Cell Trafficking in Multiple Myeloma

Abstract

Multiple myeloma (MM) is an incurable cancer of terminally differentiated plasma cells (PC) and represents the second most frequent hematologic malignancy in the western world. MM cells localize preferentially to the bone marrow where they interact closely with bone marrow stroma cells (BMSC) and extracellular matrix (ECM) proteins in a reciprocal pro-survival loop. Such a bone marrow niche guarantees a survival advantage for MM cells and has a crucial role in mediating drug resistance to chemotherapy agents. As the name suggests, hallmark characteristic of MM is the ability to localize in multiple, distant bone sites causing disruption of the normal bone architecture and impairment of normal hematopoiesis. The pathogenic mechanisms of MM rely then not only on proliferation of cancerous cells, but also on the ability of myeloma cells to traffic between sites and home to appropriate survival niches. Identifying the mechanisms that regulate the homing of MM cells to the bone marrow, the MM-BMSC interaction and the trafficking of MM cells from the bloodstream to distant bone locations is therefore crucial to design new, more effective therapies capable of overcoming the maladaptive interaction between BMSCs and MM and help in finding a cure for MM.

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

“…The activation of the SDF1/CXCR4 axis promotes trans-endothelial migration, bone marrow homing, migration and adhesion of MM cells. The CXCR4 expression is correlated with bortezomib resistance in cell lines and the use of CXCR4 inhibitors may enhance the sensitivity of MM cells by disrupting their adhesion to the BMSCs [147]. Another potential cause for drug resistance in MM is activation of the myristoylated alanine-rich c-kinase substrate (MARCKS) membrane protein, that has an important role in cell adhesion and metastatic spread.…”

Drug targets and resistance mechanisms in multiple myeloma

“…SDF-1 (CXCL12) is constitutively expressed and released by BMSCs and fibroblasts, while its receptor CXCR4 is expressed by MM cells. Activation of the SDF-1/CXCR4 axis promotes trans-endothelial migration, bone marrow homing, migration and adhesion of MM cells [170] . The MUC1 oncogene is known to confer tumor cells with resistance to apoptosis and necrosis.…”

Drug resistance-related microRNAs in hematological malignancies: Translating basic evidence into therapeutic strategies

“…The interaction between BMSCs and MM cells contributes to bone disease, genetic instability, and, more importantly, drug resistance [127][128][129][130]. BMSCs provided survival support and protected myeloma cells from bortezomib induced apoptosis via suppressing miR-15a/-16 expression.…”