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Article ; Online: A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

Smith, Tim A D / West, Catharine M L / Joseph, Nuradh / Lane, Brian / Irlam-Jones, Joely / More, Elisabet / Mistry, Hitesh / Reeves, Kimberley J / Song, Yee Pei / Reardon, Mark / Hoskin, Peter J / Hussain, Syed A / Denley, Helen / Hall, Emma / Porta, Nuria / Huddart, Robert A / James, Nick D / Choudhury, Ananya

EBioMedicine

2024 Volume 101, Page(s) 105032

Abstract: Background: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature ... ...

Abstract	Background: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. Methods: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). Primary endpoint: invasive loco-regional control (ILRC); secondary overall survival. Findings: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. Interpretation: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. Funding: Cancer Research UK, NIHR, MRC.
MeSH term(s)	Humans ; Disease-Free Survival ; Dose Fractionation, Radiation ; Hypoxia ; Mitomycin ; Biomarkers ; Treatment Outcome
Chemical Substances	Mitomycin (50SG953SK6) ; Biomarkers
Language	English
Publishing date	2024-02-21
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2024.105032
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Article ; Online: Comparison of multiple gene expression platforms for measuring a bladder cancer hypoxia signature.

Smith, Tim A D / Lane, Brian / More, Elisabet / Valentine, Helen / Lunj, Sapna / Abdelkarem, Omneya A / Irlam-Jones, J / Shabbir, Rekaya / Vora, Shrushti / Denley, Helen / Reeves, Kimberley J / Hoskin, Peter J / Choudhury, Ananya / West, Catharine M L

Molecular medicine reports

2022 Volume 26, Issue 2

Abstract: Tumour hypoxia status provides prognostic information and predicts response to hypoxia‑modifying treatments. A previous study by our group derived a 24‑gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to ... ...

Abstract	Tumour hypoxia status provides prognostic information and predicts response to hypoxia‑modifying treatments. A previous study by our group derived a 24‑gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to compare platforms for generating signature scores, identify cut‑off values for prospective studies, assess intra‑tumour heterogeneity and confirm hypoxia relevance. Briefly, RNA was extracted from prospectively collected diagnostic biopsies of muscle invasive bladder cancer (51 patients), and gene expression was measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Cross‑platform transferability of the gene signature was assessed using regression and concordance analysis. The cut‑off values were the cohort median expression values. Intra‑ and inter‑tumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks (2‑18) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24 h), and extracted RNA was run on custom TLDA cards. Hypoxia scores (HS) values showed good agreement between platforms: Clariom S vs. TLDA (r=0.72, P<0.0001; concordance 73%); Clariom S vs. NanoString (r=0.84, P<0.0001; 78%); TLDA vs. NanoString (r=0.80, P<0.0001; 78%). Cut‑off values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (Clariom S). Intra‑tumour heterogeneity in gene expression and HS (coefficient of variation 3.9%) was less than inter‑tumour (7.9%) variability. HS values were higher in bladder cancer cells exposed to hypoxia compared with normoxia (P<0.02). In conclusion, the present study revealed that application of the 24‑gene bladder cancer hypoxia signature was platform agnostic, cut‑off values determined prospectively can be used in a clinical trial, intra‑tumour heterogeneity was low and the signature was sensitive to changes in oxygen levels
MeSH term(s)	Biomarkers, Tumor/genetics ; Gene Expression ; Gene Expression Profiling ; Humans ; Hypoxia/genetics ; Oxygen ; Prospective Studies ; RNA ; Retrospective Studies ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology
Chemical Substances	Biomarkers, Tumor ; RNA (63231-63-0) ; Oxygen (S88TT14065)
Language	English
Publishing date	2022-06-22
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2469505-1
ISSN	1791-3004 ; 1791-2997
ISSN (online)	1791-3004
ISSN	1791-2997
DOI	10.3892/mmr.2022.12777
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Article ; Online: Outcomes of radiosensitisation in elderly patients with advanced bladder cancer.

