Supplementary-Figure 4 Absolute numbers of HSPCs and MSCs after G-CSF and G-CSF+PTH/ZA treatment and in Mx 1fl/fl knockout mice (A) The absolute number of HSPCs per femur was lower after treatment with G-CSF, whereas the number of MSCs was higher, n=12/14 in 3 experiments. (B) Addition of PTH/ZA to G-CSF did not affect HSPCs further, but reduced the absolute number of MSCs, n=14/14 in 3 experiments. (C) Conditional deletion of integrin 1 (Mx 1fl/fl) in the bone marrow had no effect on HSPCs, but led to increased absolute numbers of MSCs, n=6/9 in 2 experiments. Expression of MSC markers on low-passage human MSCs (D) In order to evaluate potential MSC markers, adherent human bone marrow cells (passages 0 or 1) were dissociated from the plates and stained for flow cytometry analysis. Shown is a graph summarizing the findings. In addition, in each panel the unstained control is shown on the left and the bone marrow staining on the right (E). The cells were 79% positive for CD31, 91% positive for CD44, 22% positive for CD56, 95% positive for CD73, 59% positive for CD140b, 61% positive for CD144, 72% positive for CD146, 87% positive for CD271, 87% positive for CD349, 90% positive for FAP, 90% positive for MSCA1, and 92% positive for Stro1; n=4 different aspirates.
ARTICLE ABSTRACT
Breast and prostate cancer cells home to the bone marrow, where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSCs by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers, suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this MSC subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.Significance: These findings establish an inverse relationship between a subpopulation of mesenchymal stromal cells and cancer cells in the bone marrow. Cancer Res; 78(1); 129–42. ©2017 AACR.
