14 results on '"Diane V. Lefley"'
Search Results
2. IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
- Author
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Claudia Tulotta, Diane V. Lefley, Charlotte K. Moore, Ana E. Amariutei, Amy R. Spicer-Hadlington, Lewis A. Quayle, Russell O. Hughes, Khawla Ahmed, Victoria Cookson, Catherine A. Evans, Jayakumar Vadakekolathu, Paul Heath, Sheila Francis, Emmanuel Pinteaux, A. Graham Pockley, and Penelope D. Ottewell
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Breast 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.
- Published
- 2021
- Full Text
- View/download PDF
3. Oestradiol Contributes to Differential Antitumour Effects of Adjuvant Zoledronic Acid Observed Between Pre- and Post-Menopausal Women
- Author
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Victor G. Canuas-Landero, Christopher N. George, Diane V. Lefley, Hannah Corness, Munitta Muthana, Caroline Wilson, and Penelope D. Ottewell
- Subjects
breast cancer ,zoledronic acid ,oestradiol ,menopause ,bone microenvironment ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
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 in bone; however, while postmenopausal women also incur survival benefit, none is seen in premenopausal women treated with adjuvant bisphosphonates. In the current study, we have used mouse models to investigate the role of oestradiol in modulating potential antitumour effects of Zol. Pre-, peri-, and post-menopausal concentrations of oestradiol were modelled in BALB/c wild-type, BALB/c nude, and C57BL/6 mice by ovariectomy followed by supplementation with oestradiol. Mice also received 40 mg/kg/day goserelin to prevent ovariectomy-induced increases in follicle-stimulating hormone (FSH). Metastasis was modelled following injection of MDA-MB-231, 4T1, or E0771 cells after ovariectomy and saline or 100 μg/kg Zol administered weekly. Supplementing ovariectomised mice with 12.5 mg/ml, 1.38 mg/ml, and 0 ng/ml oestradiol, in the presence of goserelin, resulted in serum concentrations of 153.16 ± 18.10 pg/ml, 48.64 ± 18.44 pg/ml, and 1.00 ± 0.27 pg/ml oestradiol, which are equivalent to concentrations found in pre-, peri-, and post-menopausal humans. Osteoclast activity was increased 1.5–1.8-fold with peri- and post-menopausal compared with premenopausal oestradiol, resulting in a 1.34–1.69-fold reduction in trabecular bone. Zol increased trabecular bone in all groups but did not restore bone to volumes observed under premenopausal conditions. In tumour-bearing mice, Zol reduced bone metastases in BALB/c (wild-type and nude), with greatest effects seen under pre- and post-menopausal concentrations of oestradiol. Zol did not affect soft tissue metastases in immunocompetent BALB/c mice but increased metastases 3.95-fold in C57BL/6 mice under premenopausal concentrations of oestradiol. In contrast, Zol significantly reduced soft tissue metastases 2.07 and 4.69-fold in immunocompetent BALB/c and C57BL/6 mice under postmenopausal oestradiol, mirroring the results of the clinical trials of (neo)adjuvant bisphosphonates. No effects on soft tissue metastases were observed in immunocompromised mice, and differences in antitumour response did not correlate with musculoaponeurotic fibrosarcoma (MAF), macrophage capping protein (CAPG), or PDZ domain containing protein GIPC1 (GIPC1) expression. In conclusion, oestradiol contributes to altered antitumour effects of Zol observed between pre- and post-menopausal women. However, other immunological/microenvironmental factors are also likely to contribute to this phenomenon.
- Published
- 2021
- Full Text
- View/download PDF
4. Erratum to: Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo
- Author
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Ingunn Holen, Jacob Whitworth, Faith Nutter, Alyson Evans, Hannah K. Brown, Diane V. Lefley, Ivana Barbaric, Mark Jones, and Penelope D. Ottewell
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2017
- Full Text
- View/download PDF
5. Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis
- Author
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Jiabao Zhou, Jennifer M. Down, Christopher N. George, Jessica Murphy, Diane V. Lefley, Claudia Tulotta, Marwa A. Alsharif, Michael Leach, and Penelope D. Ottewell
- Subjects
RC0254 ,Cancer Research ,Oncology ,breast cancer ,bone metastasis ,IL1β ,mouse models ,RG - Abstract
Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.