Christodoulou, Marianna / Reeves, Kimberley J / Hodgson, Clare / Zeniou, Anthi / Slevin, Finbar / Kennedy, Jason / Hoskin, Peter J / Henry, Ann / Choudhury, Ananya

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2018 Volume 129, Issue 3, Page(s) 499–506

Abstract: Introduction: There is little evidence to guide treatment in elderly patients with muscle invasive bladder cancer (MIBC). We evaluated the efficacy and tolerability of concurrent radical radiotherapy with gemcitabine radiosensitisation (GemX) in elderly ...

Abstract	Introduction: There is little evidence to guide treatment in elderly patients with muscle invasive bladder cancer (MIBC). We evaluated the efficacy and tolerability of concurrent radical radiotherapy with gemcitabine radiosensitisation (GemX) in elderly patients with MIBC and compared outcomes to those from the bladder carbogen and nicotinamide (BCON) phase III trial. Materials and methods: Data were retrospectively analysed for patients who received GemX from two oncology centres in the UK. Elderly was defined as aged ≥75 at the start of GemX. Following transurethral resection of bladder tumour, patients received neo-adjuvant platinum-based chemotherapy followed by radiotherapy concurrently with weekly gemcitabine. A separate, age-specific analysis was performed in the BCON cohort. Overall survival (OS), disease specific survival (DSS) and local progression free survival (LPFS) were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression. Results: Out of 167 patients who received GemX, 61 were elderly (36.5%) with a median age of 78 years. Elderly patients had worse performance status (p = 0.020) and co-morbidities (p = 0.030). A similar proportion of patients received planned dose radiotherapy in both groups (p = 0.260), although fewer elderly patients received all four cycles of concurrent chemotherapy (p = 0.017) due to toxicity. For OS, age had some prognostic power; HR 1.04 (95% CI 1.00-1.08; p = 0.068). Overall survival and LPFS in elderly patients were comparable between CON and GemX (HR 1.13, 95% CI 0.69-1.85; p = 0.616 and HR 0.85, 95% CI 0.41-1.74; p = 0.659 respectively). Discussion: Radiosensitisation is safe and effective and should be considered for fit elderly patients with MIBC.
MeSH term(s)	Aged ; Aged, 80 and over ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/therapeutic use ; Female ; Humans ; Male ; Radiation-Sensitizing Agents/therapeutic use ; Retrospective Studies ; Treatment Outcome ; Urinary Bladder Neoplasms/mortality ; Urinary Bladder Neoplasms/radiotherapy
Chemical Substances	Radiation-Sensitizing Agents ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R)
Language	English
Publishing date	2018-06-02
Publishing country	Ireland
Document type	Clinical Trial, Phase III ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2018.05.022
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Article ; Online: Vascular smooth muscle cell stiffness and adhesion to collagen I modified by vasoactive agonists.

Hong, Zhongkui / Reeves, Kimberley J / Sun, Zhe / Li, Zhaohui / Brown, Nicola J / Meininger, Gerald A

PloS one

2015 Volume 10, Issue 3, Page(s) e0119533

Abstract: In vascular smooth muscle cells (VSMCs) integrin-mediated adhesion to extracellular matrix (ECM) proteins play important roles in sustaining vascular tone and resistance. The main goal of this study was to determine whether VSMCs adhesion to type I ... ...

Abstract	In vascular smooth muscle cells (VSMCs) integrin-mediated adhesion to extracellular matrix (ECM) proteins play important roles in sustaining vascular tone and resistance. The main goal of this study was to determine whether VSMCs adhesion to type I collagen (COL-I) was altered in parallel with the changes in the VSMCs contractile state induced by vasoconstrictors and vasodilators. VSMCs were isolated from rat cremaster skeletal muscle arterioles and maintained in primary culture without passage. Cell adhesion and cell E-modulus were assessed using atomic force microscopy (AFM) by repetitive nano-indentation of the AFM probe on the cell surface at 0.1 Hz sampling frequency and 3200 nm Z-piezo travelling distance (approach and retraction). AFM probes were tipped with a 5 μm diameter microbead functionalized with COL-I (1 mg\ml). Results showed that the vasoconstrictor angiotensin II (ANG-II; 10-6) significantly increased (p<0.05) VSMC E-modulus and adhesion probability to COL-I by approximately 35% and 33%, respectively. In contrast, the vasodilator adenosine (ADO; 10-4) significantly decreased (p<0.05) VSMC E-modulus and adhesion probability by approximately -33% and -17%, respectively. Similarly, the NO donor (PANOate, 10-6 M), a potent vasodilator, also significantly decreased (p<0.05) the VSMC E-modulus and COL-I adhesion probability by -38% and -35%, respectively. These observations support the hypothesis that integrin-mediated VSMC adhesion to the ECM protein COL-I is dynamically regulated in parallel with VSMC contractile activation. These data suggest that the signal transduction pathways modulating VSMC contractile activation and relaxation, in addition to ECM adhesion, interact during regulation of contractile state.
MeSH term(s)	Angiotensin II/pharmacology ; Animals ; Cell Adhesion ; Collagen Type I/metabolism ; Male ; Microscopy, Atomic Force ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Nitric Oxide Donors/pharmacology ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Collagen Type I ; Nitric Oxide Donors ; Angiotensin II (11128-99-7)
Language	English
Publishing date	2015-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0119533
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Article ; Online: Is nitric oxide important in photodynamic therapy?

