Cancer Mesenchymal Stem Cells Research Articles

The role of mesenchymal stem cells in cancer and prospects for their use in cancer therapeutics.

Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.

Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

Mesenchymal stem cells (MSCs) are among the most frequently used cell type for regenerative medicine. A large number of studies have shown the beneficial effects of MSC-based therapies to treat different pathologies, including neurological disorders, cardiac ischemia, diabetes, and bone and cartilage diseases. However, the therapeutic potential of MSCs in cancer is still controversial. While some studies indicate that MSCs may contribute to cancer pathogenesis, emerging data reported the suppressive effects of MSCs on cancer cells. Because of this reality, a sustained effort to understand when MSCs promote or suppress tumor development is needed before planning a MSC-based therapy for cancer. Herein, we provide an overview on the therapeutic application of MSCs for regenerative medicine and the processes that orchestrates tissue repair, with a special emphasis placed on cancer, including central nervous system tumors. Furthermore, we will discuss the current evidence regarding the double-edged sword of MSCs in oncological treatment and the latest advances in MSC-based anti-cancer agent delivery systems.

The multifaceted role of mesenchymal stem cells in cancer.

Mesenchymal stem cells (MSCs) are multipotent stem cells derived from the mesoderm that give rise to several mesenchymal lineages, including osteoblasts, adipocytes, chondrocytes and myocytes. Their potent ability to home to tumors coupled with their differentiation potential and immunosuppressive function positions MSCs as key regulators of tumor fate. Here we review the existing knowledge on the involvement of MSCs in multiple tumor-promoting processes, including angiogenesis, epithelial-mesenchymal transition, metastasis, immunosuppression and therapy resistance. We also discuss the clinical potential of MSC-based therapy for cancer.

Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development.

Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self‐renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro‐or anti‐tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115–2125

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.

Abstract 5904: Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells

Abstract The tumor microenvironment contains cancer cells, non-cancerous cells, and extracellular components such as extracellular matrix (ECM). Previous studies have demonstrated that interactions between the cells and the microenvironment contribute to cancer progression via chemical stimuli, such as growth factors, and mechanical stimuli, such as stiffness of the ECM. Recently, it has been reported that mesenchymal stem cells (MSCs) differentiate into cancer associated fibroblasts (CAFs) in response to chemical stimuli from cancer cells and thereby promote cancer progression. However, the contribution of mechanical stimuli to MSCs in cancer is poorly understood. In this study, we revealed that MSCs showed CAF phenotypes and promote mammary cancer progression in response to mechanical stimuli. On a stiff substrate, MSCs treated with conditioned media from cancer cell culture expressed increased levels of alpha smooth muscle actin (alpha-SMA), a marker of CAFs, compared to the MSCs cultured on a soft substrate. MSCs grown on a stiff substrate displayed higher expression and activity of YAP and increased phosphorylation of myosin light chain (MLC) compared to MSCs grown on a soft substrate. In addition, knockdown of YAP by shRNA decreased the expression of alpha-SMA and phosphorylation of MLC in MSCs on a stiff substrate. Pharmacological inhibition of MLC phosphorylation by H1152 treatment also reduced expression of alpha-SMA and activity of YAP in MSCs. Cell-cell communication between MSCs and carcinoma cells was bi-directional, as conditioned medium from MSCs cultured on a stiff substrate, but not a soft substrate, increased growth of mammary carcinoma cells. The soluble factor prosaposin was highly secreted by the MSCs on a stiff substrate, and the addition of recombinant prosaposin increased proliferation and survival of mammary carcinoma cells. Furthermore, secretion of prosaposin was promoted in YAP-overexpressed MSCs on a soft substrate. Mammary carcinoma cells treated with prosaposin showed increased level of phosphorylation in Akt at T308. In addition, inhibition of phosphorylation of Akt at T308 prevented proliferation and survival in mammary carcinoma cells. These results suggest that increased stiffness of the ECM in the tumor microenvironment induces differentiation of MSCs to CAFs via YAP and actomyosin contractility, secretion of prosaposion from MSCs, and as a result, trigger progression of mammary cancer via phosphorylation of Akt at T308. Citation Format: Seiichiro Ishihara, David R. Inman, Wan-Ju Li, Suzanne M. Ponik, Patricia J. Keely. Stiffness of extracellular matrix regulates breast cancer progression by stimulating mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5904. doi:10.1158/1538-7445.AM2017-5904

