Bone marrow mesenchymal stromal cells retain their tumor-educated phenotype after treatment of multiple myeloma

Abstract

Background & Aim Multiple myeloma (MM) is a type of blood cancer characterized by abnormal plasma cells (PC) accumulation in the bone marrow. Disease development is strongly affected by interactions between MM and tumor microenvironment (TME) composed of various cell types including mesenchymal stromal cells (MSC), immune cells, endothelium and others. Influenced by tumor cells, MSC aquire the tumor-associated phenotype and play a key role in TME. TME MSC contribute to survival of residual tumor clone and thus to early relapse. The aim of the study was to compare the MSC from patients with different types of response to treatment and MSC from healthy donors (HD). Methods, Results & Conclusion Three HD and twelve patients (49-71 years) after standard bortezomib-based treatment followed by autologous hematopoietic stem cell transplantation were enrolled in the study: 3 non-respondes (NR) and 9 patients with partial or complete response (PoCR). Trepanobiopsy samples were studied for PC and microvessels density by immune histochemistry. Primary cultures of the MSC were obtained from BM and studied for the proliferation rate, osteogenic differentiation and the presence of TME markers (α-smooth muscle actin, senescence-associated β-galactosidase, non-coding DNA transcripts) by cell counting, immunofluorescent staining, specific chromogenic staining and FISH. Increased microvessel density was revealed in MSC from all MM patients and correlated with PC number in the myelogram. MSC from all NR and 37,5% PoCR patients had decreased proliferation rate. The osteogenic potential was decreased more in NR than in PoCR patients and HD. Expression of markers of cancer-associated MSC was also increased in cultures from NR to a greater extent than in cultures from PoCR patients and HD. Thus, the MSC phenotype of MM patients differed from the one of HD and displayed features of cancer-associated fibroblasts phenotype. The impairment of hematopoietic niche may be the cause of the incurability of MM. The work was supported by grants from the Grants’ Council of the President of RF (MK-6706.2018.7) and RSF (19-74-20102).