CDH1 and IL1-beta expression dictates FAK and MAPKK-dependent cross-talk between cancer cells and human mesenchymal stem cells

Is Figure S1 showing transfer of cellular components between hMSCs and cancer cells. (DOCX 214 kb

Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells

Additional file 5: Figure S4. BMP2 expression in CRC cell lines from the Cancer Cell Line Encyclopedia. Data are presented as mRNA expression (Log2)

In vitro differentiation of human skin-derived multipotent stromal cells into putative endothelial-like cells

<p>Abstract</p> <p>Background</p> <p>Multipotent stem cells have been successfully isolated from various tissues and are currently utilized for tissue-engineering and cell-based therapies. Among the many sources, skin has recently emerged as an attractive source for multipotent cells because of its abundance. Recent literature showed that skin stromal cells (SSCs) possess mesoderm lineage differentiation potential; however, the endothelial differentiation and angiogenic potential of SSC remains elusive. In our study, SSCs were isolated from human neonatal foreskin (hNFSSCs) and adult dermal skin (hADSSCs) using explants cultures and were compared with bone marrow (hMSC-TERT) and adipose tissue-derived mesenchymal stem cells (hADMSCs) for their potential differentiation into osteoblasts, adipocytes, and endothelial cells.</p> <p>Results</p> <p>Concordant with previous studies, both MSCs and SSCs showed similar morphology, surface protein expression, and were able to differentiate into osteoblasts and adipocytes. Using an endothelial induction culture system combined with an in vitro matrigel angiogenesis assay, hNFSSCs and hADSSCs exhibited the highest tube-forming capability, which was similar to those formed by human umbilical vein endothelial cells (HUVEC), with hNFSSCs forming the most tightly packed, longest, and largest diameter tubules among the three cell types. CD146 was highly expressed on hNFSSCs and HUVEC followed by hADSSCs, and hMSC-TERT, while its expression was almost absent on hADMSCs. Similarly, higher vascular density (based on the expression of CD31, CD34, vWF, CD146 and SMA) was observed in neonatal skin, followed by adult dermal skin and adipose tissue. Thus, our preliminary data indicated a plausible relationship between vascular densities, and the expression of CD146 on multipotent cells derived from those tissues.</p> <p>Conclusions</p> <p>Our data is the first to demonstrate that human dermal skin stromal cells can be differentiated into endothelial lineage. Hence, SSCs represents a novel source of stem/stromal cells for tissue regeneration and the vascularization of engineered tissues. Moreover, the CD146 investigations suggested that the microenvironmental niche might contribute to direct stromal cells multipotency toward certain lineages, which warrants further investigation.</p

CXCR7 signaling promotes breast cancer survival in response to mesenchymal stromal stem cell-derived factors

Abstract The interaction between cancer cells and molecular cues provided by tumor stromal cells plays a crucial role in cancer growth and progression. We have recently reported that the outcome of interaction between tumor cells and stromal cells is dependent on the gene expression signature of tumor cells. In the current study, we observed that several cancer cell lines, e.g., MCF7 breast cancer line, exhibited growth advantage when cultured in the presence of conditioned media (CM) derived from human bone marrow stromal stem cells (hBMSCs). Regarding the underlying molecular mechanism, we have identified CXCR7 as highly expressed by MCF7 cells and that it mediated the enhanced growth in response to hBMSC CM. Regarding the clinical relevance, we found an inverse correlation between the level of tumor gene expression of CXCR7 in bladder, breast, cervical, kidney, liver, lung, pancreatic, stomach, and uterine cancers, and patients’ overall survival. Interestingly, significant positive correlation between CXCR7 and CXCL12 gene expression (Pearson = 0.3, p = 2.0 × 10–16) was observed in breast cancer patients, suggesting a biological role for the CXCR7/CXCL12 genetic circuit in breast cancer biology. Our data provide insight into the molecular mechanisms by which stromal-derived microenvironmental cues mediate CXCR7 signaling and growth enhancement of breast cancer cells. Therapeutic targeting of this circuit might provide novel therapeutic opportunity for breast cancer

Romidepsin Promotes Osteogenic and Adipocytic Differentiation of Human Mesenchymal Stem Cells through Inhibition of Histondeacetylase Activity

Bone marrow mesenchymal stem cells (BMSCs) are adult multipotent stem cells that can differentiate into mesodermal lineage cells, including adipocytes and osteoblasts. However, the epigenetic mechanisms governing the lineage-specific commitment of BMSCs into adipocytes or osteoblasts are under investigation. Herein, we investigated the epigenetic effect of romidepsin, a small molecule dual inhibitor targeting HDAC1 and HDAC2 identified through an epigenetic library functional screen. BMSCs exposed to romidepsin (5 nM) exhibited enhanced adipocytic and osteoblastic differentiation. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis and osteogenesis in romidepsin-treated BMSCs during induction into adipocytes or osteoblasts, respectively. Pharmacological inhibition of FAK signaling during adipogenesis or inhibition of FAK or TGFβ signaling during osteogenesis diminished the biological effects of romidepsin on BMSCs. The results of chromatin immunoprecipitation combined with quantitative polymerase chain reaction indicated a significant increase in H3K9Ac epigenetic markers in the promoter regions of peroxisome proliferator-activated receptor gamma (PPARγ) and KLF15 (related to adipogenesis) or SP7 (Osterix) and alkaline phosphatase (ALP) (related to osteogenesis) in romidepsin-treated BMSCs. Our data indicated that romidepsin is a novel in vitro modulator of adipocytic and osteoblastic differentiation of BMSCs

MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1

Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide. Delineating the molecular mechanisms leading to CRC development and progression, including the role of microRNAs (miRNAs), are currently being unravelled at a rapid rate. Here, we report frequent downregulation of the microRNA miR-320 family in primary CRC tissues and cell lines. Lentiviral-mediated re-expression of miR-320c (representative member of the miR-320 family) inhibited HCT116 CRC growth and migration in vitro, sensitized CRC cells to 5-Fluorouracil (5-FU), and inhibited tumor formation in SCID mice. Global gene expression analysis in CRC cells over-expressing miR-320c, combined with in silico prediction identified 84 clinically-relevant potential gene targets for miR-320 in CRC. Using a series of biochemical assays and functional validation, SOX4, FOXM1, and FOXQ1 were validated as novel gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients' specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression levels of this gene panel (SOX4, FOXM1, and FOXQ1) in The Cancer Genome Atlas (TCGA) colorectal cancer data set (319 patients) revealed significantly poor disease-free survival in patients with elevated expression of this gene panel (P-Value: 0.0058). Collectively, our data revealed a novel role for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC