July-August 2012, Volume 9, Issue 4
Microenvironment-Induced Genomic Instability in Multiple Myeloma
Published on: July 01, 2012
Dr. Anderson indicated no relevant conflicts of interest.
Koduru S, Wong E, Strowig T, et al. Dendritic cellmediated activation-induced cytidine deaminase (AID)-dependent induction of genomic instability in human myeloma. Blood. 2012;119:2302-2309.
In this study, Koduru and colleagues showed that interaction between multiple myeloma (MM) cell lines or primary MM cells and patient-derived dendritic cells (DCs) produces genomic instability in the tumor cells. Two mechanisms underlie the genomic instability: activationinduced cytidine deaminase (AID) and AID-dependent DNA double-strand breaks. These processes require direct contact between MM cells and DCs and can be abrogated, but not completely inhibited, by blocking binding of the receptor activator of NF-κB (RANK) with its cognate ligand, RANKL. Importantly, this induced genomic instability altered the biologic phenotype of tumor cells, resulting in more indolent in vivo growth of human MM cells and prolonged host survival in a murine xenograft model. These data both define an additional impact of accessory cells in the bone marrow (BM) milieu of tumor cells and suggest the use of targeted therapy aimed directly at these interactions to modifiy their sequelae.
MM represents a paradigm for the importance of the role of the microenvironment in tumor pathogenesis. Specifically, adhesion of MM cells to extracellular matrix proteins can confer cell adhesion-mediated drug resistance, and interactions between MM cells and BM accessory cells, including stromal cells and osteoclasts, can modify transcription and secretion of cytokines, thereby promoting tumor cell growth, survival, drug resistance, and migration. Interactions between MM cells and both osteoblasts and endothelial cells can similarly impact pathogenesis. Both myeloid and plasmacytoid DCs have the capacity to induce AID, and both are abnormal in MM, as they do not trigger immune effector cell responses on the one hand and can promote tumor cell growth and drug resistance on the other. Therefore, strategies targeting DCs, such as promoting their maturation or targeting MM cell-DC interactions, may both inhibit MM cell growth and drug resistance and enhance immune function.
The current study identifies induction of AID as another critical sequelae of tumor cell-DC interactions in the MM BM milieu, with this process contributing to the hallmark genomic instability observed in MM. These studies have major implications for cancer pathogenesis as current static genomic characterization of cancers does not take into account the impact of the microenvironment on tumor biology. In an ongoing process, microenvironmental factors modulate the genetic signature and thereby likely play a critical role in the constitutive and evolving genomic changes associated with progression and relapse of disease. This impact of the microenvironment must be assessed as we implement personalized medicine in cancer. Importantly, understanding the mechanisms underlying environment-mediated genomic instability suggests novel therapeutic strategies. For example, maturation of DCs with CpG oligonucleotides or Toll-receptor agonists may abrogate tumor growth, drug resistance, and AID induction while also restoring DC immune effector stimulating capacity. It is noteworthy that clinical trials are ongoing in MM with denosumab to block RANKL-induced stimulation of osteoclasts and thereby ameliorate bone disease. The current study suggests that this therapeutic strategy may also mitigate AID-dependent induction of genomic instability. These findings have implications beyond the pathobiology and therapy of myeloma, as AID is observed in breast cancer and likely other malignancies as well.
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