scholarly journals Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Surendar Aravindhan ◽  
Sura Salman Ejam ◽  
Methaq Hadi Lafta ◽  
Alexander Markov ◽  
Alexei Valerievich Yumashev ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Tumor Tissue ◽  
Angiogenic Therapy ◽  
Final Destination ◽  
Tumour Vasculature

AbstractA crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

scholarly journals Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Atsuhito Uneda ◽  
Kazuhiko Kurozumi ◽  
Atsushi Fujimura ◽  
Kentaro Fujii ◽  
Joji Ishida ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Cells ◽  
In Silico ◽  
Tumor Tissue ◽  
The Cancer Genome Atlas ◽  
Macrophage Infiltration ◽  
Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

2021 ◽  
Vol 22 ◽  
Author(s):  
Soheila Montazersaheb ◽  
Ezzatollah Fathi ◽  
Ayoub Mamandi ◽  
Raheleh Farahzadi ◽  
Hamid Reza Heidari
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Cell Types ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Tumorigenic Potential ◽  
Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

Mesenchymal Stem Cells Mediated Drug Delivery in Tumor-Targeted Therapy

2020 ◽  
Vol 17 ◽  
Author(s):  
Mengying Xie ◽  
Lei Tao ◽  
Ziqi Zhang ◽  
Wei Wang
Keyword(s):  
Drug Delivery ◽  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Targeted Therapy ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Therapeutic Agents ◽  
Oncolytic Viruses ◽  
Tumor Tropism

: Mesenchymal stem cells (MSCs) possess unique properties that make them potential carriers for cancer therapy. MSCs have been documented to have low immunogenicity, positive safety in clinical trials, and the ability to selectively homing to inflammation and tumor sites. Thisreview aims to introduce tumor tropism mechanism and effects of MSCs on tumor cells, and give an overview of MSCs in delivering gene therapeutic agents, oncolytic viruses and chemotherapeutics, as well as the application of MSCs-derived exosomes in tumor-targeted therapy.

scholarly journals Bone Marrow-Derived Mesenchymal Stem Cells Migrate toward Hormone-Insensitive Prostate Tumor Cells Expressing TGF-β via N-Cadherin

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1572
Author(s):  
Jinok Noh ◽  
Jinyeong Yu ◽  
Wootak Kim ◽  
Aran Park ◽  
Ki-Sook Park
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Prostate Tumor ◽  
Prostate Tumors ◽  
Migration Assay ◽  
Prostate Tumor Cells

The prostate tumor microenvironment plays important roles in the metastasis and hormone-insensitive re-growth of tumor cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into prostate tumors to facilitate tumor microenvironment formation. However, the specific intrinsic molecules mediating BM-MSCs’ migration to prostate tumors are unknown. BM-MSCs’ migration toward a conditioned medium (CM) of hormone-insensitive (PC3 and DU145) or hormone-sensitive (LNCaP) prostate tumor cells was investigated using a three-dimensional cell migration assay and a transwell migration assay. PC3 and DU145 expressed transforming growth factor-β (TGF-β), but LNCaP did not. Regardless of TGF-β expression, BM-MSCs migrated toward the CM of PC3, DU145, or LNCaP. The CM of PC3 or DU145 expressing TGF-β increased the phosphorylation of Smad2/3 in BM-MSCs. Inactivation of TGF-β signaling in BM-MSCs using TGF-β type 1 receptor (TGFBR1) inhibitors, SB505124, or SB431542 did not allow BM-MSCs to migrate toward the CM. The CM of PC3 or DU145 enhanced N-cadherin expression on BM-MSCs, but the LNCaP CM did not. SB505124, SB431542, and TGFBR1 knockdown prevented an increase in N-cadherin expression. N-cadherin knockdown inhibited the collective migration of BM-MSCs toward the PC3 CM. We identified N-cadherin as a mediator of BM-MSCs’ migration toward hormone-insensitive prostate tumor cells expressing TGF-β and introduced a novel strategy for controlling and re-engineering the prostate tumor microenvironment.