Reeves, Kimberley J / Reed, Malcolm W R / Brown, Nicola J

Journal of photochemistry and photobiology. B, Biology

2009 Volume 95, Issue 3, Page(s) 141–147

Abstract: Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light and oxygen to destroy abnormal tissue. The transfer of energy from the activated photosensitizer to available oxygen ...

Abstract	Photodynamic therapy (PDT) involves the use of photochemical reactions mediated through the interaction of photosensitizing agents, light and oxygen to destroy abnormal tissue. The transfer of energy from the activated photosensitizer to available oxygen results in the formation of toxic reactive oxygen species, such as singlet oxygen and free radicals, which can damage proteins, lipids, nucleic acids, and other cellular components. PDT is now commonly used in ophthalmology, dermatology and oncology however the therapeutic response to PDT exhibits variability, ranging from highly sensitive to extremely resistant. Over the last 10 years it has been suggested that nitric oxide (NO) may play a role in PDT, with evidence that NO is produced by both tumour and normal cells in addition to controlling important functions in tumour progression. NO may also influence the outcome of cancer therapies, such as PDT. PDT induces oxidative stress, vascular-mediated damage and leukocyte recruitment, processes all sensitive to NO. This review outlines the role of nitric oxide in PDT primarily focusing on vascular damage and how this may be modulated to improve therapeutic outcome.
MeSH term(s)	Neoplasms/metabolism ; Neoplasms/radiotherapy ; Nitric Oxide/metabolism ; Photochemotherapy ; Photosensitizing Agents/therapeutic use
Chemical Substances	Photosensitizing Agents ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2009-06-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	623022-2
ISSN	1873-2682 ; 1011-1344
ISSN (online)	1873-2682
ISSN	1011-1344
DOI	10.1016/j.jphotobiol.2009.02.005
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Article ; Online: Evaluation of fluorescent plasma markers for in vivo microscopy of the microcirculation.

Reeves, Kimberley J / Brookes, Zoë L S / Reed, Malcolm W R / Brown, Nicola J

Journal of vascular research

2012 Volume 49, Issue 2, Page(s) 132–143

Abstract: This study evaluated four fluorescent-protein conjugates to monitor microcirculatory variables using the murine cremaster muscle and determined acute and long-term responses to repeated administration of FITC-BSA [conjugated at the University of ... ...

