Mesenchymal stromal cells, colony-forming unit fibroblasts, from bone marrow of untreated advanced breast and lung cancer patients suppress fibroblast colony formation from healthy marrow.
We have shown that bone marrow (BM) from untreated advanced lung and breast cancer patients (LCP and BCP) have a reduced number of colony-forming unit fibroblasts (CFU-Fs) 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 stromal cells also inhibits the colony-forming efficiency (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 similar to colony numbers and colony size of patients' CFU-F. Stromal cells from both of these types of colonies appeared relatively larger and lacked the characteristic spindle morphology typically seen in healthy stromal cells. We developed an arbitrary mesenchymal stromal cell maturational index by taking three measures consisting of stromal cell surface area, longitudinal and horizontal axis. All stromal indices derived from HV-CFU-F grown in patients' CM were similar to those from stromal elements derived from patients' CFU-F. These indices were markedly higher than stromal indices typical of HV-CFU-F cultured in healthy CM or standard medium [alpha-medium plus 20% heat-inactivated fetal bovine serum (FBS)]. Patients' CM had increased concentrations of the CFU-F inhibitor, GM-CSF, and low levels of bFGF and Dkk-1, strong promoters of self-renewal of MSCs, compared to the levels quantified in CM from HV-CFU-F. Moreover, the majority of patients' MSCs were unresponsive in standard medium and healthy CM to give CFU-F, indicating that the majority of mesenchymal stromal cells from patients' CFU-F are locked in maturational arrest. These results show that alterations of GM-CSF, bFGF, and Dkk-1 are associated with deficient cloning and maturation arrest of CFU-F. Defective autocrine and paracrine mechanisms may be involved in the BM microenvironments of LCP and BCP.
Hofer
Erica Leonor
EL
Agencia Nacional de Promoción Científica, Tecnológica y de Innovación Productiva, Buenos Aires, Argentina.
Labovsky
Vivian
V
La Russa
Vincent
V
Vallone
Valeria Fernández
VF
Honegger
Alba Elizabeth
AE
Belloc
Carlos Gabriel
CG
Wen
Huei Chi
HC
Bordenave
Raúl Horacio
RH
Bullorsky
Eduardo Oscar
EO
Feldman
Leonardo
L
Chasseing
Norma Alejandra
NA
D001854:Bone Marrow Cells / Q000378:metabolism*; D001943:Breast Neoplasms / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism*; D013997:Time Factors
D017077:Culture Media, Conditioned; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016222:Fibroblast Growth Factor 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor