2.42 Mimicking the Tumor Microenvironment: Three Different Co-culture Systems Induce a Similar Phenotype but Different Proliferative Signals in Primary Chronic Lymphocytic Leukemia Cells

Department of Haematology, King's College London, London, UK.
British Journal of Haematology (Impact Factor: 4.96). 06/2012; 158(5):589-99. DOI: 10.1111/j.1365-2141.2012.09191.x
Source: PubMed

ABSTRACT Interactions in the tumour microenvironment can promote chronic lymphocytic leukaemia (CLL) cell survival, proliferation and drug resistance. A detailed comparison of three co-culture systems designed to mimic the CLL lymph node and vascular microenvironments were performed; two were mouse fibroblast cell lines transfected with human CD40LG or CD31 and the third was a human microvascular endothelial cell line, HMEC-1. All three co-culture systems markedly enhanced CLL cell survival and induced a consistent change in CLL cell phenotype, characterized by increased expression of CD38, CD69, CD44 and ITGA4 (CD49d); this phenotype was absent following co-culture on untransfected mouse fibroblasts. In contrast to HMEC-1 cells, the CD40LG and CD31-expressing fibroblasts also induced ZAP70 expression and marked CLL cell proliferation as evidenced by carboxyfluorescein succinimidyl ester labelling and increased Ki-67 expression. Taken together, our data show that co-culture on different stroma induced a remarkably similar activation phenotype in CLL cells but only the CD40LG and CD31-expressing fibroblasts increased ZAP70 expression and CLL cell proliferation, indicating that ZAP70 may play a critical role in this process. This comparative study reveals a number of striking similarities between the co-culture systems tested but also highlights important differences that should be considered when selecting which system to use for in-vitro investigations.

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    • "Adhesion to microvascular endothelial cells promotes CLL survival, activation and drug resistance (Badoux et al., 2011; Cols et al., 2012; Hamilton et al., 2012; Maffei et al., 2012, 2014). CLL cells bind to β1 and β2 integrins (Maffei et al., 2012) and to BAFF and APRIL on the surface of microvascular endothelial cells (Cols et al., 2012). "
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    ABSTRACT: Chronic Lymphocytic Leukemia (CLL) is a prototype microenvironment-dependent B-cell malignancy, in which the neoplastic B cells co-evolve together with a supportive tissue microenvironment, which promotes leukemia cell survival, growth, and drug-resistance. Chemo-immunotherapy is an established treatment modality for CLL patients, resulting in high rates of responses and improved survival, especially in low-risk CLL. New, alternative treatments target B-cell receptor (BCR) signaling and the Chemokine (C-X-C motif) Receptor 4 (CXCR4)- Chemokine (C-X-C motif) Ligand 12 (CXCL12) axis, which are key pathways of CLL-microenvironment cross talk. The remarkable clinical efficacy of inhibitors targeting the BCR-associated kinases bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase delta (PI3Kδ) challenge established therapeutic paradigms and corroborate the central role of BCR signaling in CLL pathogenesis. In this review, we discuss the cellular and molecular components of the CLL microenvironment. We also describe the emerging therapeutic options for CLL patients, with a focus on inhibitors of CXCR4-CXCL12 and BCR signaling.
    Pharmacology [?] Therapeutics 12/2014; 144(3). DOI:10.1016/j.pharmthera.2014.07.003 · 7.75 Impact Factor
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    • "), suggesting that membrane-bound CD40LG is the more efficient inducer. Hamilton et al (2012) described a consistent increase of CD38 expression by all three different co-culture systems, in line with previous studies suggesting that CD38 expression (i) is increased by microenvironmental influences and (ii) determines the strength of the proliferative response (Patten et al, 2008). Although our data confirm a T cell-dependent upregulation of CD38 expression, we could not detect increased in vitro proliferation rates of CD38-high CLL cells (Fig S2). "
    British Journal of Haematology 12/2012; 160(5). DOI:10.1111/bjh.12151 · 4.96 Impact Factor
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    British Journal of Haematology 12/2012; 160(5). DOI:10.1111/bjh.12154 · 4.96 Impact Factor
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