Mesenchymal Stromal Cells, CFU-F, From Bone Marrow of untreated Advanced Breast and Lung Cancer Patients Suppress Fibroblast Colonies Formation From Healthy Marrow

ERICA LEONOR HOFER; VIVIAN LABOVSKY; VINCENT LA RUSSA; VALERIA FERNÁNDEZ VALLONE; ALBA ELIZABETH HONEGGER; CARLOS GABRIEL BELLOC; HUEI CHI WEN; RAUL HORACIO BORDENAVE; EDUARDO OSCAR BULLORSKY; LEONARDO FELDMAN; NORMA ALEJANDRA CHASSEING

Stem Cells and Development

Mary Ann Liebert, Inc

Lugar: New Rochelle, NY; Año: 2010 vol. 19 p. 359 - 370

1557-8534

We have shown that bone marrows (BM) from untreated advanced lung and breast cancer patients (LCP andBCP) have a reduced number of colony-forming units-fi broblast (CFU-F) or mesenchymal stem cells (MSCs).Factors that regulate the proliferation and differentiation of CFU-F are produced by the patients’ BM microenvironment.We have now examined whether conditioned media (CM) from patients’ CFU-F-derived stromalcells also inhibits the colony-forming effi ciency (CFE) of CFU-F in primary cultures from healthy volunteers(HV)-BM. Thus the number and proliferation potential of HV-CFU-F were also found to be decreased and similarto colony numbers and colony size of patients’ CFU-F. Stromal cells from both of these types of coloniesappeared relatively larger and lacked the characteristic spindle morphology typically seen in healthy stromalcells. We developed an arbitrary mesenchymal stromal cell maturational index by taking three measures consistingof stromal cell surface area, longitudinal and horizontal axis. All stromal indices derived from HV-CFU-Fgrown in patients’ CM were similar to those from stromal elements derived from patients’ CFU-F. These indiceswere markedly higher than stromal indices typical of HV-CFU-F cultured in healthy CM or standard medium[α-medium plus 20% heat-inactivated fetal bovine serum (FBS)]. Patients’ CM had increased concentrations ofthe CFU-F inhibitor, GM-CSF, and low levels of bFGF and Dkk-1, strong promoters of self-renewal of MSCs,compared to the levels quantifi ed in CM from HV-CFU-F. Moreover, the majority of patients’ MSCs were unresponsivein standard medium and healthy CM to give CFU-F, indicating that the majority of mesenchymal stromalcells from patients’ CFU-F are locked in maturational arrest. These results show that alterations of GM-CSF,bFGF, and Dkk-1 are associated with defi cient cloning and maturation arrest of CFU-F. Defective autocrine andparacrine mechanisms may be involved in the BM microenvironments of LCP and BCP.