Abstract
BackgroundWe systematically analyzed multiple myeloma (MM) cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents.Design and MethodsUsing flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null) mice (NSG).ResultsMyeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID). Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses.ConclusionsOur results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.
Highlights
Multiple myeloma (MM) is characterized by monoclonal plasma cell proliferation, where the latter have undergone somatic hypermutation, antigen selection and IgH switching in germinal centers
We show here that 1) the NSG i.t. model is superior over the NOD/SCID i.t. model for outgrowth of cancer cells, 2) fluorescence-based in vivo imaging (IVI) can be used for analyzing growth of MM cells in vivo, 3) L363 cells engraft better than RPMI8226 cells and 4) MM bone marrow (BM) cells can engraft mice using the NSG i.t. model and can be used to assess and personalize treatment strategies
Remarkable engraftment differences were observed in different mouse strains. This was assessed by means of a) take-rates (= number of tumorbearing mice), b) quantitative L363 / RPMI8226 engraftment via flow-cytometry (Figure 1) and fluorescence-IVI (Figure 2+3A) and c) survival rates (Figure 3B)
Summary
Multiple myeloma (MM) is characterized by monoclonal plasma cell proliferation, where the latter have undergone somatic hypermutation, antigen selection and IgH switching in germinal centers. Human tumor xenograft models using immunodeficient mice mimic the clinical situation [5,6], models involving subcutaneous or intraperitoneal tumor implantation do not accurately reproduce the growth behavior and drug sensitivity patterns of leukemia or lymphoma diseases. They do not reflect the systemic nature of diffuse myeloma lesions involving the BM microenvironment, which plays a pivotal role in MM. Conclusions: Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies
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