Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile.
Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34(+) cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period.
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada, Pamplona, Spain;
Bruno
B
Paiva
Teresa
T
Paino
Jose-Maria
JM
Sayagues
Mercedes
M
Garayoa
Laura
L
San-Segundo
Montserrat
M
Martín
Ines
I
Mota
María-Luz
ML
Sanchez
Paloma
P
Bárcena
Irene
I
Aires-Mejia
Luis
L
Corchete
Cristina
C
Jimenez
Ramon
R
Garcia-Sanz
Norma C
NC
Gutierrez
Enrique M
EM
Ocio
Maria-Victoria
MV
Mateos
Maria-Belen
MB
Vidriales
Alberto
A
Orfao
Jesús F
JF
San Miguel
D015703:Antigens, CD / Q000097:blood; D002453:Cell Cycle; D002940:Circadian Rhythm; D020732:Cytogenetic Analysis; D006801:Humans; D016130:Immunophenotyping; D009101:Multiple Myeloma / Q000097:blood* / Q000235:genetics / Q000276:immunology; D009360:Neoplastic Cells, Circulating / Q000145:classification / Q000276:immunology / Q000473:pathology*; D010950:Plasma Cells / Q000145:classification / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D014410:Tumor Stem Cell Assay
D015703:Antigens, CD