- Published
- 2022
- Full Text
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6. IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
- Author
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Sheila E. Francis, Charlotte K. Moore, Victoria J. Cookson, Diane V. Lefley, Russell Hughes, Paul R. Heath, Catherine A. Evans, Amy R. Spicer-Hadlington, Khawla Ahmed, A. Graham Pockley, Jayakumar Vadakekolathu, Ana E. Amariutei, Penelope D. Ottewell, Emmanuel Pinteaux, Lewis A. Quayle, and Claudia Tulotta
- Subjects
0301 basic medicine ,Combination therapy ,medicine.medical_treatment ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Immune system ,Medicine ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,RC254-282 ,business.industry ,Bone metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell migration ,medicine.disease ,030104 developmental biology ,Zoledronic acid ,Cytokine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Tumour immunology ,business ,medicine.drug - Abstract
Breast 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.
- Published
- 2021
7. Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts
- Author
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Hannah K. Brown, Fawaz Arshad, Diane V. Lefley, Claudia Tulotta, Ingunn Holen, Faith Howard, Rachel Eyre, Steven Bradbury, Penelope D. Ottewell, Robert Clarke, J. Mark Wilkinson, and D Alferez
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Cell Survival ,Biopsy ,Bone Neoplasms ,Breast Neoplasms ,Mice, SCID ,lcsh:RC254-282 ,Bone and Bones ,Immunophenotyping ,Metastasis ,Bone remodeling ,Mice ,03 medical and health sciences ,ER+ ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,In vivo ,Surgical oncology ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,030304 developmental biology ,PDX ,0303 health sciences ,Neovascularization, Pathologic ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Bone metastasis ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunohistochemistry ,3. Good health ,Disease Models, Animal ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Heterografts ,ER− ,Female ,business ,Research Article - 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 breast cancer metastasis to a human bone microenvironment has stunted the development of effective treatments for this condition. To address this problem, we have developed humanised mouse models in which breast cancer patient-derived xenografts (PDXs) metastasise to human bone implants with low variability and high frequency. Methods To model the human bone environment, bone discs from femoral heads of patients undergoing hip replacement surgery were implanted subcutaneously into NOD/SCID mice. For metastasis studies, 7 patient-derived xenograft tumours (PDX: BB3RC32, ER+ PR+ HER2−; BB2RC08, ER+ PR+ ER2−; BB6RC37, ER− PR− HER2− and BB6RC39, ER+ PR+ HER2+), MDA-MB-231-luc2, T47D-luc2 or MCF7-Luc2 cells were injected into the 4th mammary ducts and metastases monitored by luciferase imaging and confirmed on histological sections. Bone integrity, viability and vascularisation were assessed by uCT, calcein uptake and histomorphometry. Expression profiling of genes/proteins during different stages of metastasis were assessed by whole genome Affymetrix array, real-time PCR and immunohistochemistry. Importance of IL-1 was confirmed following anakinra treatment. Results Implantation of femoral bone provided a metabolically active, human-specific site for tumour cells to metastasise to. After 4 weeks, bone implants were re-vascularised and demonstrated active bone remodelling (as evidenced by the presence of osteoclasts, osteoblasts and calcein uptake). Restricting bone implants to the use of subchondral bone and introduction of cancer cells via intraductal injection maximised metastasis to human bone implants. MDA-MB-231 cells specifically metastasised to human bone (70% metastases) whereas T47D, MCF7, BB3RC32, BB2RC08, and BB6RC37 cells metastasised to both human bone and mouse bones. Importantly, human bone was the preferred metastatic site especially from ER+ PDX (100% metastasis human bone compared with 20–75% to mouse bone), whereas ER-ve PDX developed metastases in 20% of human and 20% of mouse bone. Breast cancer cells underwent a series of molecular changes as they progressed from primary tumours to bone metastasis including altered expression of IL-1B, IL-1R1, S100A4, CTSK, SPP1 and RANK. Inhibiting IL-1B signalling significantly reduced bone metastasis. Conclusions Our reliable and clinically relevant humanised mouse models provide significant advancements in modelling of breast cancer bone metastasis.
