Bone marrow mesenchymal stem cells orchestra a pro-inflammatory microenvironment creating a pre-metastatic niche in untreated advanced breast cancer patients

BORZONE FR,; FERNÁNDEZ VALLONE VB; BATAGELJ E; MARTINEZ LM; GIORELLO MB; CHOI H; FELDMAN L; CHASSEING NA; LABOVSKY V; BORDENAVE R H; DIMASE F

Mar del Plata

Congreso; Reunión Anual Conjunta Sociedad Argentina de Investigación Clínica (SAIC, LXI Reunión Anual), la Sociedad Argentina de Inmunología (SAI, LXIV Reunión Anual) y la Sociedad Argentina de Farmacología Experimental (SAFE, XLVIII Reunión Anual); 2016

SAI, SAIC, SAFE

Medicina (Bs.As.) 2016, vol 76 sup 1: abst 130, pg 130. Abstract: Most of advanced breast cancer patients (BCP) develop osteolytic bone metastasis. Our previous studies demonstrated that bone marrow-mesenchymal stem cells (BM-MSC) of untreated BCP (invasive ductal carcinoma, stage III-B, without metabolic bone disease) have a decrease of self-renewal, proliferation, and osteogenic/ adipogenic differentiation capacities, as well as, a positive regulation of osteoclastogenic process versus healthy volunteers (HV). Also, we observed elevated levels of TBARS in BM-plasma from these patients, suggesting an increase in reactive oxygen species (ROS) production. It has been proposed that, the oxidative stress inhibits β-catenin signaling, and thus, increase RANKL/OPG ratio, as well as, CCL-2 expression in BM-stromal cells leading to bone resorption. Therefore, we hypothesized that the BM-MSC orchestra a pro-inflammatory microenvironment leading to future imbalance of bone metabolism, and thus favoring bone metastasis appearance in advanced-BCP. We evaluated total and mitochondrial ROS levels in BM-MSC from BCP and HV. Also, we quantified the levels of CCL-2, RANKL and OPG in conditioned medium (CM) of colony-forming unit fibroblast (CFU-F) primary cultures (1CFU-F=1MSC) from both groups. Finally, we investigated the membrane-RANKL expression in BM-MSC. Data showed higher levels of intracellular ROS in MSC from BCP vs HV (p=0.02). Moreover, CCL-2 levels in BCP were higher than HV-values (p=0.0374). In contrast, OPG levels were lower in BCP (p=0.0482). Although the RANKL levels in these CM were lower than detectable doses, membrane-RANKL expression/MSC was higher in BCP compared with HV. In conclusion, high levels of ROS, CCL-2 and membrane-RANKL in BM-MSC would increase bone resorption, leading to breast tumor cells invasion and proliferation. Taken together, the BM-MSC of advanced BCP creates an ideal environment (?pre-metastatic niche?) for the metastatic development. Keywords: breast cancer, bone marrow, mesenchymal stem cells, pre-metastatic niche, oxidative stress, osteoclastogenic factors