Cancer Stem Cells in Multiple Myeloma

Abstract

Over the last few years, the hypothesis that rare stem cell-like cells are responsible for tumor initiation and maintenance, namely the cancer stem cell (CSC) theory, has remarkably changed the way to approach cancer biology. The scientific relevance of this theory is based, in fact, not only on the existence of hierarchically organized, self-renewing malignant progenitor cells within each tumor, but also on the assumption that their drug resistance may account for the high frequency of relapse that renders incurable most tumors despite their treatment with specific cytotoxic drugs. The view that CSCs may descend from normal stem cells finds its historical background in studies on acute myeloid leukemia where the leukemic clone is organized according to a defined hierarchy in which the majority of tumor cells rapidly proliferate, while quiescent “ leukemic stem cells” resembling early hematopoietic progenitors remain as a potential reservoir of cancer propagation due to their chemoresistance to specific cytotoxic protocols. Recently, however, a large number of studies have turned the CSC theory into more than an idea, since clear experimental evidence has demonstrated the existence of CSCs in a number of tumors. Indeed, brain (Singh et al., 2004), intestinal (O'Brien et al., 2007) and breast cancers (Al-Hajj et al., 2003) have been shown to arise from rare cells, organized in a precise hierarchy resembling that of stem cells, which are capable of generating a differentiated progeny by repetitive asymmetric divisions. In most of these tumors, however, the earliest event driving the malignant transformation remains elusive and the original cell is far from being defined, since both histological and cell-surface marker profiles of the bulk tumor cells do not necessarily resemble those of the lineage-related stem cell. These observations, moreover, have been interpreted to suggest that CSCs could derive either from normal stem cells or from committed progenitor cells that have acquired the ability to self-renew due to specific genetic mutations (Visvader, 2011). Similar controversies have arisen with hematological malignancies of both myeloid and lymphoid origin, including multiple myeloma (MM). In fact, differently from acute leukemia, in the initial phases of most chronic lymphoproliferative disorders, neoplastic cells do not resemble early hematopoietic stem cells, but rather cellular elements in late maturation phases, as clearly demonstrated in chronic myeloid leukemia (Jamieson et al., 2004). In MM, malignant plasma cells are characterized by unique patterns of immunoglobulin (Ig) and surface antigen expression, thus suggesting that the tumor bulk is exclusively composed of terminally differentiated cells with high proliferation potential.