Mesenchymal stem cells in early entry of breast cancer into bone marrow.
BACKGROUND
An understanding of BC cell (BCC) entry into bone marrow (BM) at low tumor burden is limited when compared to highly metastatic events during heavy tumor burden. BCCs can achieve quiescence, without interfering with hematopoiesis. This occurs partly through the generation of gap junctions with BM stroma, located close to the endosteum. These events are partly mediated by the evolutionary conserved gene, Tac1.


RESULTS
This study focuses on the role of mesenchymal stem cells (MSCs), Tac1, SDF-1 and CXCR4 in BCC entry into BM. The model is established in studies with low numbers of tumor cells, and focuses on cancer cells with low metastatic and invasion potential. This allowed us to recapitulate early event, and to study cancer cells with low invasive potential, even when they are part of larger numbers of highly metastatic cells. A novel migration assay showed a facilitating role of MSCs in BCC migration across BM endothelial cells. siRNA and ectopic expression studies showed a central role for Tac1 and secondary roles for SDF-1alpha and CXCR4. We also observed differences in the mechanisms between low invasive and highly metastatic cells. The in vitro studies were verified in xenogeneic mouse models that showed a preference for low invasive BCCs to BM, but comparable movement to lung and BM by highly metastatic BCCs. The expressions of Tac1 and production of SDF-1alpha were verified in primary BCCs from paired samples of BM aspirates and peripheral blood.


CONCLUSIONS
MSC facilitate BCC entry into BM, partly through Tac1-mediated regulation of SDF-1alpha and CXCR4. We propose a particular population of BCC with preference for BM could be isolated for characterization. This population might be the subset that enter BM at an early time period, and could be responsible for cancer resurgence and resistance to current therapies.
Department of Medicine, New Jersey Medical School-UMDNJ, Newark, New Jersey, United States of America.
Kelly E
KE
Corcoran
Katarzyna A
KA
Trzaska
Helen
H
Fernandes
Margarette
M
Bryan
Marcelo
M
Taborga
Venkatesh
V
Srinivas
Kathryn
K
Packman
Prem S
PS
Patel
Pranela
P
Rameshwar
D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4