The role of N-cadherin in the multiple myeloma cancer stem cell niche
Abstract
Multiple myeloma is an incurable plasma cell malignancy with a median age at diagnosis of approximately 70 years. This disease is the second most common hematopoietic cancer, and over 10,000 deaths in the United States were attributed to myeloma in 2009. Many cancers contain rare cancer stem cells, which are multipotent, contain unlimited proliferative capability, are drug resistant, and have an increased DNA repair capacity. The cancer stem cell is highly regulated by the niche in which it resides. Therefore, targeting the niche components may help treat cancer. We propose that myeloma cancer stem cells reside in a similar niche environment as does the hematopoietic stem cell (HSC). N-cadherin, a homotypic transmembrane adhesion protein, is an important part of the HSC niche. Inhibition of N-cadherin in HSCs leads to decreased niche adhesion, increased proliferation, and decreased stemness. The objective of this study is to determine the role of N-cadherin in regulating the multiple myeloma cancer stem cell. An in vitro co-culture assay containing mesenchymal stem cells (MSCs) and myeloma cells was utilized in this study. N-cadherin functional blocking antibodies and peptides were used to assay the effects of N-cadherin inhibition on multiple myeloma cells. Inhibition of N-cadherin did not change the number of myeloma cells bound to the mesenchymal stem cells after three days of co-culture. Myeloma cells adherent to MSCs comprised the proliferative fraction and were resistant to N-cadherin mediated cell death. The non-adherent cells remained in G O and 70-80% died upon N-cadherin blocking. The blocking antibodies and peptides did not affect the number of myeloma cancer stem cells present in the co-culture. These data illustrate that the function of N-cadherin in the hematopoietic and myeloma niche spaces may not be as similar as expected. In the myeloma niche, N-cadherin functions to increase survival, but does not appear to affect quiescence, adhesion, or stemness. As N-cadherin inhibition was toxic to a sub-population of myeloma cells, N-cadherin may be a viable target if combined with other therapeutic agents.
Degree
M.S.
Advisors
Kirshner, Purdue University.
Subject Area
Biology|Molecular biology|Cellular biology
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