Bone marrow cells participate in tumor vessel formation that supports the growth of Ewing’s sarcoma in the lung

Abstract

An MHC-mismatch bone marrow (BM) transplant Ewing's sarcoma mouse model was used to investigate whether BM cells participate in the vessel formation that support Ewing's sarcoma lung metastasis. BM cells from H-2K b/d donor mice were transplanted into sublethally irradiated H-2K d recipient mice. Donor BM cells were identified using the H-2K b marker. Engraftment was confirmed by identifying the H-2K b IL-1β-type specific polymorphism. After engraftment highly lung metastatic TC71-PM4 cells were injected intravenously. Mice were sacrificed 10 weeks after tumor cell injection. Hematoxylin-and-eosin staining was performed to identify lung metastatic foci. These tumors were then evaluated using immunohistochemical analysis. H-2K b -positive cells were found in lung metastases but not in normal lung, liver or spleen tissues. Injection of CM-Dillabeled BM cells into tumor bearing and control mice showed that nonspecific organ migration occurred at 24 h, but that these cells were absent 1 week later in control mice. These data suggest that the migration of the H-2K b BM cells to lung nodules was specific because these cells were observed 14 weeks after transplantation. Co-localization of H-2K b and CD31 or VE-Cadherin demonstrated that some endothelial cells were BM-derived. Co-localization of H-2K b and Desmin, smooth muscle actin (α-SMA) or PDGFR-β indicated that a fraction of pericytes was also BMderived. These results suggest that BM cells participate in the vascular formation that supports the growth of Ewing's sarcoma lung metastases. BM cells migrated to the metastatic tumor and differentiated into endothelial cells and pericytes. These data indicated that targeting this process may have therapeutic potential.

Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion

“…These data confirmed that REST plays a critical role in maintaining and expanding ES tumor vessels that are required for tumor growth. These findings together with our previous studies show that interfering with vascular formation and expansion severely retards not only tumor growth but also metastasis to the lung [16][17][18][19][20][21]. REST is therefore a potential target for ES therapy.…”

Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination

“…Interestingly, studies in experimental models have indicated that mature pericytes protect endothelial cells against VEGFR-directed therapies [ 22 , 23 ]. The recent demonstration that tumor cells are able to induce pericyte maturation of the neovasculature during early formation of micrometastatic foci [ 24 ] might provide one explanation for the lack of efficacy of bevacizumab in eradicating occult metastatic disease in colorectal cancer.…”

Hypoxia induces lineage modulation of Ewing’s sarcoma tumor cells into EWS-FLI-1 + vascular pericytes

“…We have shown that in ES, migration of bone marrow stem cells to the tumor site and differentiation of these cells into pericytes plays a role in the formation of new tumor blood vessels [9][10][11][12][13][14][15]. Interfering with tumor pericyte formation, similar to interfering with endothelial progenitor cells, significantly interfered with tumor vascular expansion, tumor growth and metastases [9][10][11][12][13][14][15][16]. These bone marrow-derived stem cells had migrated into the tumor area in response to VEGF165 and SDF-1 [14,17,18].…”