Mesenchymal Stroma/stem Cells Research Articles

Stem Cells for Cancer Therapy: Translating the Uncertainties and Possibilities of Stem Cell Properties into Opportunities for Effective Cancer Therapy.

Cancer recurrence and drug resistance following treatment, as well as metastatic forms of cancer, are trends that are commonly encountered in cancer management. Amidst the growing popularity of personalized medicine and targeted therapy as effective cancer treatment, studies involving the use of stem cells in cancer therapy are gaining ground as promising translational treatment options that are actively pursued by researchers due to their unique tumor-homing activities and anti-cancer properties. Therefore, this review will highlight cancer interactions with commonly studied stem cell types, namely, mesenchymal stroma/stem cells (MSC), induced pluripotent stem cells (iPSC), iPSC-derived MSC (iMSC), and cancer stem cells (CSC). A particular focus will be on the effects of paracrine signaling activities and exosomal miRNA interaction released by MSC and iMSCs within the tumor microenvironment (TME) along with their therapeutic potential as anti-cancer delivery agents. Similarly, the role of exosomal miRNA released by CSCs will be further discussed in the context of its role in cancer recurrence and metastatic spread, which leads to a better understanding of how such exosomal miRNA could be used as potential forms of non-cell-based cancer therapy.

Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial-Mesenchymal Transition.

Epithelial–mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.

MSC stimulate ovarian tumor growth during intercellular communication but reduce tumorigenicity after fusion with ovarian cancer cells

The tumor microenvironment enables important cellular interactions between cancer cells and recruited adjacent populations including mesenchymal stroma/stem cells (MSC). In vivo cellular interactions of primary human MSC in co-culture with human SK-OV-3 ovarian cancer cells revealed an increased tumor growth as compared to mono-cultures of the ovarian cancer cells. Moreover, the presence of MSC stimulated formation of liver metastases. Further interactions of MSC with the ovarian cancer cells resulted in the formation of hybrid cells by cell fusion. Isolation and single cell cloning of these hybrid cells revealed two differentially fused ovarian cancer cell populations termed SK-hyb1 and SK-hyb2. RNA microarray analysis demonstrated expression profiles from both parental partners whereby SK-hyb1 were attributed with more SK-OV-3 like properties and SK-hyb2 cells displayed more similarities to MSC. Both ovarian cancer hybrid populations exhibited reduced proliferative capacity compared to the parental SK-OV-3 cells. Moreover, the fused populations failed to develop tumors in NODscid mice. Together, these data suggested certain stimulatory effects on ovarian tumor growth in the presence of MSC. Conversely, fusion of MSC with SK-OV-3 cells contributed to the generation of new cancer hybrid populations displaying a significantly reduced tumorigenicity.

Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC)

BackgroundFusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear.MethodsFunctional changes were investigated in vitro and in vivo following spontaneous fusion and hybrid cell formation between primary human MSC and human MDA-MB-231 breast cancer cells. Thus, lentiviral eGFP-labeled MSC and breast cancer cells labeled with mcherry resulted in dual-fluorescing hybrid cells after co-culture.ResultsDouble FACS sorting and single cell cloning revealed two different aneuploid male hybrid populations (MDA-hyb1 and MDA-hyb2) with different STR profiles, pronounced telomerase activities, and enhanced proliferative capacities as compared to the parental cells. Microarray-based mRNA profiling demonstrated marked regulation of genes involved in epithelial-mesenchymal transition and increased expression of metastasis-associated genes including S100A4. In vivo studies following subcutaneous injection of the breast cancer and the two hybrid populations substantiated the in vitro findings by a significantly elevated tumor growth of the hybrid cells. Moreover, both hybrid populations developed various distant organ metastases in a much shorter period of time than the parental breast cancer cells.ConclusionTogether, these data demonstrate spontaneous development of new tumor cell populations exhibiting different parental properties after close interaction and subsequent fusion of MSC with breast cancer cells. This formation of tumor hybrids contributes to continuously increasing tumor heterogeneity and elevated metastatic capacities.

Tumor microenvironment heterogeneity: challenges and opportunities.

The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.

SCCOHT tumors acquire chemoresistance and protection by interacting mesenchymal stroma/stem cells within the tumor microenvironment.

