Myeloma as a model for the process of metastasis: implications for therapy

Abstract

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed.

Figure 1

Clinical presentations of cell dissemination and metastasis in MM. (A) Skeletal survey showing multiple lytic lesions in the skull of a patient diagnosed with symptomatic multiple myeloma (MM). These multiple lesions represent multiple sites of growth of MM cells within the BM niches in the skull. (B) A PET scan showing multiple areas of enhancement in a patient with extramedullary MM, indicating that MM cells can metastasize to areas outside the BM in a subgroup of patients with extramedullary MM. (C) Extramedullary MM presenting as a large subcutaneous mass on the shoulder of a patient with advanced disease. (D) Circulating tumor plasma cells observed in a patient with MM demonstrating that a small number of tumor cells are continuously circulating in the peripheral blood leading to cell dissemination. This patient does not have plasma cell leukemia.

Figure 2

Model of metastasis and dissemination in MM. In this schematic figure, the initial site of tumor growth of clonal plasma cells is represented by a solitary plasmacytoma (these are not clinically detected in most cases). In a small group of patients, solitary plasmacytomas do not disseminate. However, in the majority of patients, local invasion occurs, which allows some cells to egress into the peripheral circulation (circulating tumor cells) followed by specific homing into BM niches and local micrometastasis. Micrometastasis is represented by the clinical condition of MGUS. MGUS can progress to macrometastasis or colonization after a long latency period, leading to symptomatic disease with multiple lytic lesions, anemia, hypercalcemia, and renal failure. Genes regulating tumor initiation, metastasis initiation, metastasis progression, and metastasis virulence are represented in the figure. This is not a complete list of genes that could regulate cell trafficking in MM but represents some of the known regulators in cell dissemination and progression in MM.

Figure 3

In vivo tracking of tumor cell trafficking in a MM mouse model. (A) Depletion of CD138⁺ patient cells from the circulation occurs with the same kinetics as MM.1S cell line. MM.1S (n = 4) or MM patient sample cells (n = 5) were labeled with fluorescent cytoplasmic or membrane dyes, injected into mice, and immediately the proportion of cells remaining in the circulation was measured by in vivo flow cytometry and plotted against time (adapted from Figure 3 of Runnels et al with permission). (B) MM cells position themselves in proximity to the vasculature. 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine–stained MM.1S cells were injected intravenously into Col2.3-GFP mice at a dose of 100 000 cells per mouse. Immediately before imaging, the mice were injected with the vascular marker Quantum Dots 800. The mice were imaged within 2, 6, and 72 hours after MM cell injection. Z stacks were acquired from multiple regions in the calvaria of the mice. Distances were measured and tabulated between MM cells and osteoblasts or endosteal surface for the first 6 hours after MM cell injection. (Adapted from Figure 3 of Runnels et al with permission). (C) Imaging at 72 hours after MM cell injection. The image demonstrates the relationship of the MM cells (white) to the vasculature (red), osteoblasts (green), and bone (blue) during the first 72 hours after cell injection. Scale bars represent 100 μm. (Adapted from Figure 3 of Runnels et al with permission). (D) Imaging shows vessel formation around an area of GFP-positive MM cells growing in a cluster in close association to blood vessels. Immediately before imaging, the mice were injected with the vascular marker Quantum Dots 800. The MM1S cells are GFP-positive (green color). Scale bars represent 100 μm. (E) Primary plasma cells injected from a patient with plasma cell leukemia and allowed to engraft and proliferate for 8 weeks. A green-fluorescently labeled anti-CD138 antibody was injected intravenously just before imaging to allow imaging of the cells.

Figure 4

The BM niche in MM. Schematic representation of the BM niches in MM. MM cells interact with many cellular elements in the BM, including osteoclasts, osteoblasts, stromal cells, and endothelial cells. Multiple cytokines and chemokines are secreted in response to these cell-cell interactions, leading to enhanced tumor growth, inhibition of osteoblasts, and increased osteoclast activity.