Migration Capacity of Bone Marrow-Mesenchymal Stem Cells from Patients with Advanced Breast Cancer: a Novel Approach of Bone Pre-Metastatic Niche

MUNICOY J.; FERNÁNDEZ-VALLONE V.; GIORELLO MB.; YANNARELLI G.; LABOVSKY V.; FELDMAN L.; CHASSEING NA.; BORZONE F.; PICCIONI F.; BATAGELJ E.; MARTINEZ L.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Recent reports indicated that self-renewal, proliferation, as well as migration capacity of bone marrow (BM) mesenchymal stem cells (MSC) are essential properties for bone regeneration processes. We found that MSC from untreated advanced breast cancer patients (BCP, invasive ductal, stage III-B) have lower cloning, proliferation and osteogenic differentiation capacities than healthy donors (HD)-MSC. Also, BCP-MSC favoured osteoclastogenesis from BM hematopoietic precursors. Here, we aimed to evaluate migratory capacity of MSC from BM of advanced BCP and different parameters that regulate it, which is indispensable for the processes of osteogenesis and bone vascularization. For this purpose, we studied the % of MSC that express CD146 and the level of expression/MSC (Flow Cytometry=FC), as well as TERT activity (RT-PCR), telomere length (RT-PCR), and intracytoplasmatic/mitochondrial ROS production (FC) in MSC of BCP and HD. Also, we analyzed the expression of total and phosphorylated (P) β-catenin in these stem cells (Western-blot and immunocytochemistry) and the production of pro-MMP-2, active-MMP-2, SDF-1 and CCL-2 levels (ELISA) in conditioned media of fibroblast colony forming units (1CFU-F = 1MSC). Finally, we studied their migration capacity (Transwell assay). The results indicated that BCP-MSC vs HD-MSC had: lower % of MSC-CD146(+) [p=0.0446]; decreased CD146 relative fluorescence index (p=0.0023); decreased TERT activity (p=0.0416); increased P-β-catenin expression (p=0.0001); increased P-β-catenin/ total β-catenin ratio (p=0.0410); increased total ROS levels (p=0.0286); decreased SDF-1, pro and active MMP-2 levels (p=0.0334, 0.0010, 0.0030); increased CCL-2 level (p=0.0370) and poor migration capacity (p=0.0376). Findings suggest that alteration of MSC migration provide more insight to better defining the development of the BM and bone ?pre-metastatic niche?. Also, data show some possible targets aimed to restore migratory capacity of BCP-MSC. Key words: breast cancer, bone marrow, mesenchymal stem cells, migration capacity.