Mesenchymal Stem Cells in Cancer: a New Link to Neutrophils

Mesenchymal stem cells (MSCs) have been considered as one of the key components of tumor microenvironment and are believed to play critical roles in cancer progression. MSCs within tumor microenvironment acquire novel functions that are not observed in normal MSCs. Emerging evidence suggest that tumor-resident MSCs could skew immune cells to a tumor-promoting phenotype, leading to the escape from immune surveillance. As neutrophils are predominant innate immune cells, we recently explored the interaction between tumor-resident MSCs and neutrophils. Our results revealed that tumor-resident MSCs regulate the chemotaxis, survival, activation, and function of neutrophils in gastric cancer through the IL-6–STAT3 signaling pathway. Intriguingly, neutrophils activated by tumor-resident MSCs could strongly induce the differentiation of normal MSCs into CAFs, forming a feedback loop to synergistically prompt cancer progression. Our findings indicate that the regulation of neutrophil biology and function by tumor-resident MSCs may present a novel mechanism for the role of MSCs in remodeling cancer microenvironment and provide a potential target for the treatment of gastric cancer.

Cytoplasmic NANOG-Positive Stromal Cells Promote Human Cervical Cancer Progression

Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell gene NANOG, a divergent homeodomain transcription factor that is independent of leukemia inhibitory factor, has been reported to be expressed in germ cells and in several tumor types. However, the short-term expression and role of NANOG in cervical cancer remain unclear. In the present study, we demonstrate that NANOG exhibits cellular shuttling behavior and increasing stromal distribution during the progression of cervical cancer. Our molecular data using RT-PCR and restriction enzyme digestion show that NANOG is mainly transcribed from the NANOG gene in cervical cancer. In addition, IHC using confocal microscopy suggests that mesenchymal stem cells (MSCs) are one type of cytoplasmic NANOG-positive cells in cervical cancer stroma. Co-culture of cervical cancer-derived MSCs with SiHa cells showed increased proliferation characteristics in vitro and enhanced tumor growth in vivo. Our results show, for the first time to our knowledge, that MSCs are a source of cytoplasmic NANOG expression in the cervical cancer stroma and that they participate in the progression of cervical cancer both in vitro and in vivo. Our study provides evidence that NANOG is a cervical cancer progression marker and also serves as a starting point for a more extensive exploration of the cellular translocation of NANOG and the multifunctionality of the stromal microenvironment.

Probing the role of mesenchymal stem cells in salivary gland cancer on biomimetic microdevices

Mesenchymal stem cells (MSCs) are the progenitors of stromal cells, which have been found to interact with cancer cells and represent an important target for cancer therapies. Salivary gland cancer is an aggressive malignant epithelial tumor and can easily disseminate to distant sites in vivo. In this work, we probed the role of MSCs in salivary gland cancer in an in vivo like tumor microenvironment by using a series of functional microfluidic devices for 2D and 3D assays. The results demonstrated that MSCs could be recruited by salivary gland cancer cells (ACC-M) and this effect was potentially mediated by TGF-β secreted by cancer cells. In addition, MSCs exhibited the ability to squeeze into ACC-M spheroids by dispersing the cell-cell connection and reducing the expression of E-cadherin in cancer cells. In particular, MSCs exhibited the ability to enhance the invasion of salivary cancer under a chemokine CXCL12 gradient, indicating the involvement of a CXCL12-CXCR4 pathway and the tumor-promoting properties of MSCs in cancer progression. This study recreated an in vivo-like tumor microenvironment by constructing a series of functional microdevices and explored the role of MSCs in ACC invasion for the first time. It provides a unique platform to open up new options to target stromal cells for cancer therapy and also analyzed the potential risk of using MSCs as drug delivery carriers for therapeutic purposes in carcinoma treatment.

Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-β1 and upregulate expression of regulatory molecules on T cells: Do they protect breast cancer cells from the immune response?