- Published
- 2019
8. Interactions between oestradiol and zoledronic acid in the bone microenvironment; physiological changes altering metastatic potential of breast cancer cells in pre- and post-menopausal women
- Author
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Victor Canuas-Landero, Diane V. Lefley, Penelope D. Ottewell, Caroline Wilson, and Christopher N. George
- Subjects
Zoledronic acid ,RC925-935 ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cancer research ,Medicine ,Orthopedics and Sports Medicine ,Breast cancer cells ,Diseases of the musculoskeletal system ,business ,Pre and post ,medicine.drug - Published
- 2021
9. Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment
- Author
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J. Mark Wilkinson, Robert E. Coleman, Steven Bradbury, Katy Freeman, Andrew M. Hanby, Penelope D. Ottewell, Ingunn Holen, Amy R. Spicer-Hadlington, Diane V. Lefley, Walter M Gregory, Faith Nutter, Janet E. Brown, Victoria J. Cookson, Gloria Allocca, Claudia Tulotta, Lisa Hambley, Xinming Liu, Paul R. Heath, and Marianna Kruithof-de Julio
- Subjects
0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Stromal cell ,Interleukin-1beta ,Apoptosis ,Bone Neoplasms ,Breast Neoplasms ,Mice, SCID ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Mice, Inbred NOD ,Tumor Cells, Cultured ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Aged ,Cell Proliferation ,Tumor microenvironment ,business.industry ,Bone metastasis ,Middle Aged ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Case-Control Studies ,030220 oncology & carcinogenesis ,Humanized mouse ,Cancer research ,Female ,Bone marrow ,business ,Follow-Up Studies - Abstract
Purpose: Breast cancer bone metastases are incurable, highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL1B by tumor cells drives metastasis and growth in bone. Experimental Design: Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B antibody canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell–derived IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with IL1B/control. Results: In tissue samples from >1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05–3.26; P = 0.02) and other sites (HR = 2.09; 95% CI, 1.26–3.48; P = 0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusions: Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
- Published
- 2019
10. Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics
- Author
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William R. English, Olga Greco, Claudia Coralli-Foxon, Constantino Carlos Reyes-Aldasoro, Diane V. Lefley, Andrew J. Steele, Gabi U. Dachs, Sheila Harris, Gillian M. Tozer, Sofia Santos, and Chryso Kanthou
- Subjects
Vascular Endothelial Growth Factor A ,Cell signaling ,Pathology ,Carcinogenesis ,Fibrosarcoma ,lcsh:Medicine ,Apoptosis ,Signal transduction ,ERK signaling cascade ,Receptor tyrosine kinase ,Mice ,Cell Movement ,Molecular Cell Biology ,Basic Cancer Research ,Medicine and Health Sciences ,Protein Isoforms ,AKT signaling cascade ,Neoplasm Metastasis ,lcsh:Science ,Multidisciplinary ,Cell Death ,biology ,Signaling cascades ,Cell migration ,Extracellular Matrix ,Cell biology ,Gene Expression Regulation, Neoplastic ,STAT signaling ,Oncology ,TA ,Cell Processes ,Cellular Structures and Organelles ,Tyrosine kinase ,Research Article ,Gene isoform ,medicine.medical_specialty ,Cell Survival ,Integrin ,Cell Growth ,RC0254 ,Cell Line, Tumor ,Cell Adhesion ,medicine ,Animals ,Cell Proliferation ,Biology and life sciences ,Mesenchymal stem cell ,lcsh:R ,Receptors, Vascular Endothelial Growth Factor ,Cell culture ,Cancer cell ,biology.protein ,lcsh:Q - Abstract
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 in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120) on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188) or wild type controls (fswt) were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively) were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine kinase receptor activation. VEGF isoforms are emerging as potential biomarkers for anti-VEGF therapies. Our results reveal novel roles of individual isoforms associated with cancer growth and metastasis and highlight the importance of understanding their diverse actions.
