽

Bone Metastasis ◽

Bone Metastases ◽

Cancer Patients ◽

Statistical Significance ◽

Breast Cancer Patients ◽

Parathyroid Hormone Related Protein ◽

Increased Risk ◽

Breast Cancer Bone Metastasis

e21039 Background: Bone metastasis of breast cancer significantly compromises patient morbidity and mortality. Currently, no reliable methods detect or predict patients at increased risk for developing bone metastasis. We utilized 3 independent cohorts of breast cancer patients to validate a highly discriminatory plasma-based proteomic profile that identifies breast cancer bone metastasis. The identity of the most discriminatory protein component identified was a parathyroid hormone-related protein fragment, PTHrP(12-48). Methods: Plasma samples collected from 21 breast cancer patients with clinical evidence of a bone metastasis and 21 patients with no evidence of bone metastasis from time of diagnosis to clinical outcome were evaluated. A novel mass spectrometry-based assay using human serum spiked with synthetic PTHrP(12-48) was used to measure PTHrP(12-48) concentrations (pg/μl). Statistical significance was assessed by one-way ANOVA. ROC curves evaluated the diagnostic potential of PTHrP(12-48) and a simple logistic regression derived from the combined measurement of PTHrP(12-48) and NTx. Results: PTHrP(12-48) concentrations ranged between 11.6 and 92.1 pg/μl in bone metastasis patients and between 4.5 and 34.2 pg/μl in patients without bone metastases. PTHrP(12-48) was significantly increased in bone metastasis plasma (p < 0.05). No significant correlation was identified between PTHrP(12-48) and NTx. ROC analysis of PTHrP(12-48), threshold 18 pg/μl, classified the two groups with high accuracy. Class prediction by the PTHrP(12-48)/NTx logistic regression model increased diagnostic specificity. Conclusions: The measurement of PTHrP(12-48) in patient plasma has potential as a viable clinical measure of bone metastasis. In combination with serum NTx, PTHrP(12-48) may assist in identifying bone metastases in patients presenting with low to normal bone turnover markers.

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Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1

Thrombosis and Haemostasis ◽

10.1160/th04-11-0712 ◽

2005 ◽

Vol 93 (04) ◽

pp. 779-786 ◽

Cited By ~ 40

Author(s):

Buddy Setyono-Han ◽

Jörg Stürzebecher ◽

Wolfgang Schmalix ◽

Bernd Muehlenweg ◽

Anieta Sieuwerts ◽

...

Keyword(s):

Breast Cancer ◽

Tumour Growth ◽

Cancer Metastasis ◽

Primary Tumour ◽

Single Agent ◽

Subcutaneous Administration ◽

Axillary Lymph ◽

Maximal Effect ◽

Dependent Manner ◽

Primary Tumour Growth

SummaryThe serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are often elevated in malignant tumours, hence, inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies. WX-UK1, a derivative of 3-aminophenylalanine in the L-conformation with inhibitory antiproteolytic properties, was tested for its specificity spectrum using specific chromogenic paranitroanilide peptide substrates. The corresponding D-enantiomer of WX-UK1 was used as a control. The anti-tumour and anti-metastatic (number of lung foci and weight of the axillary lymph nodes) properties were studied by subcutaneous administration of WX-UK1 to Brown Norwegian (BN) rats carrying orthotopically transplanted BN472 rat breast tumours. WX-UK1 selectively inhibited tumour-related proteases from rats and humans such as uPA, plasmin, or thrombin in the sub or low micromolar range. The activity was stereoselective as the D-enantiomer of WX-UK1 inhibited uPA and plas-min at approximately 70-fold higher Ki values than the active L-form. Chronical administration of the L-enantiomer of WXUK1 impaired primary tumour growth and metastasis of BN472 rat breast cancer in a dose-dependent manner. The minimum inhibitory dosage with maximal effect was between 0.15 and 0.3 mg/kg/day. The inactive D-enatiomer of WX-UK1 was not active in this respect. Daily treatment with WX-UK1 for up to 35 days was well tolerated as judged by the unchanged body and organ weight development. In conclusion, our results provide evidence that WX-UK1 as a single agent inhibits breast tumour growth and metastasis in vivo, and thus is a promising candidate drug to treat human cancer.

