Document Detail


Fluorescence-based experimental model to evaluate the concomitant effect of drugs on the tumour microenvironment and cancer cells.
MedLine Citation:
PMID:  22428569     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The response of the tumour microenvironment to anti-cancer drugs can influence treatment efficacy. Current drug-screening methodologies fail to distinguish and quantify simultaneously the concomitant effect of drugs on the tumour stroma and cancer cells. To overcome this limitation we have developed a fluorescence-based experimental model that employs mCherry-labelled stromal cells (e.g. bone marrow fibroblastic stromal cells) co-cultured in direct contact with enhanced green fluorescent protein-labelled tumour cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumour cells. Additionally, we used fluorescence-based image analysis to determine morphological changes that correlate with cell function (e.g. morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with multiple myeloma cells via a process involving Src/c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone mediated by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment.
Authors:
Karthik Ramasamy; Hazera Khatun; Lee Macpherson; Mathew P Caley; Justin Sturge; Ghulam J Mufti; Stephen A Schey; Yolanda Calle
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-20
Journal Detail:
Title:  British journal of haematology     Volume:  157     ISSN:  1365-2141     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-10     Completed Date:  2012-07-09     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  564-79     Citation Subset:  IM    
Copyright Information:
© 2012 Blackwell Publishing Ltd.
Affiliation:
Division of Cancer Studies, Department of Haematological Medicine, Kings College London, UK.
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Bone Marrow / drug effects,  pathology
Bone Resorption / drug therapy
Cell Line
Cell Proliferation / drug effects
Coculture Techniques
Dexamethasone / pharmacology
Drug Screening Assays, Antitumor / methods*
High-Throughput Screening Assays
Humans
Multiple Myeloma / drug therapy,  metabolism,  pathology*
Oncogene Proteins v-abl / antagonists & inhibitors
Osteoclasts / metabolism,  pathology
Pyrimidines / pharmacology
Stromal Cells / drug effects,  metabolism
Thiazoles / pharmacology
Tumor Microenvironment / drug effects*
src-Family Kinases / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/Actins; 0/Antineoplastic Agents; 0/Oncogene Proteins v-abl; 0/Pyrimidines; 0/Thiazoles; 50-02-2/Dexamethasone; EC 2.7.10.2/src-Family Kinases; RBZ1571X5H/dasatinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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