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

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, and lenalidomide into the treatment of MM has significantly improved response, progression and survival rates. However, in spite of these improvements, MM is still regarded as incurable since 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. 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. In human MM this minor population of CD138 negative cells has been found to be highly tumorigenic in immunodeficient NOD/Scid mice and relatively resistant to many drugs compared to 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. Therefore, the expression of CD138 by tumorigenic MM cells remains controversial. It is possible that these disparate findings are due to 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 physiologic context by studying the syngeneic immunocompetent 5T33MM mouse model of MM.