A5049349662- Bone health and treatments
- Cancer Cells and Metastasis
- Inflammatory mediators and NSAID effects
- Cytokine Signaling Pathways and Interactions
- Bone Metabolism and Diseases
- Angiogenesis and VEGF in Cancer
- Radiopharmaceutical Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Sarcoma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- TGF-β signaling in diseases
- Periodontal Regeneration and Treatments
- Cervical Cancer and HPV Research
- Cancer Research and Treatments
- Bone and Joint Diseases
- Wnt/β-catenin signaling in development and cancer
- Estrogen and related hormone effects
- Cancer, Lipids, and Metabolism
- Prostate Cancer Treatment and Research
- bioluminescence and chemiluminescence research
- Vascular Tumors and Angiosarcomas
- Chemokine receptors and signaling
- Lung Cancer Treatments and Mutations
- Hippo pathway signaling and YAP/TAZ
University of Sheffield
2012-2024
Weston Park Cancer Centre
2021
University of Eastern Finland
2008
We have recently identified interleukin 1B (IL-1B) as a potential biomarker for predicting breast cancer patients at increased risk developing bone metastasis. In mouse models, IL-1B and its receptor (IL-1R1) are upregulated in cells that metastasise to compared with do not. now investigated the functional role of IL-1 by blocking IL-1R signalling clinically licensed antagonist, anakinra.6-week old female BALB/c mice received subcutaneous or intra-venous injection MDA-MB-231-IV MCF7 cells....
Abstract Purpose: Breast cancer bone metastases are incurable, highlighting the need for new therapeutic targets. After colonizing bone, breast cells remain dormant, until signals from microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL1B by tumor drives metastasis and growth in bone. Experimental Design: Tumor/stromal IL1 receptor 1 (IL1R1) expression was assessed patient samples effects IL1R antagonist, Anakinra, or antibody canakinumab...
The potent antiresorptive drug zoledronic acid (Zol) enhances the antitumor effects of chemotherapy agents in vitro. We investigated clinically achievable doses doxorubicin (Dox) and Zol, given alone, sequence, combination, on growth established breast tumors vivo. Female MF1 nude mice were inoculated subcutaneously with 5 × 10 human cancer MDA-MB-436 cells that stably expressed green fluorescent protein (ie, MDA-G8 cells). Beginning day 7 after tumor cell injection, injected weekly for 6...
Abstract Dissemination of tumour cells to the bone marrow is an early event in breast cancer, however may lie dormant for many years before metastases develop. Treatment not curative, therefore new adjuvant therapies which prevent colonisation disseminated into metastatic lesions are required. There evidence that cancer stem (CSCs) within tumours capable metastasis, but mechanism by these colonise unknown. Here, we establish marrow-derived IL1β stimulates cell inducing intracellular NFkB and...
Abstract Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast develop disease recurrence in and available treatments are only palliative. We have previously shown that production the pro-inflammatory cytokine interleukin-1B (IL-1B) by cells drives preclinical vivo models. In current study, we investigated how IL-1B from tumour microenvironment interact to affect primary growth through regulation immune system, whether targeting IL-1 driven changes...
Patients with advanced breast cancer frequently develop bone metastases, and at this stage, the disease is considered incurable. Here, we show that a 6-week course of weekly administration doxorubicin (2 mg/kg), followed 24 hours later by bisphosphonate zoledronic acid (100microg/kg), causes substantial inhibition MDA-MB-436 tumor burden in immunocompromised mice, compared single agents. Molecular analysis tumors from animals treated sequentially showed reduced numbers proliferating cells...
Combination therapy, using agents that target the microenvironment as well cancer cells, is common in treatment of advanced breast cancer. Here, we show a 6-week course weekly sequential administration cytotoxic drug doxorubicin (2 mg/kg), followed 24 hr later by antiresorptive agent zoledronic acid (100 microg/kg), causes substantial inhibition subcutaneous MDA-MB-436 tumor growth immunocompromised mice, leading to significantly increased survival. Tumor did not resume following withdrawal...
Abstract Background Late-stage breast cancer preferentially metastasises to bone; despite advances in targeted therapies, this condition remains incurable. The lack of clinically relevant models for studying metastasis a human bone microenvironment has stunted the development effective treatments condition. To address problem, we have developed humanised mouse which patient-derived xenografts (PDXs) metastasise implants with low variability and high frequency. Methods model environment,...
