• Cartilage repair
• Chondrogenesis
• Chondrogenic differentiation
• Regenerative medicine
• Tissue engineering

• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Regeneration/physiology
• Animals
• Mesenchymal Stem Cell Transplantation
• Chondrogenesis/physiology
• Cartilage/metabolism
• Cartilage/physiology
• Cell Differentiation
• Chondrocytes/metabolism
• Chondrocytes/cytology
• Signal Transduction

• bladder cancer
• kidney cancer
• mesenchymal stem cells
• prostate cancer
• renal pelvis cancer

• Male
• Humans
• Urinary Bladder
• Prostate
• Kidney
• Extracellular Vesicles/metabolism
• Urologic Neoplasms/therapy
• Urologic Neoplasms/metabolism
• Mesenchymal Stem Cells/metabolism

• EQUicycler
• actin
• bone
• cancer
• cyclic
• cytoskeleton
• elongation
• extracellular
• invasion
• loading
• mechanical
• metastasis
• prostate
• static
• stimuli

• 2213958 National Science Foundation

• cancer therapy
• cell-free therapy
• drug delivery vehicle
• extracellular vesicles
• mesenchymal cells

• ITMS 2014+: 313011V446 Operational Program Integrated Infrastructure

• bone
• cancer
• chemokine
• metastasis
• prostate
• therapy

• American Cancer Society
• National Cancer Institute

• engineered modification
• extracellular vesicle
• gene editing
• targeted delivery

• Extracellular Vesicles/metabolism
• Drug Delivery Systems
• Drug Carriers/metabolism
• Signal Transduction
• Nanoparticles
• Membrane Proteins/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism

• Cancer treatment
• Drug delivery system
• Exosomes
• Gastrointestinal cancer
• Mesenchymal stem cells
• Transplanting miRNA

Bone metastasis is a frequent complication of solid tumors and leads to a reduced overall survival. Although much progress has been made in the field of tumor therapy in the last years, bone metastasis depicts a stage of the disease with a lack of appropriate therapeutical options. Hence, this review aims to present the role of AKT in bone metastasis of solid tumors to place the spotlight on AKT as a possible therapeutical approach for patients with bone metastases. Furthermore, we intended to discuss postulated underlying molecular mechanisms of the bone metastasis-promoting effect of AKT, especially in highly bone-metastatic breast, prostate, and lung cancer. To conclude, this review identified the AKT kinase as a potential therapeutical target in bone metastasis and revealed remaining questions, which need to be addressed in further research projects.

Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.

• AKT
• bone metastasis
• breast cancer
• cancer metastasis
• osteolysis
• prostate cancer
• protein kinase B
• solid tumors
• vicious cycle

Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.

• Cell therapy
• Mesenchymal stem/stromal cell
• Single cell imaging
• Systemic safety
• biodistribution

• Bone marrow mesenchymal stem cell
• Fuzheng Yiliu decoction
• Glioma
• IL-12

• Animals
• Bone Marrow Cells
• Drugs, Chinese Herbal
• Glioma/drug therapy
• Glioma/genetics
• Interleukin-12/genetics
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells
• Mice
• Mice, Inbred BALB C
• Mice, Nude

• Gansu Provincial Department of Finance Research Service Expenses Project
• Yunnan Provincial Department of Education
• Gansu University of Chinese Medicine (CN)
• Universidad Nacional del Centro de la Provincia de Buenos Aires (AR)

• Chronic lymphocytic leukemia
• IL-17
• IL-23
• interleukins

• Different malignancy cancer cells
• Indirect co-culture
• Invasiveness
• Mesenchymal stem cells
• PTBP1

• Animals
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Coculture Techniques
• Female
• Gene Expression
• Gene Silencing
• HCT116 Cells
• HT29 Cells
• Heterogeneous-Nuclear Ribonucleoproteins/genetics
• Heterogeneous-Nuclear Ribonucleoproteins/metabolism
• Humans
• Interferon Type I/metabolism
• Mesenchymal Stem Cells/metabolism
• Mice
• Paracrine Communication
• Polypyrimidine Tract-Binding Protein/genetics
• Polypyrimidine Tract-Binding Protein/metabolism
• RNA, Small Interfering/genetics
• STAT1 Transcription Factor
• Signal Transduction

• AQP1
• CXCR4
• ovine mesenchymal stem cells

• Animals
• Aquaporin 1/metabolism
• Cell Differentiation/physiology
• Cell Movement/physiology
• Cell Proliferation/physiology
• Culture Media, Conditioned/metabolism
• Mesenchymal Stem Cells/metabolism
• Paracrine Communication/physiology
• Receptors, CXCR4/metabolism
• Sheep/metabolism
• Signal Transduction/physiology
• Wound Healing/physiology

Improving the knowledge of angiomyolipoma physiopathology might help in refining its pharmacological treatment. We investigated if angiomyolipoma cells have migratory properties, how their growth and motility can be influenced by the hormonal milieu, and if this can be related to a specific gender.

Primary cells were isolated from angiomyolipomas surgically resected for therapeutical reasons in a female and in a male patient. The genetic control demonstrated no TSC2 deletion. Bi- (wound healing) and three-dimensional (transwell assay) migration were analyzed in vitro in basal conditions and under the influence of 17- β-estradiol and SDF-1α.