Mesenchymal Stem Cells, Immune Cells and Tumor Cells Crosstalk: A Sinister Triangle in the Tumor Microenvironment

2019 ◽  
Vol 14 (1) ◽  
pp. 43-51 ◽  
Author(s):  
Mahboobeh Razmkhah ◽  
Shabnam Abtahi ◽  
Abbas Ghaderi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor-associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis. Here, we present an overview of the latest findings on Janusfaced roles that MSCs play in the tumor microenvironment [TME], with a concise focus on innate and adaptive immune responses.

Shared and Divergent Stimulatory Effects of S100A4 and Uric Acid on Proliferation and Chemotaxis of Mesenchymal Stem Cells (MSCs). Interplay Between Necrotic Tumor Material and Immunosuppressive MSCs within Tumor Microenvironment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3239-3239
Author(s):  
Judith Luiza Eisenbacher ◽  
Tatjana Yildiz ◽  
Hubert Schrezenmeier ◽  
Ramin Lotfi
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
Uric Acid ◽  
Tumor Microenvironment ◽  
Tumor Tissue ◽  
Chemotactic Activity ◽  
Necrotic Tumor ◽  
Tumor Material ◽  
Dose Dependent

Abstract Abstract 3239 Background: Necrotic cell death is a characteristic feature of advanced solid tumor. S100 proteins and uric acid (UA) are released from necrotic (tumor) tissue regardless of tumor's origin. Both of these factors are known to influence immune response. Mesenchymal stem cells (MSCs) are often found within tumor microenvironment and are associated with poor prognosis of cancer patients in terms of metastasis and survival. MSCs seem to play a crucial role within tumor microenvironment probably due to their immunosuppressive capacity interfering with the specific anti-tumor immune response. Underlying mechanisms for MSC accumulation and stimulation in tumor tissue are not well characterized yet. S100A4 is known to promote metastasis in certain tumors such as colorectal cancer, but the exact mechanism of this effect still remains unclear. UA not only induces an acute inflammatory response but is also known to maintain chronic inflammation. In our previous experiments, we could already show that necrotic tumor material is capable of inducing chemotaxis and proliferation of MSCs. Focusing on S100A4 and UA, we now sought to characterize individual known factors within necrotic material which may be responsible for described effects. Materials and Methods: Proliferation assays were performed using CYQUANT Assay (Invitrogen) based on fluorescent staining of nucleic acid. Migration of fluorescent-labeled MSCs was assessed using FluoroBlok (BD) two-chamber chemotaxis plates, fluorescence within the bottom chamber of migration plates was measured with PolarStar plate reader (BMG). Results: We tested the influence of recombinant human S100A4 at concentrations between 50 and 1000 ng/ml on MSC proliferation and could demonstrate divergent effects depending on the chosen S100A4 concentration: S100A4 at concentrations not higher than 100 ng/ml enhanced the proliferation of MSCs in a dose dependent manner up to 50%, whereas concentrations above 100 ng/ml inhibited MSC proliferation down to 50% compared to medium containing 5% human serum without S100A4. We tested the chemotactic activity of recombinant human S100A4 at concentrations between 0.01 and 1000 ng/ml on MSCs and could demonstrate a dose dependent chemotactic activity up to 80% of the response which was achieved by positive control (50% FBS). By adding UA to suboptimal concentration of S100A4 (100ng/ml), we could enhance the chemotactic activity of S100A4 on MSCs. In contrast to its enhancing effect on MSC migration, UA inhibited dose dependently the proliferation inducing effect of S100A4 with strongest effect at 300μg UA/ml resulting in about 50% inhibition of proliferation compared to medium containing 100ng/ml S100A4 without additional UA. ELISA assays confirmed the presence of S100A4 in the necrotic tumor material which we had used in our previous experiments with similar stimulatory effects on MSCs in terms of proliferation and chemotaxis. Conclusions: MSCs are often found within tumor tissue and may influence the biologic behavior of tumor and host's immune response to tumor. We could characterize UA and S100A4 as bioactive factors within necrotic (tumor) material. Whereas S100A4 stimulated both proliferation as well as chemotaxis of MSCs, UA enhanced the chemotactic acitivity of S100A4 while inhibiting its proliferation inducing effect. Comparing our new data with our previous observations using tumor lysates to induce chemotaxis and proliferation of MSCs the overall effect of necrotic material seems to be rather proliferative and chemotactic even though some factors like UA may interfere with mentioned overall effects. Keeping in mind that MSCs can act as potent immunosuppressive cells, we conclude that tumor necrosis rather inhibits an effective anti-tumor immune response by favoring accumulation and proliferation of MSCs within tumor microenvironment. Our observations shed some light into the biology of MSCs within tumor microenvironment and open new questions concerning the interplay between MSCs, necrotic tumor cells and tumor progression. Possible strategies to break the described vicious circle by rather inducing an apoptotic tumor cell death or by reducing bioactive factors released from necrotic tissue within tumor microenvironment may be considered. Additionally, clinical investigations using specific antibodies to S100A4 or influencing serum concentrations of UA in tumor patients may be performed. Disclosures: No relevant conflicts of interest to declare.