Abstract	This study evaluated four fluorescent-protein conjugates to monitor microcirculatory variables using the murine cremaster muscle and determined acute and long-term responses to repeated administration of FITC-BSA [conjugated at the University of Sheffield (UoS)] within a dorsal microcirculatory chamber (DMC) in rats. For analysis of the cremaster muscle, male C3H/HeN mice were anaesthetized, the cremaster muscle was exteriorized, then TRITC-BSA, TRITC-dextran, FITC-BSA, FITC-BSA (UoS) or FITC-dextran (0.25 ml/100 g) were administered systemically. The microcirculation was viewed with epi-illumination every 10 min for 120 min. For analysis of the DMC, male Wistar rats were implanted with the chamber. Three weeks later, FITC-BSA (UoS) was administered systemically, and the microcirculation response was monitored using three different protocols. In addition, in vitro stability of fluorescent conjugates was measured over 8 h. With regard to the cremaster muscle, initially no differences in interstitial fluorescence or vessel diameter were observed between the four fluorescent conjugates. By the end of the study, interstitial fluorescence from TRITC-dextran, FITC-dextran and FITC-BSA (Sigma) was significantly (p < 0.05) increased compared to FITC-BSA (UoS). With regard to the DMC, there was no interstitial fluorescence leakage after 180 min or 5 weeks despite repeated administration, but a significant (p < 0.05) leak was detected between 4 and 24 h. FITC-BSA (UoS) was the most stable fluorescent conjugate both in vitro and in vivo and was comparable with other conjugates for evaluating skeletal muscle microcirculation using fluorescent in vivo microscopy.
MeSH term(s)	Animals ; Dextrans ; Fluorescein-5-isothiocyanate/analogs & derivatives ; Male ; Mice ; Mice, Inbred C3H ; Microcirculation/physiology ; Microscopy, Fluorescence/methods ; Muscle, Skeletal/blood supply ; Rats ; Rats, Wistar ; Rhodamines ; Serum Albumin, Bovine
Chemical Substances	Dextrans ; Rhodamines ; fluorescein isothiocyanate bovine serum albumin ; fluorescein isothiocyanate dextran ; Serum Albumin, Bovine (27432CM55Q) ; tetramethylrhodamine isothiocyanate (4158-89-8) ; Fluorescein-5-isothiocyanate (I223NX31W9)
Language	English
Publishing date	2012
Publishing country	Switzerland
Document type	Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1105259-4
ISSN	1423-0135 ; 1018-1172
ISSN (online)	1423-0135
ISSN	1018-1172
DOI	10.1159/000331281
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Zs.A 513: Show issues

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Article ; Online: Selective measurement and manipulation of adhesion forces between cancer cells and bone marrow endothelial cells using atomic force microscopy.

Reeves, Kimberley J / Hou, Jia / Higham, Susan E / Sun, Zhe / Trzeciakowski, Jerome P / Meininger, Gerald A / Brown, Nicola J

Nanomedicine (London, England)

2013 Volume 8, Issue 6, Page(s) 921–934

Abstract: Aims: The lack of understanding of the biology of bone cancer metastasis has limited the development of effective treatment strategies. The aim of this study was to characterize tumor cell adhesion molecules and determine active tumor cell interactions ... ...

Abstract	Aims: The lack of understanding of the biology of bone cancer metastasis has limited the development of effective treatment strategies. The aim of this study was to characterize tumor cell adhesion molecules and determine active tumor cell interactions with human bone marrow endothelial (BME) cells using atomic force microscopy. Materials & methods: A single prostate (PC3) cancer cell was coupled (concanavalin A) to the atomic force microscopy cantilever then placed in contact with BME cells for cell force spectroscopy measurements. Results & discussion: Strong adhesive interactions between PC3 and BME cells were significantly (p < 0.05) reduced by anti-ICAM-1, anti-β1 and anti-P-selectin, but not anti-VCAM-1. The combined blocking antibodies or the therapeutic agent zoledronic acid significantly (p < 0.005) reduced the adhesive interactions by 65 and 63%, respectively, which was confirmed using a functional in vitro assay. Conclusion: Atomic force microscopy provides a highly sensitive screening assay to determine and quantify nanoscale adhesion events between different cell types important in the metastatic cascade.
MeSH term(s)	Bone Marrow Cells/cytology ; Cell Adhesion ; Cell Adhesion Molecules/analysis ; Cell Adhesion Molecules/immunology ; Cell Movement ; Elasticity ; Endothelial Cells/cytology ; Humans ; Integrin beta1/analysis ; Integrin beta1/immunology ; Intercellular Adhesion Molecule-1/analysis ; Intercellular Adhesion Molecule-1/immunology ; Male ; Microscopy, Atomic Force ; P-Selectin/analysis ; P-Selectin/immunology ; Prostate/immunology ; Prostate/pathology ; Prostatic Neoplasms/immunology ; Prostatic Neoplasms/pathology ; Vascular Cell Adhesion Molecule-1/analysis ; Vascular Cell Adhesion Molecule-1/immunology
Chemical Substances	Cell Adhesion Molecules ; Integrin beta1 ; P-Selectin ; Vascular Cell Adhesion Molecule-1 ; Intercellular Adhesion Molecule-1 (126547-89-5)
Language	English
Publishing date	2013-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2277839-1
ISSN	1748-6963 ; 1743-5889
ISSN (online)	1748-6963
ISSN	1743-5889
DOI	10.2217/nnm.12.139
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Zs.A 6617: Show issues

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Article: Evaluation of Fluorescent Plasma Markers for in vivo Microscopy of the Microcirculation

Reeves, Kimberley J. / Brookes, Zoë L.S. / Reed, Malcolm W.R. / Brown, Nicola J.

