Cancer-associated Mesenchymal Stem Cells Research Articles

Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.

Retraction: Exosomes from cancer-associated mesenchymal stem cells transmit TMBIM6 to promote the malignant behavior of hepatocellular carcinoma via activating PI3K/AKT pathway

Retraction: Exosomes from cancer-associated mesenchymal stem cells transmit TMBIM6 to promote the malignant behavior of hepatocellular carcinoma via activating PI3K/AKT pathway

Role of cancer-associated mesenchymal stem cells in the tumor microenvironment: A review.

Mesenchymal stem cells (MSCs) were applied to the therapy for degenerative diseases, immune, and inflammation. In tumor microenvironments (TME), different sources of MSCs showed that tumor-promoting and -inhibiting effects were mediated by different signaling pathways. Cancer-associated MSCs (CaMSCs) could be recruited from bone marrow or local tissues and mainly showed tumor-promoting and immunosuppressive effects. The transformed CaMSCs preserve the characteristics of stem cells, but the properties of regulating TME are different. Hence, we specifically focus on CaMSCs and discuss the detailed mechanisms of regulating the development of cancer cells and immune cells. CaMSCs could be a potential therapeutic target in various types of cancer. However, the detailed mechanisms of CaMSCs in the TME are relatively less known and need further study.

The role of mesenchymal stem cells in the ovarian cancer precarcinoma microenvironment (091)

<b>Objectives:</b> Research on ovarian cancer (OC) initiation has primarily focused on the transformation from normal epithelium to invasive serous carcinoma; however, the role of the stromal microenvironment in cancer initiation is largely unexplored. We previously demonstrated that mesenchymal stem cells (MSCs), stromal progenitor cells in the OC microenvironment, are reprogrammed by tumor cells into cancer-associated MSCs (CA-MSCs). These reprogrammed CA-MSCs promote cancer growth, chemoresistance, and metastases. We sought to determine if changes in the stromal microenvironment occur prior to OC initiation. We identified a subset of MSCs in the fallopian tubes of women with germline <i>BRCA</i> mutations without cancer that have acquired a CA-MSC phenotype, which we term high-risk MSCs (HR-MSCs). We hypothesized that HR-MSCs acquire a tumor supportive phenotype prior to OC initiation that enhances the transformation of the normal epithelium into carcinoma. <b>Methods:</b> MSCs and fallopian tube epithelial cells (FTE) were isolated from fallopian tubes of women with germline <i>BRCA</i> mutations undergoing risk-reducing salpingo-oophorectomies without findings of cancer or pre-cancerous lesions upon standard pathologic examination. MSCs were characterized as low-risk (LR-MSCs) or high-risk (HR-MSCs) using a previously described MSC classifier score. Co-cultures were performed using normal FTE, <i>BRCA</i>-mutated (<i>BRCA</i>mut) FTE, and <i>BRCA</i>/p53-mutated FTE with LR-MSCs or HR-MSCs. FTE and MSC growth and proliferation were assessed using <i>in vitro</i> assays. We investigated the impact of HR-MSCs on FTE DNA damage after co-culture using FTE alone as control with yH2AX foci quantification. Long-term organoid co-cultures of MSCs and FTE were implanted into NSG mice to assess tumor initiation capacity. <b>Results:</b> HR-MSCs significantly enhance <i>BRCA</i>mut FTE growth compared to LR-MSCs. HR-MSCs also induced DNA damage in FTE. Strikingly, DNA damage induced by HR-MSCs was similar to that seen with hydrogen peroxide (H2O2) treatment of FTE. HR-MSCs also increased the survival of <i>BRCA</i>mut FTE after the induction of DNA damage by H2O2 treatment, indicating that HR-MSCs induce FTE DNA damage and promote survival of DNA-damaged FTE. HR-MSCs were also able to induce full malignant transformation as injecting HR-MSCs + <i>BRCA</i>mut FTE organoids-initiated tumors in one of three mice, and HR-MSCs + <i>BRCA</i>/p53-mut FTE organoids-initiated tumors in two of three mice (one of which developed metastasis). No mice injected with LR-MSCs or FTE alone developed tumors. <b>Conclusions:</b> A subset of women with <i>BRCA</i> mutations at high risk for OC contains fallopian tube-derived MSCs, which functionally support ovarian cancer initiation. These HR-MSCs increase FTE proliferation, induce FTE DNA damage, enhance survival of DNA-damaged FTE, and ultimately have the capacity to induce full malignant transformation with tumor initiation and metastasis <i>in vivo</i>. This highlights a critical role for the stromal microenvironment in OC initiation.Fig. 1

Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer.

