Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

Abstract

IntroductionMesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors.MethodsBone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR.ResultsBoth co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage inflammatory protein-2, vascular endothelial growth factor, transforming growth factor-beta and IL-6) was increased.ConclusionThese results indicate that BM-MSCs promote tumor growth and suggest that the crosstalk between tumor cells and BM-MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.

The zebrafish/tumor xenograft angiogenesis assay as a tool for screening anti-angiogenic miRNAs

“…The zebrafish/ tumor xenograft angiogenesis assay is based on the grafting of mammalian tumor cells in the proximity of the developing SIV plexus at 48 hpf. To evaluate whether the assay could be used for the validation of anti-angiogenic miRNAs, we transfected them in DU-145 prostate cancer cell line often used for investigating tumor angiogenesis (Connolly and Rose 1998;Arbiser et al 2002;Zhang et al 2013). Firstly we evaluated the miR-125a, miR-320, miR-487b and miR-492 endogenous expression levels in DU-145 cells in comparison to normal prostate cells (FirstChoice Human Prostate Total RNA, Ambion).…”

Conditioned medium from mesenchymal stem cells enhances the migration of hepatoma cells through CXCR4 up-regulation and F-actin remodeling

“…To avoid this possible safety concern, recent attention hasbeen focused on using MSC-CM to develop a cell-free therapeutic approach in stem cell therapy (Timmers et al 2011;Ivanova-Todorova et al 2012;Osugi et al 2012;Cantinieaux et al 2013). However, Zhang et al (2013) found that both co-culturing with MSCs and treatment with MSC-CM enhances the growth of 4T1 breast cancer cells. Our data also show a significantly increased migratory ability of rat hematoma CBRH-7919 cells in the presence of MSC-CM.…”

Poly r(C) Binding Protein-1 is Central to Maintenance of Cancer Stem Cells in Prostate Cancer Cells

“…Since it has been previously suggested that TGF-β can contribute to stemness of prostate cancer cells [12,13], we sought to determine the effect of TGF-β on the abundance of CD44+CD24- population in the LNCaP cell line. Fluorescent activated cell sorting (FACS) revealed that CD44+CD24- were significantly enriched in LNCaP cells treated with TGF-β for 7 days (22.35 ± 0.94% in mock treated vs 95.23 ± 2.34% in TGF-β treated cells; P < 0.01) (Fig.…”

“…It has been elucidated by various research groups that TGF-β secreted from the tumor microenvironment and bone marrow derived mesenchymal cells both contribute to stemness of prostate cancer cells [12,13]. However, not much, if any, is known about the underlying mechanisms that contribute to the maintenance of PCa stem cell population in the presence of secreted TGF-β.…”