The Cancer Stem Cell Concept in Multiple Myeloma – From Phenomenology to Characterisation

European Haematology, 2010;4:94-6

Abstract:

Although there have been great developments in the treatment regimes offered to patients with multiple myeloma (MM), it is still an incurable disease. An emerging idea in MM research is the concept of the cancer stem cell, which has been identified in other cancer types in an attempt to explain incurability. The cancer stem cell is defined in the same manner as regular tissue stem cells. They are thought to be infrequent among the tumour cells, quiescent and able to maintain their population by self-renewal. Although ‘the cancer stem cell’ has not yet been identified, substantial evidence has been gathered over the past few years suggesting that a tumour-initiating cell population may be present in MM. Further characterisation of B-lineage subsets in bone marrow and blood, including memory B cells and plasmablasts, is necessary to support the concept that the cancer stem cell is one of the central players in the pathogenesis of this disease.
Acknowledgement: On behalf of the Myeloma Stem Cell Network (MSCNET).
Keywords: Multiple myeloma, cancer stem cell, clonotypic, self-renewal, plasma cell
Disclosure: The authors have no conflicts of interest to declare.
Received: December 03, 2009 Accepted February 19, 2010 Citation European Haematology, 2010;4:94-6
Correspondence: Kirsten Fogd, Department of Haematology, Aalborg Hospital, Aarhus University Hospital, Sdr. Skovvej 15, 9000 Aalborg, Denmark. E: kifo@rn.dk

Clinical Features of Multiple Myeloma
Multiple myeloma (MM) is a lethal haematological malignancy with an incidence of 40–60 per 1,000,000 per year. The tumour cells are malignant plasma cells of the same clonal origin, and secrete high amounts of monoclonal antibody, known as the M-component. MM is usually preceded by an age-dependent pre-malignancy called monoclonal gammopathy of undetermined significance (MGUS), which is present in >2% of adults over 50 years of age. At diagnosis, MM is characterised by having a high intramedullary tumour-cell content (>10%), osteolytic bone lesions and/or an increasing tumour mass. Progression of intramedullary myeloma is associated with increasingly severe secondary features (lytic bone lesions, anaemia, immunodeficiency and renal impairment) and also, in a fraction of patients, the occurrence of tumour cells in extramedullary sites, such as the blood, pleural fluid and skin. Historically, the prognosis of MM patients has been unfavourable, and to date no patients have been cured. In order to further improve the treatment of MM patients, new individualised treatment strategies are needed, ideally based on new knowledge of the pathogenesis of the disease.
The Cancer Stem Cell Model
One approach for obtaining new knowledge of the pathogenesis of MM is the cancer stem cell (CSC) hypothesis. This hypothesis has gained acceptance in recent years as a model to explain certain aspects of cancer biology. Like organ tissue stem cells, CSCs are thought to be rare and to enter the cell cycle infrequently.1 Furthermore, CSCs are expected to be able to self-renew, thereby maintaining the CSC population, as well as differentiating into different cell types in the tumour, sustaining and reforming the tumour. This implies that CSCs are relatively resistant to therapies designed to target cycling cells, thereby surviving therapy; this means that the tumour can reform after the end of therapy, leading to disease recurrence.1 The first documentation of the existence of CSCs was in acute myelogenous leukaemia (AML) in 1997 by John Dick and co-workers. Using the non-obese diabetic (NOD)/severe combined immunodeficiency disease (SCID) mouse model, a CD34+CD38- cell fraction representing 0.1–1% of the leukaemic cell population was shown to contain the leukaemia-initiating cell or leukaemic stem cell (LSC). In other fractions, only clonogenic leukaemia progenitors were found, and these were unable to regenerate the tumour after serial transplantation in mice.2 The presence of a CSC has now also been indicated in other cancer types, such as breast cancer,3 brain tumours4 and, recently, lung cancer.5
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Keywords: Multiple myeloma, cancer stem cell, clonotypic, self-renewal, plasma cell