Simple SummaryMetformin is a drug commonly used to treat diabetes but it may play a role in cancer treatment. It is not known exactly how metformin acts on cancer cells and cells in the tumor microenvironment (TME). Our previous work suggested that metformin may be altering specific cells in the tumor microenvironment called cancer-associated mesenchymal stem cells (CA-MSC). The aim of this study was to build on our previous work to understand the impact of metformin on the TME. We demonstrated that when individuals with epithelial ovarian cancer received metformin in addition to chemotherapy, their tumors were less likely to have CA-MSC and T regulatory cells, which are both known to promote tumor growth, when compared to tumors from individuals who received chemotherapy alone. Additional experiments with ovarian cancer cells and tumors grown in mice suggested that metformin might be best used to prevent tumor growth rather than treat advanced stage disease.Controversy persists regarding metformin’s role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin’s impact on the human TME, focusing on the interplay of stroma and immune infiltrates. Tumor samples from (i) 38 patients treated with metformin and chemotherapy and (ii) 44 non-metformin matched controls were included in a tissue microarray (TMA). The TMA was used to compare the presence of CA-MSC, desmoplasia and immune infiltrates in the TME. In vitro and in vivo models examined metformin’s role in alteration of the CA-MSC phenotype. The average percentage of CA-MSC was significantly lower in metformin-treated than in chemotherapy alone-treated tumors (p = 0.006). There were fewer regulatory T-cells in metformin-treated tumors (p = 0.043). Consistent with CA-MSC’s role in excluding T-cells from tumor islets, the T-cells were primarily present within the tumor stroma. Evaluation of metformin’s impact in vitro suggested that metformin cannot reverse a CA-MSC phenotype; however, the in vivo model where metformin was introduced prior to the establishment of the CA-MSC phenotype supported that metformin can partially prevent the reprogramming of normal MSC into CA-MSC. Metformin treatment led to a decrease in both the presence of protumorigenic CA-MSC and in immune exclusion of T cells, leading to a more immune-permissive environment. This suggests clinical utility in prevention and in treatment for early-stage disease and putatively in immune therapy.

Abstract 1151: Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery

Abstract Introduction: Castration-resistant prostate cancer (CRPC) has poor response to androgen deprivation therapy, which is caused by a sustained androgen receptor (AR) signal and therefore is considered as an incurable disease. MicroRNA let-7c has been implied as a tumor suppressor in prostate cancer by antagonizing AR expression and activity. In addition to cancer cells, our group previously also demonstrated that downregulation of let-7c by cancer-associated mesenchymal stem cells (MSCs) triggering a reactive stromal response to facilitate prostate cancer growth and metastasis (PLoS ONE 8(8): e71637). Accordingly, treatment with exogenous let-7c would target both cancer cells and their associated MSCs and could be an attractive therapeutic approach to effectively inhibit CRPC recurrence and prevent metastasis. Exosomes are nanometer-sized membrane-bound vesicles with functions as mediators of cell-cell communication, which have the absolute predominance in biocompatibility for clinical applications in drug delivery and gene therapy. Objective: By taking the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of using MSC-derived exosomes as an exogenous let-7c delivery system to target CRPC. Methods: Relative miRNA-let-7c expression across various prostate cancer cell lines was examined using q-RT PCR. MSC-derived exosomes were collected from a 3A6 human bone marrow-derived MSC cell line after cell transfection with pre-miR negative control and pre-miR-let-7c, and further characterized through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot. The effects of either naked or MSC-exosome encapsulated let-7c on CRPC cells was determined by WST-1 cell proliferation assay and wound healing migration assay. Results: MiRNA-let-7c expression was confirmed to be downregulated in most of CRPC-like cell lines compared with androgen-sensitive LNCaP. Overexpression of pre-miR-let-7 inhibited the ability of cell proliferation and migration of prostate cancer cells. Exogenous microRNAs can be successfully packaged into MSC-exosomes by cell transfection, without a disruption of exosome integrity. Treatment of CRPC-like PC3 (AR-negative) and CWR22r-v1 (AR-positive) cells with MSC-exosome encapsulated let-7c effectively delivered let-7c into cells and resulted in a significant reduction in cancer cell growth and metastasis in vitro. Conclusion: Herein, we have provided in vitro evidences to prove the concept that microRNA let-7c is a potential therapeutic intervention for CRPC, as well as MSC-derived exosomes can serve as a therapeutic let-7c delivery system to target the CRPC. Further in vivo validation of distribution and therapeutic efficacy of MSC-exosome-delivered let-7c in CRPC xenograft mouse model is currently being explored. Citation Format: Ida Kurniawati, Chia-Yen Hsueh, Shian-Ying Sung, Chia-Ling Hsieh. Targeting castration-resistant prostate cancer using mesenchymal stem cell exosomes for therapeutic microRNA let-7c delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1151.