Bisphosphonates (BPs) are effective inhibitors of tumor-induced bone resorption. Recent studies have demonstrated that BPs inhibit growth, attachment and invasion cancer cells in culture promote apoptosis. The mechanisms responsible for the observed anti-tumor effects beginning to be elucidated. Recently, we reported nitrogen-containing bisphosphonates (N-BPs) induce formation a novel ATP analog (ApppI) as consequence inhibition farnesyl diphosphate synthase mevalonate pathway. Similar...
Abstract Introduction The majority of deaths from breast cancer are a result metastases; however, little is understood about the genetic alterations underlying their onset. Genetic profiling has identified adhesion molecule plakoglobin as being three-fold reduced in expression primary tumors that have metastasized compared with nonmetastatic tumors. In this study, we demonstrate functional role for shedding tumor cells site into circulation. Methods We investigated effects knockdown on cell...
<i>Background/Aims:</i> The cytotoxic agent paclitaxel and the anti-resorptive drug zoledronic acid are used in early advanced breast cancer setting, respectively. Both agents have been demonstrated to anti-tumour anti-endothelial actions. Combining with induces a synergistic increase apoptotic cell death vitro, suggesting an increased effect vivo, but any specific effects on normal microvasculature potential side-effects of this combination remain be established....
Abstract Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel improved response to treatment the anti-VEGFA antibody bevacizumab. To uncover underlying mechanism these observations, we administered therapy mice bearing luminescent mouse fibrosarcomas expressing single or their wild-type counterparts all (fs120, fs164, fs188, fsWT). Expression more conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT);...
Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms OI. Previous reports have indicated that administration TGFβ-targeted antibodies maybe potential therapeutic benefit to OI patients. However, direct targeting TGFβ likely cause multiple adverse effects including simulation autoimmunity. In the current study we use patient-derived normal fibroblasts, osteoblasts OIM mouse models determine Losartan, an angiotensin II receptor...
Vascular endothelial growth factor-A (VEGF) is produced by most cancer cells as multiple isoforms, which display distinct biological activities. VEGF plays an undisputed role in tumour growth, vascularisation and metastasis; nevertheless the functions of individual isoforms these processes remain poorly understood. We investigated effects three main murine (VEGF188, 164 120) on cell behaviour, using a panel fibrosarcoma we developed that express them individually under endogenous promoter...
Antiangiogenic therapy based on blocking the actions of vascular endothelial growth factor-A (VEGF) can lead to "normalization" blood vessels in both animal and human tumors. Differential expression VEGF isoforms affects tumor maturity, which could influence normalization process response subsequent treatment. Fibrosarcoma cells expressing only VEGF120 or VEGF188 were implanted either subcutaneously (s.c.) dorsal skin-fold "window" chambers SCID mice. was associated with fragility...
Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or IL1β antibody, Canakinumab, prevents and almost eliminates breast growth in bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of pathway (Caspase-1, IRAK1) could reduce metastases without increasing outside Inhibition via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1...
Clinical trials have demonstrated that adding zoledronic acid (Zol) to (neo)adjuvant standard of care has differential antitumour effects in pre- and post-menopausal women: Both benefit from reduced recurrence bone; however, while postmenopausal women also incur survival benefit, none is seen premenopausal treated with adjuvant bisphosphonates. In the current study, we used mouse models investigate role oestradiol modulating potential Zol. Pre-, peri-, concentrations were modelled BALB/c...
Abstract Background Murine fibrosarcoma cell lines that express single VEGF isoforms (VEGF120 VEGF165 and VEGF188) a wild-type control (VEGFWT) have been developed. The most extreme differences in vascular properties are observed between VEGF120 VEGF188 tumors, with tumors developing more immature vessels. These impact on therapeutic outcome. We hypothesised differential signaling through receptors 1 2 underlie the isoform-specific differences. Methods VEGFWT, VEGF164 were implanted...
Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)
Abstract We aimed to determine the influence of differential tumor cell expression vascular endothelial growth factor A (VEGF) isoforms on lung metastasis and response radiotherapy. hypothesized that other adaptations microenvironment, in individual VEGF isoforms, would impact progression treatment response. Mouse fibrosarcoma cells exclusively express either VEGF120, 164 or 188 (fs120, fs164 fs188 respectively) expressing all three (fsWT) were grown as sub-cutaneous implants SCID mice....
Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)