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The role of IL-1B in breast cancer bone metastasis

Endocrine Related Cancer ◽

10.1530/erc-17-0309 ◽

2018 ◽

Vol 25 (7) ◽

pp. R421-R434 ◽

Cited By ~ 25

Author(s):

Claudia Tulotta ◽

Penelope Ottewell

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Tumour Microenvironment ◽

Tumour Cells ◽

Breast Cancer Patients ◽

Potential Biomarker ◽

Increased Risk ◽

Breast Cancer Bone Metastasis ◽

New Treatments

Approximately 75% of patients with late-stage breast cancer will develop bone metastasis. This condition is currently considered incurable and patients’ life expectancy is limited to 2–3 years following diagnosis of bone involvement. Interleukin (IL)-1B is a pro-inflammatory cytokine whose expression in primary tumours has been identified as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In this review, we discuss how IL-1B from both the tumour cells and the tumour microenvironment influence growth of primary breast tumours, dissemination into the bone metastatic niche and proliferation into overt metastases. Recent evidence indicates that targeting IL-1B signalling may provide promising new treatments that can hold tumour cells in a dormant state within bone thus preventing formation of overt bone metastases.

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Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis

Geburtshilfe und Frauenheilkunde ◽

10.1055/s-0028-1088610 ◽

2008 ◽

Vol 68 (S 01) ◽

Author(s):

C Schem ◽

DO Bauerschlag ◽

J Weimer ◽

M Zhang ◽

W Jonat ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Breast Cancer Bone Metastasis ◽

Cox2 Expression

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Osteoblast-Derived PTHRP and Breast Cancer Bone Metastasis

10.21236/ada625302 ◽

2004 ◽

Author(s):

Andrew Karaplis

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Breast Cancer Bone Metastasis

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Biological and Toxicological Evaluation of N-(4methyl-phenyl)-4-methylphthalimide on Bone Cancer in Mice

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190207130732 ◽

2019 ◽

Vol 19 (5) ◽

pp. 667-676

Author(s):

José R. Santin ◽

Gislaine F. da Silva ◽

Maria V.D. Pastor ◽

Milena F. Broering ◽

Roberta Nunes ◽

...

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

In Silico ◽

Bone Matrix ◽

Micronucleus Assay ◽

Repeated Treatment ◽

Toxicological Evaluation ◽

Toxicological Analysis ◽

Breast Cancer Bone Metastasis

Background: It was recently demonstrated that the phthalimide N-(4-methyl-phenyl)-4- methylphthalimide (MPMPH-1) has important effects against acute and chronic pain in mice, with a mechanism of action correlated to adenylyl cyclase inhibition. Furthermore, it was also demonstrated that phthalimide derivatives presented antiproliferative and anti-tumor effects. Considering the literature data, the present study evaluated the effects of MPMPH-1 on breast cancer bone metastasis and correlated painful symptom, and provided additional toxicological information about the compound and its possible metabolites. Methods: In silico toxicological analysis was supported by in vitro and in vivo experiments to demonstrate the anti-tumor and anti-hypersensitivity effects of the compound. Results: The data obtained with the in silico toxicological analysis demonstrated that MPMPH-1 has mutagenic potential, with a low to moderate level of confidence. The mutagenicity potential was in vivo confirmed by micronucleus assay. MPMPH-1 treatments in the breast cancer bone metastasis model were able to prevent the osteoclastic resorption of bone matrix. Regarding cartilage, degradation was considerably reduced within the zoledronic acid group, while in MPMPH-1, chondrocyte multiplication was observed in random areas, suggesting bone regeneration. Additionally, the repeated treatment of mice with MPMPH-1 (10 mg/kg, i.p.), once a day for up to 36 days, significantly reduces the hypersensitivity in animals with breast cancer bone metastasis. Conclusion: Together, the data herein obtained show that MPMPH-1 is relatively safe, and significantly control the cancer growth, allied to the reduction in bone reabsorption and stimulation of bone and cartilage regeneration. MPMPH-1 effects may be linked, at least in part, to the ability of the compound to interfere with adenylylcyclase pathway activation.

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