Lung cancer-associated mesenchymal stem cells promote tumor metastasis and tumorigenesis by induction of epithelial-mesenchymal transition and stem-like reprogram.

Mesenchymal stem cells (MSCs) have attracted more attention in antitumor therapy by using MSCs as vehicles or targeting modulators of MSCs. But their role and mechanisms in tumor progression are less known. In the present study, we successfully isolated pairs of MSCs from lung cancer (LC-MSCs) and adjacent tumor-free tissues. Based on the coculture system in vitro and animal studies in vivo, we originally found that LC-MSCs significantly promoted tumor metastasis and tumorigenesis both in vitro and in vivo. Partial epithelial–mesenchymal transition (EMT) was induced in lung cancer cells by LC-MSCs by the evidence of remarkable increase in snail and slug expression but not in other EMT-associated genes. The expression of stem related genes also escalated significantly. And spheroids perfectly formed when tumor cells were co-incubated with LC-MSCs. These results revealed a close link of partial EMT and acquisition of stem-like traits in lung cancer cells which was induced by LC-MSCs and greatly promoted metastasis and tumorigenesis in lung cancer. Our findings provided a new insight into LC-MSCs in tumor progression and helped to identify LC-MSCs as a potential vehicle or target for lung cancer therapy.

G6PD-NF-κB-HGF Signal in Gastric Cancer-Associated Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Gastric Cancer Cells by Upregulating the Expression of HK2.

Background: Tumor-associated stromal cells have been widely recognized for their tumor-promoting capability involving paracrine signaling. However, the underlying mechanism and the effects of the molecules in the glycolysis pathway in gastric cancer-associated mesenchymal stem cells (GCMSCs) and gastric cancer cells on tumor progression remain unclear.Methods: The expression of hepatocyte growth factor (HGF) in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by enzyme-linked immunosorbent assay (ELISA). The effect of HGF derived from GCMSCs on the proliferation, metastasis, and HK2 expression of gastric cancer cells was evaluated in vitro and in vivo. The effects of G6PD on the production of HGF in mesenchymal stem cells (MSCs) were analyzed by immunoblotting.Results: HGF derived from GCMSCs promoted glycolysis, proliferation, and metastasis of gastric cancer by upregulating c-Myc-HK2 signal. The progression of the disease induced by GCMSCs decelerated in the absence of HK2. The expression of G6PD activated NF-κB signaling and stimulated the production of HGF in GCMSCs. Blocking HGF derived from GCMSCs decreased proliferation, metastasis, and angiogenesis of gastric cancer cells in vivo.Conclusions: GCMSCs highly expressed G6PD and facilitated the progression of gastric cancer through the G6PD-NF-κB-HGF axis coordinates. Blocking HGF derived from GCMSCs is a potential new therapeutic target for the treatment of gastric cancer.

Mesenchymal Stem Cells in the Tumor Microenvironment.