Journal of Vascular Research

2012 Volume 49, Issue 2, Page(s) 132–143

Institution	Microcirculation Research Group, Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Sheffield, UK
Abstract	This study evaluated four fluorescent-protein conjugates to monitor microcirculatory variables using the murine cremaster muscle and determined acute and long-term responses to repeated administration of FITC-BSA [conjugated at the University of Sheffield (UoS)] within a dorsal microcirculatory chamber (DMC) in rats. For analysis of the cremaster muscle, male C3H/HeN mice were anaesthetized, the cremaster muscle was exteriorized, then TRITC-BSA, TRITC-dextran, FITC-BSA, FITC-BSA (UoS) or FITC-dextran (0.25 ml/100 g) were administered systemically. The microcirculation was viewed with epi-illumination every 10 min for 120 min. For analysis of the DMC, male Wistar rats were implanted with the chamber. Three weeks later, FITC-BSA (UoS) was administered systemically, and the microcirculation response was monitored using three different protocols. In addition, in vitro stability of fluorescent conjugates was measured over 8 h. With regard to the cremaster muscle, initially no differences in interstitial fluorescence or vessel diameter were observed between the four fluorescent conjugates. By the end of the study, interstitial fluorescence from TRITC-dextran, FITC-dextran and FITC-BSA (Sigma) was significantly (p < 0.05) increased compared to FITC-BSA (UoS). With regard to the DMC, there was no interstitial fluorescence leakage after 180 min or 5 weeks despite repeated administration, but a significant (p < 0.05) leak was detected between 4 and 24 h. FITC-BSA (UoS) was the most stable fluorescent conjugate both in vitroand in vivo and was comparable with other conjugates for evaluating skeletal muscle microcirculation using fluorescent in vivo microscopy.
Keywords	Fluorochrome ; Macromolecular leak ; Fluorescent-protein conjugate ; In vivo microscopy ; Dorsal microcirculatory chamber ; Endothelial integrity ; Microcirculation
Language	English
Publishing date	2012-01-18
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Research Paper
ZDB-ID	1105259-4
ISSN	1423-0135 ; 1018-1172
ISSN (online)	1423-0135
ISSN	1018-1172
DOI	10.1159/000331281
Database	Karger publisher's database

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Article ; Online: The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer.

Wang, Ning / Reeves, Kimberley J / Brown, Hannah K / Fowles, Anne C M / Docherty, Freyja E / Ottewell, Penelope D / Croucher, Peter I / Holen, Ingunn / Eaton, Colby L

Journal of experimental & clinical cancer research : CR

2015 Volume 34, Page(s) 124

Abstract: Background: While both preclinical and clinical studies suggest that the frequency of growing skeletal metastases is elevated in individuals with higher bone turnover, it is unclear whether this is a result of increased numbers of tumour cells arriving ... ...