Chemotherapeutic drug testing of SCCOHT-1 and BIN-67 tumor cells revealed synergistic growth-inhibition of >95% invitro with a combination of foretinib and FK228. Application of this drug combination in vivo in NODscid mice-induced SCCOHT-1GFP tumors was associated with ~6-fold reduction in tumor mass within 10days, whereby synergistic effects of the two compounds remained undetectable compared to previous results with foretinib treatment alone. Histopathologic evaluation revealed a reduced vascularization and a lower amount of proliferating cells in the treated tumors. Surprisingly, a simultaneous significant accumulation of extracellular matrix structures with positive elastin-van Gieson staining was observed following foretinib/FK228 exposure. Expression analysis of treated animal tumors exhibited various changes including increased mouse transcript levels of elastin, laminin, and fibronectin. In parallel, markers for mesenchymal stroma/stem cells (MSC) including CD73 and CD90 were detectable in all mouse tumors suggesting a possible involvement of these cells in extracellular matrix restructure. Indeed, incubation of MSC with FK228 or foretinib/FK228 demonstrated morphologic alterations and enhanced expression of laminin and fibronectin. Moreover, a co-culture of MSC with lentiviral-labeled SCCOHT-1GFP cells contributed to protection of the tumor cells against FK228-mediated cytotoxicity. Furthermore, explant cultures of SCCOHT-1GFP-induced tumors acquired an increased resistance to FK228 and a combination of foretinib/FK228 in contrast to foretinib alone. Together, these data suggested that FK228-mediated extracellular matrix protein expression by MSC contributes to increased protection and enhanced resistance of SCCOHT tumors which could represent a more general mechanism of MSC during drug-induced alterations of a tumor microenvironment.

Interaction of MSC with tumor cells.

Tumor development and tumor progression is not only determined by the corresponding tumor cells but also by the tumor microenvironment. This includes an orchestrated network of interacting cell types (e.g. immune cells, endothelial cells, fibroblasts, and mesenchymal stroma/stem cells (MSC)) via the extracellular matrix and soluble factors such as cytokines, chemokines, growth factors and various metabolites. Cell populations of the tumor microenvironment can interact directly and indirectly with cancer cells by mutually altering properties and functions of the involved partners. Particularly, mesenchymal stroma/stem cells (MSC) play an important role during carcinogenesis exhibiting different types of intercellular communication. Accordingly, this work focusses on diverse mechanisms of interaction between MSC and cancer cells. Moreover, some functional changes and consequences for both cell types are summarized which can eventually result in the establishment of a carcinoma stem cell niche (CSCN) or the generation of new tumor cell populations by MSC-tumor cell fusion.

Molecular Mechanisms of PPAR-γ Governing MSC Osteogenic and Adipogenic Differentiation.

Sharing the same precursor cell lineage located in the bone marrow, mesenchymal stroma/stem cells (MSCs), osteoblasts and adipocytes have a reciprocal relationship in differentiation and function. The nuclear transcription factor peroxisome-proliferator- activated receptor-gamma (PPAR-γ) has been found expressed in both osteoblasts and adipocytes, as well as in MSCs, suggesting its crucial role in regulating adipocyte formation and osteoblast development. It has been observed in animal models that upregulated PPAR-γ activity results in bone loss where marrow adiposity is facilitated, while downregulated PPAR-γ activity leads to bone mass elevation. Evidence suggests that the dual function of PPAR-γ in either anti-osteoblastic or pro-adipocytic aspects is determined by its ligand. Furthermore, various cytokines and extracellular signaling pathways are involved in the transactivation of PPAR-γ, which can trigger the adipogenesis/osteoblastogenesis switch. PPAR-γ, therefore, shows tremendous potential in novel strategies for bone tissue engineering and clinical application. This review summarizes the regulatory function of PPAR-γ in MSC differentiation, as well as the cytokine and extracellular signaling pathways participating in the cross-talk between adipogenesis and osteoblastogenesis.

Human mesenchymal stroma/stem cells exchange membrane proteins and alter functionality during interaction with different tumor cell lines.

To analyze effects of cellular interaction between human mesenchymal stroma/stem cells (MSC) and different cancer cells, direct co-cultures were performed and revealed significant growth stimulation of the tumor populations and a variety of protein exchanges. More than 90% of MCF-7 and primary human HBCEC699 breast cancer cells as well as NIH:OVCAR-3 ovarian adenocarcinoma cells acquired CD90 proteins during MSC co-culture, respectively. Furthermore, SK-OV-3 ovarian cancer cells progressively elevated CD105 and CD90 proteins in co-culture with MSC. Primary small cell hypercalcemic ovarian carcinoma cells (SCCOHT-1) demonstrated undetectable levels of CD73 and CD105; however, both proteins were significantly increased in the presence of MSC. This co-culture-mediated protein induction was also observed at transcriptional levels and changed functionality of SCCOHT-1 cells by an acquired capability to metabolize 5'cAMP. Moreover, exchange between tumor cells and MSC worked bidirectional, as undetectable expression of epithelial cell adhesion molecule (EpCAM) in MSC significantly increased after co-culture with SK-OV-3 or NIH:OVCAR-3 cells. In addition, a small population of chimeric/hybrid cells appeared in each MSC/tumor cell co-culture by spontaneous cell fusion. Immune fluorescence demonstrated nanotube structures and exosomes between MSC and tumor cells, whereas cytochalasin-D partially abolished the intercellular protein transfer. More detailed functional analysis of FACS-separated MSC and NIH:OVCAR-3 cells after co-culture revealed the acquisition of epithelial cell-specific properties by MSC, including increased gene expression for cytokeratins and epithelial-like differentiation factors. Vice versa, a variety of transcriptional regulatory genes were down-modulated in NIH:OVCAR-3 cells after co-culture with MSC. Together, these mutual cellular interactions contributed to functional alterations in MSC and tumor cells.