The interactions between tumor cells and the non-malignant stromal and immune cells that make up the tumor microenvironment (TME) are critical to the pathophysiology of cancer. Mesenchymal stem cells (MSCs) are multipotent stromal stem cells found within most cancers and play a critical role influencing the formation and function of the TME. MSCs have been reported to support tumor growth through a variety of mechanisms including (i) differentiation into other pro-tumorigenic stromal components, (ii) suppression of the immune response, (iii) promotion of angiogenesis, (iv) enhancement of an epithelial-mesenchymal transition (EMT), (v) enrichment of cancer stem-like cells (CSC), (vi) increase in tumor cell survival, and (vii) promotion of tumor metastasis. In contrast, MSCs have also been reported to have antitumorigenic functions including (i) enhancement of the immune response, (ii) inhibition of angiogenesis, (iii) regulation of cellular signaling, and (iv) induction of tumor cell apoptosis. Although literature supporting both arguments exists, most studies point to MSCs acting in a cancer supporting role within the confines of the TME. Tumor-suppressive effects are observed when MSCs are used in higher ratios to tumor cells. Additionally, MSC function appears to be tissue type dependent and may rely on cancer education to reprogram a naïve MSC with antitumor effects into a cancer-educated or cancer-associated MSC (CA-MSC) which develops pro-tumorigenic function. Further work is required to delineate the complex crosstalk between MSCs and other components of the TME to accurately assess the impact of MSCs on cancer initiation, growth, and spread.

Mesenchymal Stem Cells Promote Hepatocarcinogenesis via lncRNA-MUF Interaction with ANXA2 and miR-34a.

Accumulating evidence suggests that cancer-associated mesenchymal stem cells (MSC) contribute to the development and metastasis of hepatocellular carcinoma (HCC). Aberrant expression of long noncoding RNAs (lncRNA) has been associated with these processes but cellular mechanisms are obscure. In this study, we report that HCC-associated mesenchymal stem cells (HCC-MSC) promote epithelial-mesenchymal transition (EMT) and liver tumorigenesis. We identified a novel lncRNA that we termed lncRNA-MUF (MSC-upregulated factor) that is highly expressed in HCC tissues and correlated with poor prognosis. Depleting lncRNA-MUF in HCC cells repressed EMT and inhibited their tumorigenic potential. Conversely, lncRNA-MUF overexpression accelerated EMT and malignant capacity. Mechanistic investigations showed that lncRNA-MUF bound Annexin A2 (ANXA2) and activated Wnt/β-catenin signaling and EMT. Furthermore, lncRNA-MUF acted as a competing endogenous RNA for miR-34a, leading to Snail1 upregulation and EMT activation. Collectively, our findings establish a lncRNA-mediated process in MSC that facilitates hepatocarcinogenesis, with potential implications for therapeutic targeting. Cancer Res; 77(23); 6704-16. ©2017 AACR.

YAP signaling in gastric cancer-derived mesenchymal stem cells is critical for its promoting role in cancer progression.

Cancer-associated mesenchymal stem cells (MSCs) are critically involved in tumor development and progression. However, the mechanisms of action for MSCs in cancer remain largely unknown. Herein, we reported that the expression of Yes-associated protein 1 (YAP) was higher in gastric cancer derived mesenchymal stem cells (GC-MSCs) than that in bone marrow derived MSCs (BM-MSCs). YAP knockdown not only inhibited the growth, migration and invasion, and stemness of GC-MSCs, but also suppressed their promoting effect on gastric cancer growth in vitro and in vivo. In addition, the interference of YAP expression in GC-MSCs also attenuated the promoting role of gastric cancer cells in endothelial cell tube formation and migration. Mechanistically, YAP knockdown reduced the activation of β-catenin and its target genes in gastric cancer cells by GC-MSCs. Taken together, these findings suggest that YAP activation in GC-MSCs plays an important role in promoting gastric cancer progression, which may represent a potential target for gastric cancer therapy.

MiR-374 mediates the malignant transformation of gastric cancer-associated mesenchymal stem cells in an experimental rat model.

Mesenchymal stem cells (MSCs) are a critical component of the tumor microenvironment. Upon distinct pathological stimulus, MSCs show phenotypic and functional changes. Gastric cancer is one of the leading causes of cancer-related deaths worldwide. The roles and mechanisms of MSCs in gastric cancer have not been well characterized. In the present study, we investigated the roles of MSCs in the malignant transformation from gastritis to gastric cancer using an N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer model. We isolated MSCs from the gastric tissues of normal (RGN-MSCs) and MNNG-exposed rats (RGI-MSCs), and compared the biological properties of RGI-MSCs with RGN-MSCs. We found that RGI-MSCs had increased proliferative and migratory capabilities than these capacities noted in the RGN-MSCs. In addition, RGI-MSCs produced higher levels of IL-6, CXCL10 and MCP-1 than RGN-MSCs. Moreover, RGI-MSCs promoted the migration of normal gastric mucosa epithelial cells by inducing epithelial-mesenchymal transition (EMT). The upregulation of miR-374 in RGI-MSCs was partially responsible for their increased proliferative and migratory capabilities. Collectively, our findings provide new evidence for the roles of MSCs in gastric carcinogenesis, suggesting that targeting gastric cancer-associated MSCs may represent a novel avenue for gastric cancer therapy.

