computational modeling of interactions between multiple myeloma and the bone microenvironment计算模型的多发性骨髓瘤和骨髓微环境之间的相互作用.pdf

Computational Modeling of Interactions between Multiple Myeloma and the Bone Microenvironment 1 2 2 2 3 Yan Wang *, Peter Pivonka , Pascal R. Buenzli , David W. Smith *, Colin R. Dunstan 1 Department of Infrastructure Engineering, School of Engineering, University of Melbourne, Melbourne, Victoria, Australia, 2 Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, Western Australia, Australia, 3 Department of Biomedical Engineering, School of Engineering, University of Sydney, Sydney, New South Wales, Australia Abstract Multiple Myeloma (MM) is a B-cell malignancy that is characterized by osteolytic bone lesions. It has been postulated that positive feedback loops in the interactions between MM cells and the bone microenvironment form reinforcing ‘vicious cycles’, resulting in more bone resorption and MM cell population growth in the bone microenvironment. Despite many identified MM-bone interactions, the combined effect of these interactions and their relative importance are unknown. In this paper, we develop a computational model of MM-bone interactions and clarify whether the intercellular signaling mechanisms implemented in this model appropriately drive MM disease progression. This new computational model is based on the previous bone remodeling model of Pivonka et al. [1], and explicitly considers IL-6 and MM-BMSC (bone marrow stromal cell) adhesion related pathways, leading to formation of two positive feedback cycles in this model. The progression of MM disease is simulated numerically, from normal bone physiology to a well established MM disease state. Our simulations are consistent with known behaviors and data reported for both normal bo