Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma

Abstract

BackgroundMultiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy.Material and MethodsA mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology.ResultsStrong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and α4β1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells.ConclusionsThis study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens.

Intratibial Injection of Human Multiple Myeloma Cells in NOD/SCID IL-2Rγ(Null) Mice Mimics Human Myeloma and Serves as a Valuable Tool for the Development of Anticancer Strategies

“…Similar observations have been reported by other groups examining different models of solid tumors and leukemia [21]. That a convenient, reliable and sensitive tracking of myeloma cells is indeed valuable with whole body imaging techniques in living animals has been demonstrated by various groups [22,23]. Bioluminescence and fluorescence imaging are widely used for determination of tumor load in preclinical in vivo studies.…”

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

“…Next, we confirmed the ability of OSI-906 to overcome CAM-DR using another murine model, in which MOPC315.BM.Luc murine MM cells were injected intravenously into syngeneic BALB/c mice. Because MOPC315.BM.Luc cells engraft in the BM and interact with the BM microenvironment, this model accurately reflects human disease and is considered suitable for tropism analysis and drug testing (35)(36)(37). Using this model, we confirmed that CY was not able to inhibit the growth of MM cells engrafted in the BM, whereas OSI-906 alone significantly reduced tumor growth ( Figure 14, A and B).…”

Systemic therapy with oncolytic myxoma virus cures established residual multiple myeloma in mice

“…To determine the acute effects of viral treatment on MRD, animals were killed 24 hours after the final treatment and tumor burden was directly measured using flowcytometry. 16 The results indicated that, in saline treated animals ( n = 10), CD138 hi /CD4 + MOPC-315 cells made up ~18% of the viable cells in the BM (Figure 3a). In contrast, all mice treated with MYXV ( n = 12) displayed a significantly reduced number of MOPC-315 cells in their BM (6.4%, P < 0.0001) indicating that viral treatment could acutely debulk MRD in vivo .…”