Abstract	Background: While both preclinical and clinical studies suggest that the frequency of growing skeletal metastases is elevated in individuals with higher bone turnover, it is unclear whether this is a result of increased numbers of tumour cells arriving in active sites or of higher numbers of tumour cells being induced to divide by the bone micro-environment. Here we have investigated how the differences in bone turnover affect seeding of tumour cells and/or development of overt osteolytic bone metastasis using in vivo models of hormone-independent breast and prostate cancer. Methods: Cohorts of 6 (young) and 16 (mature)-week old BALB/c nude mice were culled 1, 7 and 21 days after received intracardiac injection of luciferase expressing human prostate (PC3) or breast cancer (MDA-MB-231) cell lines labelled with a fluorescent cell membrane dye (Vybrant DiD). The presence of growing bone metastases was determined by bioluminescence using an in vivo imaging system (IVIS) and followed by anatomical confirmation of tumour metastatic sites post mortem, while the presence of individual fluorescently labelled tumour cells was evaluated using two-photon microscopy ex vivo. The bone remodelling activities were compared between young and mature naïve mice (both male and female) using micro-CT analysis, ELISA and bone histomorphometry. Results: Both prostate and breast cancer cells generated higher numbers of overt skeletal lesions in young mice (~80%) than in mature mice (~20%). Although mature mice presented with fewer overt bone metastases, the number of tumour cells arriving/colonizing in the tibias was comparable between young and mature animals. Young naïve mice had lower bone volume but higher bone formation and resorption activities compared to mature animals. Conclusions: Our studies suggest that higher frequencies of growing osteolytic skeletal metastases in these models are linked to increased bone turnover and not to the initial number of tumour cells entering the bone microenvironment.
MeSH term(s)	Animals ; Bone Neoplasms/pathology ; Bone Neoplasms/secondary ; Breast Neoplasms/pathology ; Cell Count ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Neoplastic Cells, Circulating/pathology ; Osteolysis/pathology ; Prostatic Neoplasms/pathology ; Transplantation, Heterologous
Language	English
Publishing date	2015-10-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-015-0240-8
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Article ; Online: Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models.

Wang, Ning / Docherty, Freyja E / Brown, Hannah K / Reeves, Kimberley J / Fowles, Anne C M / Ottewell, Penelope D / Dear, T Neil / Holen, Ingunn / Croucher, Peter I / Eaton, Colby L

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2014 Volume 29, Issue 12, Page(s) 2688–2696

Abstract: It has been suggested that metastasis-initiating cells gain a foothold in bone by homing to a metastastatic microenvironment (or "niche"). Whereas the precise nature of this niche remains to be established, it is likely to contain bone cell populations ... ...

Abstract	It has been suggested that metastasis-initiating cells gain a foothold in bone by homing to a metastastatic microenvironment (or "niche"). Whereas the precise nature of this niche remains to be established, it is likely to contain bone cell populations including osteoblasts and osteoclasts. In the mouse tibia, the distribution of osteoblasts on endocortical bone surfaces is non-uniform, and we hypothesize that studying co-localization of individual tumor cells with resident cell populations will reveal the identity of critical cellular components of the niche. In this study, we have mapped the distribution of three human prostate cancer cell lines (PC3-NW1, LN-CaP, and C4 2B4) colonizing the tibiae of athymic mice following intracardiac injection and evaluated their interaction with potential metastatic niches. Prostate cancer cells labeled with the fluorescent cell membrane dye (Vybrant DiD) were found by two-photon microscopy to be engrafted in the tibiae in close proximity (∼40 µm) to bone surfaces and 70% more cancer cells were detected in the lateral compared to the medial endocortical bone regions. This was associated with a 5-fold higher number of osteoblasts and 7-fold higher bone formation rate on the lateral endocortical bone surface compared to the medial side. By disrupting cellular interactions mediated by the chemokine (C-X-C motif) receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis with the CXCR4 inhibitor AMD3100, the preferential homing pattern of prostate cancer cells to osteoblast-rich bone surfaces was disrupted. In this study, we map the location of prostate cancer cells that home to endocortical regions in bone and our data demonstrate that homing of prostate cancer cells is associated with the presence and activity of osteoblast lineage cells, and suggest that therapies targeting osteoblast niches should be considered to prevent development of incurable prostate cancer bone metastases.
MeSH term(s)	Animals ; Bone Neoplasms/metabolism ; Bone Neoplasms/pathology ; Bone Neoplasms/secondary ; Cell Line, Tumor ; Chemokine CXCL12/metabolism ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Receptors, CXCR4/metabolism
Chemical Substances	CXCL12 protein, human ; CXCR4 protein, human ; Chemokine CXCL12 ; Receptors, CXCR4
Language	English
Publishing date	2014-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632783-7
ISSN	1523-4681 ; 0884-0431
ISSN (online)	1523-4681
ISSN	0884-0431
DOI	10.1002/jbmr.2300
Database	MEDical Literature Analysis and Retrieval System OnLINE

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