Immunomodulatory function of bone marrow derived mesenchymal stem cells in cancer has recently been investigated. But the resident mesenchymal stem cells as whole in cancer and in the breast cancer tissue have not been studied well. In the present work we isolated adipose derived stem cells (ASCs) from breast cancer and normal breast tissues to investigate the expressions of IL-4, IL-10 and transforming growth factor (TGF)-β1 in ASCs and to see if ASCs isolated from patients can modulate the regulatory molecules on peripheral blood lymphocytes. Our results showed that IL-10 and TGF-β1 have significantly higher mRNA expressions in ASCs isolated from breast cancer patients than those from normal individuals ( P value <0.05). The culture supernatant of ASCs isolated from breast cancer patients with pathological stage III induced upregulation of the mRNA expression levels of IL-4, TGF-β1, IL-10, CCR4 and CD25 in PBLs. In addition, the percentage of CD4+CD25 highFoxp3 + T regulatory cells was increased in vitro. When the same culture supernatant was added to ASCs isolated from normal subjects augmentation of the mRNA expressions of IL-4, IL-10, IL-8, MMP2, VEGF and SDF-1 in normal ASCs was also observed. These data collectively conclude that resident ASCs in breast cancer tissue may have crucial roles in breast tumor growth and progression by inducing regulatory molecules and promoting anti-inflammatory reaction within the tumor microenvironment. Further investigation is required to see if the immune suppression induced by ASCs is an independent property from tumor cells or ASCs gain their immunosuppressive potential from malignant cells.

Bone marrow-derived mesenchymal stem cells and the tumor microenvironment

Over the last decade, there has been a growing interest in the role of mesenchymal stem cells (MSC) in cancer progression. These cells have the potential to give rise to a variety of mesenchymal cells like osteoblasts, chondrocytes, adipocytes, fibroblasts, and muscle cells. In contrast to their hematopoetic counterparts, MSC are not as clearly defined, which makes the interpretation of their role in cancer progression more complex. However, the nature of the relationship between MSC and tumor cells appears dual. Primary and metastatic tumors attract MSC in their microenvironment where they become tumor-associated fibroblasts, affect tumor cell survival and angiogenesis, and have an immunomodulatory function, and vice versa in the bone marrow MSC attract tumor cells and contribute to a microenvironment that promotes osteolysis, tumor growth, survival, and drug resistance. Whether MSC are pro- or anti-tumorigenic is a subject of controversial reports that is in part explained by the complexity of their interaction with tumor cells and the large range of cytokines and growth factors they produce. The study of these interactions is a fertile ground of investigation that--as already demonstrated in the case of myeloma--should lead to novel therapeutic approaches in cancer. In this article, the biology and role of MSC in cancer is reviewed with a primary focus on bone marrow-derived MSC.

The bad and the good of mesenchymal stem cells in cancer: Boosters of tumor growth and vehicles for targeted delivery of anticancer agents

In cancer biology, mesenchymal stem cells (MSCs) display aspects that can appear contradictory. On one hand, these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer. On the other hand, due to this excellent aptitude to home-in on tumor tissues, regardless their location in the host's body, MSCs are considered to be extremely selective vehicles to reach cancer cells specifically. Recently, MSC sustainment of cancer cell growth is a hot research topic. Indeed, these cells are known to sustain tumor angiogenesis and metastasis formation, to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism. On the other hand, since scientists became able to take advantage of their extremely selective capability to target cancer cells, MSCs are now also thought of in a different light. Indeed, MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents, ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs. On this basis, investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells, on the other. As with the two faces of Janus, this review will concisely explore the research activity in these two apparently conflicting fields.

Mesenchymal Stem Cells in Cancer

It is becoming increasingly evident that stromal cells such as macrophages, mast cells, adipocytes and mesenchymal cells associated with tumors significantly contribute to tumorigenesis. Some types of cancer indeed profoundly rely on extrinsic signals afforded by infiltrating or neighbouring cells for survival, proliferation and dissemination. Tissue disruption that results from tumor growth further activates tissue repair and inflammatory reactions that significantly shape the nature of the developing tumors. Over the past recent years, several studies have revealed that mesenchymal stem cells (MSCs) are recruited to tumors and play a particularly important role in the regulation of both solid and haematological malignancies. The tumor-homing properties of MSCs have further led to studies investigating their therapeutic use as targeted delivery vehicles of gene products. I hereafter discuss the role of MSCs in cancer.

Mesenchymal Stem Cells in Cancer: Tumor-Associated Fibroblasts and Cell-Based Delivery Vehicles

Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.