GM-CSF Mediates Mesenchymal-Epithelial Cross-talk in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer-associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis. The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal-epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886-99. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

Cancer-associated mesenchymal stem cells aggravate tumor progression.

Mesenchymal stem cells (MSCs) have both stemness and multi-modulatory activities on other cells, and the immunosuppressive and tumor-promotive mechanisms have been intensively investigated in cancer. The role of MSCs appears to be revealed in tumor aggravation, and targeting MSCs seems to be a promising strategy for treating cancer patients. However, it is still impractical in clinical therapy, since the precise MSCs are poorly understood in the in vivo setting. In previous studies, MSCs were obtained from different sources, and were prepared by ex vivo expansion for a long term. The inconsistent experimental conditions made the in vivo MSCs obscure. To define the MSCs in the host is a priority issue for targeting MSCs in cancer therapy. We recently identified a unique subpopulation of MSCs increasing in mice and human with cancer metastasis. These MSCs are specifically expanded by metastatic tumor cells, and promote tumor progression and dissemination accompanied by immune suppression and dysfunction in the host, more powerfully than normal MSCs growing without interference of cancer. In this review, we summarize current knowledge of the role of MSCs in tumor aggravation, along with our new findings of the bizarre MSCs.

Ovarian cancer microenvironment: implications for cancer dissemination and chemoresistance acquisition

Ovarian adenocarcinoma is characterized by a late detection, dissemination of cancer cells into the whole peritoneum, and the frequent acquisition of chemoresistance. If these particularities can be explained in part by intrinsic properties of ovarian cancer cells, an increased number of studies show the importance of the tumor microenvironment in tumor progression. Ovarian cancer cells can regulate the composition of their stroma in promoting the formation of ascitic fluid, rich in cytokines and bioactive lipids, and in stimulating the differentiation of stromal cells into a pro-tumoral phenotype. In return, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, or other peritoneal cells, such as adipocytes and mesothelial cells can regulate tumor growth, angiogenesis, dissemination, and chemoresistance. This review focuses on the current knowledge about the roles of stromal cells and the associated secreted factors on tumor progression. We also summarize the different studies showing that targeting the microenvironment represents a great potential for improving the prognosis of patients with ovarian adenocarcinoma.

Mesenchymal stem cells derived from breast cancer tissue promote the proliferation and migration of the MCF-7 cell line in vitro

Mesenchymal stem cells (MSCs) are critical in promoting cancer progression, including tumor growth and metastasis. MSCs, as a subpopulation of cells found in the tumor microenvironment, have been isolated from several tumor tissues, but have not been isolated from breast cancer tissue to date. Therefore, the purpose of this study was to isolate MSCs from primary human breast cancer tissue, and to study the effect of breast cancer MSCs (BC-MSCs) on the proliferation and migration of the MCF-7 cell line in vitro. MSCs were isolated and identified from primary breast cancer tissue obtained from 9 patients. The MCF-7 cell line was treated with 10 and 20% breast cancer-associated MSC (BC-MSC)-conditioned medium (CM) for 10–48 h, and changes in proliferation and migration were observed. Furthermore, we investigated the migration of 10 and 20% CM concentrations on MCF-7 through a scratch wound assay and a transwell migration assay. We successfully isolated and identified MSCs from primary breast cancer tissues. BC-MSCs showed characteristics similar to those of bone marrow MSCs, and possessed the capability of multipotential differentiation into osteoblasts and adipocytes. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that 10 and 20% CM concentrations increased the proliferation of MCF-7 cells to different levels. The results also revealed a greater increase in different levels compared with the control group. In conclusion, MSCs were confirmed to exist in human breast cancer tissues, and BC-MSCs may promote the proliferation and migration of breast cancer cells.

Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-miR155-SOCS1-MMP9 axis

Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic microRNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LC-MSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013).

Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway

Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell's EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway.