Gámez Beatriz, Morris Emma V, Olechnowicz Sam W Z, Webb Siobhan, Edwards James R, Sowman Aneka, Turner Christina J, Edwards Claire M
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Centre for Translational Myeloma Research, University of Oxford, Oxford, UK.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Transl Oncol. 2022 Jan;15(1):101301. doi: 10.1016/j.tranon.2021.101301. Epub 2021 Dec 8.
Multiple myeloma is a haematological malignancy that is dependent upon interactions within the bone microenvironment to drive tumour growth and osteolytic bone disease. Metformin is an anti-diabetic drug that has attracted attention due to its direct antitumor effects, including anti-myeloma properties. However, the impact of the bone microenvironment on the response to metformin in myeloma is unknown. We have employed in vitro and in vivo models to dissect out the direct effects of metformin in bone and the subsequent indirect myeloma response. We demonstrate how metformin treatment of preosteoblasts increases myeloma cell attachment. Metformin-treated preosteoblasts increased osteopontin (OPN) expression that upon silencing, reduced subsequent myeloma cell adherence. Proliferation markers were reduced in myeloma cells cocultured with metformin-treated preosteoblasts. In vivo, mice were treated with metformin for 4 weeks prior to inoculation of 5TGM1 myeloma cells. Metformin-pretreated mice had an increase in tumour burden, associated with an increase in osteolytic bone lesions and elevated OPN expression in the bone marrow. Collectively, we show that metformin increases OPN expression in preosteoblasts, increasing myeloma cell adherence. In vivo, this translates to an unexpected indirect pro-tumourigenic effect of metformin, highlighting the importance of the interdependence between myeloma cells and cells of the bone microenvironment.
多发性骨髓瘤是一种血液系统恶性肿瘤，依赖于骨微环境中的相互作用来驱动肿瘤生长和溶骨性骨病。二甲双胍是一种抗糖尿病药物，因其直接抗肿瘤作用（包括抗骨髓瘤特性）而受到关注。然而，骨微环境对骨髓瘤中二甲双胍反应的影响尚不清楚。我们采用体外和体内模型来剖析二甲双胍在骨中的直接作用以及随后的间接骨髓瘤反应。我们证明了二甲双胍处理前成骨细胞如何增加骨髓瘤细胞的附着。经二甲双胍处理的前成骨细胞增加了骨桥蛋白（OPN）的表达，沉默该蛋白后，随后的骨髓瘤细胞黏附减少。与经二甲双胍处理的前成骨细胞共培养的骨髓瘤细胞中增殖标志物减少。在体内，在接种5TGM1骨髓瘤细胞之前，用二甲双胍治疗小鼠4周。经二甲双胍预处理的小鼠肿瘤负担增加，这与溶骨性骨病变增加和骨髓中OPN表达升高有关。总体而言，我们表明二甲双胍增加前成骨细胞中OPN的表达，增加骨髓瘤细胞的黏附。在体内，这转化为二甲双胍意想不到的间接促肿瘤发生作用，突出了骨髓瘤细胞与骨微环境细胞之间相互依存的重要性。