Effect of mesenchymal stem cells-derived exosomes on tumor microenvironment: Tumor progression versus tumor suppression

2018 ◽  
Vol 234 (4) ◽  
pp. 3394-3409 ◽  
Author(s):  
Samaneh Shojaei ◽  
Seyed Mahmoud Hashemi ◽  
Hossein Ghanbarian ◽  
Mohammad Salehi ◽  
Samira Mohammadi-Yeganeh
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Tumor Suppression

Targeting CSCs within the tumor microenvironment for cancer therapy: a potential role of mesenchymal stem cells

2012 ◽  
Vol 16 (10) ◽  
pp. 1041-1054 ◽  
Author(s):  
Bin Bao ◽  
Aamir Ahmad ◽  
Yiwei Li ◽  
Asfar S Azmi ◽  
Shadan Ali ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Potential Role

Mesenchymal Stem Cells Selectively Engraft into Tumor Stroma and Produce Potent Antitumor Proteins In Situ.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 352-352
Author(s):  
Michael Andreeff ◽  
Jennifer Dembinski ◽  
Brett M. Hall ◽  
Matus Studeny ◽  
Xiaoyang Ling ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Metastatic Breast ◽  
Firefly Luciferase ◽  
Scid Mice ◽  
Ovarian Tumors ◽  
Renilla Luciferase

Abstract The formation of stroma is essential for tumor growth and involves complex interactions between malignant tumor cells, and non-tumor stromal cells. We have previously demonstrated that mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res62:3603, 2002; JNCI96:1593, 2004,), suggesting the development of anti-cancer therapies based on the intratumoral production of agents by gene-modified MSC. However, no direct evidence has demonstrated this migration and selective engraftment into the tumor microenvironment. Therefore, we noninvasively visualized MSC using luciferase bioluminescence. MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD) and these MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 7–10 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained strong over a 15-day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, healthy Balb/C mice injected with Balb/C derived MSC-LUX initially migrated to the lungs and within 2.5 hrs had exited the lungs to remain liver and spleen resident for 5–7 days. When tumor cells were transduced with renilla luciferase constructs, the co-localization and dynamic interactions of firefly luciferase MSC and renilla luciferase tumors could be examined in detail. Mechanisms regulating the MSC-tumor interactions involve TGF-beta, HGF/c-Met, and EGFR and will be discussed. We then examined whether hMSC-producing interferon-beta (IFNb-MSC) could inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001) Intraperitoneal (IP) injections of IFN-MSC into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors. MSC injected into the ipsilateral or contralateral carotid artery were found to localize to glioma xenografts in mice and IFNb-MSC significantly (p<0.05) prolonged survival of these mice. These data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-b inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation.

scholarly journals Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Simona L. Schlereth ◽  
Nasrin Refaian ◽  
Sandra Iden ◽  
Claus Cursiefen ◽  
Ludwig M. Heindl
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Cancer Associated Fibroblasts ◽  
Therapeutic Approaches ◽  
Early Step ◽  
New Therapeutic Approaches

Lymphangiogenesis is a very early step in lymphatic metastasis. It is regulated and promoted not only by the tumor cells themselves, but also by cells of the tumor microenvironment, including cancer associated fibroblasts, mesenchymal stem cells, dendritic cells, or macrophages. Even the extracellular matrix as well as cytokines and growth factors are involved in the process of lymphangiogenesis and metastasis. The cellular and noncellular components influence each other and can be influenced by the tumor cells. The knowledge about mechanisms behind lymphangiogenesis in the tumor microenvironmental crosstalk is growing and offers starting points for new therapeutic approaches.

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