The effect of microenvironmental factors on the development of myeloma cells
Gábor Barna, Ágnes Czeti, Gábor Szalóki, Ágnes Márk, Csilla Kriston, András Matolcsy
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Multiple myeloma (MM) is an age-dependent monoclonal tumor of bone marrow plasma cells (PCs). It is the second most common hematopoietic malignancy. Introduction of autologous stem cell transplantation, proteasome inhibition and immunomodulatory agents improved the treatment of myeloma over the past two decades, but despite the overall impact of these therapies, MM remains fatal and only a small fraction of patients can be cured. The interaction between MM cells and the bone marrow microenvironment promotes drug resistance and cancer cells survival. In our research we studied how myeloma cells connect to its microenvironment and how the antigen expression pattern of MM cells changes during therapies. We focused on markers which mediates interactions between plasma cells and the microenvironment, like CD27, CD28, CD29, CD81, CD56 or intracellular markers, like VS38c, which can be useful to identify MM cells during therapies in case loss of CD38 and CD138.
We have analysed 160 samples from patients with multiple myeloma and 14 samples from healthy individuals with normal PCs by flow cytometry. Cytogenetical abnormalities such as t(4;14), del17p, 1q amplification, 1 p deletion, and t(11;14) were verified by FISH analysis.
Our results showed that the expression of CD29, CD27 and CD81 is lower in MM cells compared to normal PCs, MM patients with active CD29 showed better response to treatment. We found correlation between chromosome 11 hyperdiploidity and the decrease of CD27 expression. We detected that VS38c expression is heterogenous in MM cells. Its expression showed positive correlation with the expression of Dicer protein and the level of VS38c decreased in patients with relapsed MM. Correlation between CD28 and VS38c expression also could be detected.
Our results suggest that the alterations in stromal-cell and MM-cell interactions facilitating cell survival and the development of a more aggressive and resistant phenotype of MM. Monitoring of prognostic markers during the therapy can be the key to follow these phenotype changes and raise the possibility to personalize the therapy better to achieve longer remission and increase the chance of recovery.