- Published
- 2014
11. Mechanisms of apoptosis and cell-cycle arrest in subcutaneous breast tumours treated sequentially with doxorubicin followed by zoledronic acid
- Author
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Ingunn Holen, Penelope D. Ottewell, Robert E. Coleman, and Diane V. Lefley
- Subjects
business.industry ,Cell growth ,Pharmacology ,medicine.disease ,Metastasis ,Zoledronic acid ,Breast cancer ,In vivo ,Surgical oncology ,Apoptosis ,Poster Presentation ,medicine ,Doxorubicin ,business ,medicine.drug - Abstract
Breast cancer patients commonly receive a combination of different therapies; for patients with late-stage breast cancer involving metastasis to the bone, a chemotherapeutic agent is usually given in combination with the antiresorptive drug zoledronic acid (zol) (Novartis Pharma, Basel, Switzerland). We have previously reported that administration of doxorubicin (dox) (Pharachemie BV, Haarlem, The Netherlands) 24 hours prior to zol inhibits subcutaneous breast tumour growth, inhibits tumour cell proliferation and increases apoptosis in vivo. The aims of the present study were to determine the mechanisms by which dox and zol exert their synergistic antitumour effects.
- Published
- 2008
12. Erratum to: Loss of plakoglobin promotes cell-cell contact, increased invasion and breast cancer cell dissemination in vivo
- Author
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Jacob Whitworth, Penelope D. Ottewell, Alyson Evans, Ingunn Holen, Faith Nutter, Diane V. Lefley, Ivana Barbaric, Mark Jones, and Hannah K. Brown
- Subjects
Oncology ,Medicine(all) ,medicine.medical_specialty ,Cell cell contact ,business.industry ,Plakoglobin ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Surgical oncology ,In vivo ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Breast cancer cells ,business - Full Text
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13. Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling
- Author
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Mick D. Brown, Penelope D. Ottewell, Bruno M Simões, Austin Gurney, Robert Clarke, Diane V. Lefley, James C. McConnell, Andrew H. Sims, Kath Spence, Gillian Farnie, Sacha J Howell, Noel W. Clarke, Claudia Tulotta, Joanna Storer, Angélica Santiago-Gómez, Claire A Hart, Rachel Eyre, and D Alferez
- Subjects
0301 basic medicine ,Interleukin-1beta ,General Physics and Astronomy ,Mice, SCID ,Metastasis ,Breast cancer ,0302 clinical medicine ,Mice, Inbred NOD ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Microenvironment ,Medicine ,lcsh:Science ,Wnt Signaling Pathway ,Mice, Knockout ,Mice, Inbred BALB C ,Multidisciplinary ,Manchester Cancer Research Centre ,Cancer stem cells ,Bone metastasis ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Neoplastic Stem Cells ,Female ,Stem cell ,Science ,Mice, Nude ,Bone Neoplasms ,Breast Neoplasms ,Article ,General Biochemistry, Genetics and Molecular Biology ,Wnt ,03 medical and health sciences ,breast cancer ,stem cells ,Cancer stem cell ,Cell Line, Tumor ,Adjuvant therapy ,Animals ,Humans ,metastasis ,Autocrine signalling ,business.industry ,Bone metastases ,ResearchInstitutes_Networks_Beacons/mcrc ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,Sulfasalazine ,HEK293 Cells ,030104 developmental biology ,Cancer research ,lcsh:Q ,Bone marrow ,IL1beta ,business - 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., In breast cancer, dormant cancer cells may develop into bone metastases. Here, the authors demonstrate that microenvironmental IL1β stimulates metastatic breast cancer cell colonisation in the bone via IL1β-NFKB/CREB-Wnt pathway activation and cancer stem cell colony formation
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- View/download PDF
14. Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics.
- Author
-
Chryso Kanthou, Gabi U Dachs, Diane V Lefley, Andrew J Steele, Claudia Coralli-Foxon, Sheila Harris, Olga Greco, Sofia A Dos Santos, Constantino C Reyes-Aldasoro, William R English, and Gillian M Tozer
- Subjects
Medicine ,Science - Abstract
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 in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120) on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188) or wild type controls (fswt) were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively) were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine kinase receptor activation. VEGF isoforms are emerging as potential biomarkers for anti-VEGF therapies. Our results reveal novel roles of individual isoforms associated with cancer growth and metastasis and highlight the importance of understanding their diverse actions.
- Published
- 2014
- Full Text
- View/download PDF
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