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Tumor-initiating capacity of CD138− and CD138+ tumor cells in the 5T33 multiple myeloma model

Leukemia volume 26, pages 1436–1439 (2012)Cite this article

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Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). The introduction of novel agents that include thalidomide, bortezomib (bz) and lenalidomide into the treatment of MM has significantly improved response, progression and survival rates.1 However, in spite of these improvements, MM is still regarded as incurable as the vast majority of patients will eventually relapse and die of therapy-refractory disease. One possible explanation for disease relapse is the persistence of distinct tumor populations resistant to current therapies. According to current models, cancer stem cells or tumor-initiating cells represent minor subpopulations of tumor cells that possess the capacity to recapitulate tumors in vivo upon transplantation as well as increased drug resistance.2 In previous studies, MM has been found to consist of a heterogeneous mixture of cells. CD138-positive (CD138+) plasma cells form the tumor bulk, but studies tracking tumor-specific immunoglobulin heavy chain rearrangements have also identified relatively rare CD138-negative (CD138−) clonotypic idiotype-positive (Id+) memory B cells.3 In human MM this minor population of CD138− has been found to be highly tumorigenic in immunodeficient NOD/Scid mice and relatively resistant to many drugs compared with CD138+ plasma cells. However, other studies have demonstrated that tumor cell engraftment and growth is restricted to CD138+ plasma cells in the SCID-Hu mouse model.4 Therefore, the expression of CD138 by tumorigenic MM cells remains controversial. It is possible that these disparate findings are because of the xenografting models used to study human MM. Therefore, we investigated the functional properties, including clonogenic growth, engraftment potential and drug resistance of CD138− and CD138+ tumor populations in a more physiological context by studying the syngeneic immunocompetent 5T33 MM mouse model of MM.

These findings suggest that both CD138− and CD138+ cells contribute to disease propagation and should be considered when developing novel targeted therapeutical strategies for MM. We investigated the sensitivity of 5T33 MM CD138− and CD138+ cells to several drugs currently undergoing clinical testing in MM. We plated sorted cells in 96-well plates (1 × 103–10 × 103 cells per well), treated with the proteasome inhibitors bz and MG132, the HDAC inhibitor LBH589, and the HSP90 inhibitor 17AAG, then quantified cell viability (Figure 2b) and caspase 3/7 activity (data not shown) after 20 h. We found that 5T33 MM CD138− cells were less sensitive than CD138+ cells to all of the drugs studied (Figure 2b). Similarly, CD138− 5TGM1 cells were more viable after bz treatment than CD138+ 5TGM1 cells (57±19 vs 11±5%; data not shown). Furthermore, sensitivity to melphalan and the immunomodulatory drug lenalidomide was investigated on 5TGM1 subsets. In accordance with bz, CD138− 5TGM1 cells were more viable than CD138+ 5TGM1 cells after treatment with melphalan (52±8.5% vs 9±5%) and lenalidomide (60±14% vs 14±8.7%). We also examined the phenotype of 5T33 MM cells after in vivo treatment with bz (0.6 mg/kg, subcutaneous, 2x per week, starting 1 week after injection). Compared with a vehicle control, a tumor reduction of ∼47% was observed in bz treated mice, and the percentage of viable (7AAD-) CD138- 5T33 MM cells was significantly increased (Figure 2c). Taken together these results indicate that CD138− cells are less sensitive to treatment both in vitro and in vivo. In human MM, increased STAT3/ERK1/2 signaling in CD138− cells has been suggested to be involved in the relative drug resistance of this population.4, 7

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Acknowledgements

We would like to thank Angelo Willems and Carine Seynaeve for their expert technical assistance and Jean-Marc Lazou for the sorting of the cells. This work was financially supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vl), Swedish Cancer Society, Swedish Research Council, the European Stem cell network (EUFP6 MSCNET), the Onderzoeksraad Vrije Universiteit Brussel and the ‘Vlaamse Liga tegen Kanker’. E Menu, E Van Valckenborgh and E De Bruyne are postdoctoral fellows of FWO-Vl and S Lub is a research fellow of FWO-Vl.

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  1. Department of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel, Brussels, Belgium

    E Van Valckenborgh, S Lub, X Dehui, E De Bruyne, E Menu & K Vanderkerken

  2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    W Matsui, J Agarwal & Q Wang

  3. Department of Immunology, Rudbeck Laboratory, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    P Agarwal & H Jernberg-Wiklund

  4. Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium

    C Empsen & L van Grunsven

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Van Valckenborgh, E., Matsui, W., Agarwal, P. et al. Tumor-initiating capacity of CD138− and CD138+ tumor cells in the 5T33 multiple myeloma model. Leukemia 26, 1436–1439 (2012). https://doi.org/10.1038/leu.2011.373

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