Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy
ABSTRACT The bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells thus contributing to the lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates adhesion of normal and malignant B-cell precursors in BM, and, according to gene expression analyses from 207 children with high-risk pre-B ALL with minimal residual disease, is particularly highly expressed in patients with the poorest outcome. Therefore, we tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. For this purpose, two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 (p210+)-induced murine leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary pre-B ALL). Conditional deletion of alpha4 sensitized leukemia cell to Nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent and alpha4 blockade sensitized primary ALL cells towards chemotherapy. Combination of chemotherapy with an anti-integrin alpha4 antibody, Natalizumab, prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin alpha4 inhibition as a novel strategy for pre-B ALL.
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ABSTRACT: Interlocking gene mutations, epigenetic alterations and microenvironmental features perpetuate tumor development, growth, infiltration and spread. Consequently, intrinsic and acquired therapy resistance arises and presents one of the major goals to solve in oncologic research today. Among the myriad of microenvironmental factors impacting on cancer cell resistance, cell adhesion to the extracellular matrix (ECM) has recently been identified as key determinant. Despite the differentiation between cell adhesion-mediated drug resistance (CAMDR) and cell adhesion-mediated radioresistance (CAMRR), the underlying mechanisms share great overlap in integrin and focal adhesion hub signaling and differ further downstream in the complexity of signaling networks between tumor entities. Intriguingly, cell adhesion to ECM is per se also essential for cancer cells similar to their normal counterparts. However, based on the overexpression of focal adhesion hub signaling receptors and proteins and a distinct addiction to particular integrin receptors, targeting of focal adhesion proteins has been shown to potently sensitize cancer cells to different treatment regimes including radiotherapy, chemotherapy and novel molecular therapeutics. In this review, we will give insight into the role of integrins in carcinogenesis, tumor progression and metastasis. Additionally, literature and data about the function of focal adhesion molecules including integrins, integrin-associated proteins and growth factor receptors in tumor cell resistance to radio- and chemotherapy will be elucidated and discussed.Seminars in Cancer Biology 08/2014; 31. DOI:10.1016/j.semcancer.2014.07.009 · 9.33 Impact Factor
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ABSTRACT: Tumor inflammation, the recruitment of myeloid lineage cells into the tumor microenvironment, promotes angiogenesis, immunosuppression and metastasis. CD11b+Gr1lo monocytic lineage cells and CD11b+Gr1hi granulocytic lineage cells are recruited from the circulation by tumor-derived chemoattractants, which stimulate PI3-kinase γ (PI3Kγ)-mediated integrin α4 activation and extravasation. We show here that PI3Kγ activates PLCγ, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin α4β1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLCγ, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin α4 activation by chemoattractants or activated PI3Kγ (p110γCAAX), while activated Rap (RapV12) promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin α4β1. Similar to blockade of PI3Kγ or integrin α4β1, blockade of Rap1a suppressed both the recruitment of monocytes and granulocytes to tumors and tumor progression. These results demonstrate critical roles for a PI3Kγ-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.PLoS ONE 04/2013; 8(4):e60226. DOI:10.1371/journal.pone.0060226 · 3.53 Impact Factor
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ABSTRACT: Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal.British Journal of Haematology 01/2014; 164(6). DOI:10.1111/bjh.12725 · 4.96 Impact Factor