Critical molecular mechanisms that modify bone marrow-mesenchymal stem cell behavior in advanced breast cancer patients.

BORZONE FR; FERNÁNDEZ VALLONE VB; BATAGELJ E; YANNARELLI G; GIORELLO MB; PICCIONI F; PACIENZA N; SANMARTIN MC; MARTINEZ LM; FELDMAN L; CHASSEING NA

CABA

Congreso; Reunión Conjunta de la Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Fisiología (SAFIS) 2020.; 2020

Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Fisiología (SAFIS) .

Most of untreated advanced breast cancer patients (BCP, invasive ductal, stage IIIB) develop osteolytic bone metastasis, due to the existence of a pre-metastatic niche (PMN) that favours extravasation, migration, and proliferation of tumor cells. We found that bone marrow (BM) mesenchymal stem cells (MSC) from BCP have lower cloning, proliferation, and osteogenic differentiation capacities than healthy donors (HD) MSC. A conserved pool of functional MSC is essential for preventing the PMN formation.Thus, our aim was to identify the molecular mechanisms responsible for the loss of function in MSC from BCP. For this purpose, we studied the expression of stemness markers (OCT4, SOX2, hTERT, CD49b, CD146, telomere length), triggers osteogenic differentiation (RUNX2 and BMP2) [qPCR], and the cellular oxidative state (ROS levels) [FACS] in MSC from enriched cultures of BM aspirates from BCP vs HD. We also evaluated the morphologic characteristics [Optical Microscopy], proliferation capacity [Proliferation Assay], and cell cycle profile of MSC [FACS]. Besides, we compared the pool of MSC in BM aspirates [RosetteSepTM].The results indicated that BCP-MSC (n=7) vs HD-MSC (n=7) had: lower expression levels of OCT4 (p=0.026), SOX2 (p=0.008), hTERT (p= 0.004), CD146 (p=0.041) and higher levels of CD49b (p=0.028), RUNX2 (P=0.039) and BMP2 (P=0.033); shortened telomere length (p=0.002); increased ROS levels (p=0.036); decreased proliferative capacity (p=0.03); higher relative proportions of cells in G0/G1 phase (p=0.011) and lower in S phase (p=0.033); lower number of CFU-F (p=0.01); increased area (p=0.001), higher long (p=0.02) and short axis (p=0.001). In addition, BCP vs HD had a poor pool of BM MSC (p=0.006).In conclusion, the lower expression of OCT4 and SOX2 in MSC, would lead to an ineffective self-renewal, proliferation, and differentiation of these stem cells, providing insights about the molecular alterations in the BCP-MSC, key players in the development of the PMN.