Treatment up to 72 hours with 17-β-estradiol (0.1–100 nM), tamoxifen (0.2–20 μM) or with both, does not modify angiomyolipoma cells proliferation. On the other hand, SDF-1α and 17-β-estradiol treatment induce a significant motility increase (both bi- and three-dimensional) which becomes evident already after 2 hours of incubation. Angiomyolipoma cells express mRNA coding for SDF-1α and 17-β-estradiol receptors and secrete both the metalloproteases principally involved in malignant phenotype acquisition, i.e. MMP-2 and MMP-9.

Angiomyolipoma cells behave similarly, despite their different source. Primary angiomyolipoma cells migrate in response to hormonal milieu and soluble factors, and produce active metalloproteases, both aspects being consistent with the theory claiming they can migrate to the lungs (and/or other organs) and colonizing them. No main feature, among the aspects we analyzed, seems to be referable to the gender of origin.

Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.

We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

• mesenchymal stromal cells
• prostate cancer
• self-assembling nanoparticles
• tumor microenvironment
• zoledronic acid

• AMD3100
• CXCL12
• CXCR4
• Plerixafor
• cervical cancer
• cisplatin
• myeloid cells
• radiotherapy

• Bone marrow mesenchymal stem cells
• Chronic lymphocytic leukemia
• IL-17
• IL-6
• Microenvironment

• Cancer
• Immunology
• Inflammation
• Metastasis

• Animals
• Humans
• Inflammation/complications
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/pathology
• Lymphocytes/immunology
• Lymphocytes/metabolism
• Lymphocytes/pathology
• Macrophages/immunology
• Macrophages/metabolism
• Macrophages/pathology
• Myeloid Cells/immunology
• Myeloid Cells/metabolism
• Myeloid Cells/pathology
• Neoplasm Metastasis
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Tumor Microenvironment

• 17367 Cancer Research UK
• C49791/A17367 Cancer Research UK

• Cancer
• Metastasis
• Mouse models
• Stroma

• Animals
• Cell Lineage
• Disease Models, Animal
• Epithelial-Mesenchymal Transition
• Humans
• Mice
• Models, Biological
• Neoplasm Metastasis/pathology
• Neoplasm Metastasis/therapy
• Translational Research, Biomedical

• 17367 Cancer Research UK
• MR/N022556/1 Medical Research Council
• MR/K50080X/1 Medical Research Council
• University of Edinburgh
• European Research Council

Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, including bone marrow, adipose, and mucosa. MSCs have the capacity for self-renewal and differentiation. Reports have been published on the systemic administration of MSCs leading to functional improvements by engraftment and differentiation, thus providing a new strategy to regenerate damaged tissues. Recently, it has become clear that MSCs possess immunomodulatory properties and can therefore be used to treat diseases. However, the therapeutic effect mechanisms of MSCs are yet to be determined. Here, we investigated these mechanisms using a medication-related osteonecrosis of the jaw (MRONJ)-like mouse model.

To generate MRONJ-like characteristics, mice received intravenous zoledronate and dexamethasone two times a week. At 1 week after intravenous injection, maxillary first molars were extracted, and at 1 week after tooth extraction, MSCs were isolated from the bone marrow of the mice femurs and tibias. To compare “diseased MSCs” from MRONJ-like mice (d-MSCs) with “control MSCs” from untreated mice (c-MSCs), the isolated MSCs were analyzed by differentiation and colony-forming unit-fibroblast (CFU-F) assays and systemic transplantation of either d-MSCs or c-MSCs into MRONJ-like mice. Furthermore, we observed the exchange of cell contents among d-MSCs and c-MSCs during coculture with all combinations of each MSC type.

d-MSCs were inferior to c-MSCs in differentiation and CFU-F assays. Moreover, the d-MSC-treated group did not show earlier healing in MRONJ-like mice. In cocultures with any combination, MSC pairs formed cell–cell contacts and exchanged cell contents. Interestingly, the exchange among c-MSCs and d-MSCs was more frequently observed than other pairs, and d-MSCs were distinguishable from c-MSCs.

The interaction of c-MSCs and d-MSCs, including exchange of cell contents, contributes to the treatment potential of d-MSCs. This cellular behavior might be one therapeutic mechanism used by MSCs for MRONJ.

• Medication-related osteonecrosis of the jaw
• Mesenchymal stem cell
• Therapeutic mechanism

The isolation from brain tumors of tumor mesenchymal stem-like cells (tMSLCs) suggests that these cells play a role in creating a microenvironment for tumor initiation and progression. The clinical characteristics of patients with primary glioblastoma (pGBM) positive for tMSLCs have not been determined. This study analyzed samples from 82 patients with pGBM who had undergone tumor removal, pathological diagnosis, and isolation of tMSLC from April 2009 to October 2014. Survival, extent of resection, molecular markers, and tMSLC culture results were statistically evaluated. Median overall survival was 18.6 months, 15.0 months in tMSLC-positive patients and 29.5 months in tMSLC-negative patients (P = 0.014). Multivariate cox regression model showed isolation of tMSLC (OR = 2.5, 95% CI = 1.1~5.6, P = 0.021) showed poor outcome while larger extent of resection (OR = 0.5, 95% CI = 0.2~0.8, P = 0.011) has association with better outcome. The presence of tMSLCs isolated from the specimen of pGBM is associated with the survival of patient.

Decline in the therapeutic potential of bone marrow-derived mesenchymal stem cells (MSC) is often seen with older donors as compared to young. Although hypoxia is known as an approach to improve the therapeutic potential of MSC in term of cell proliferation and differentiation capacity, its effects on MSC from aged donors have not been well studied. To evaluate the influence of hypoxia on different age groups, MSC from young (<30 years) and aged (>60 years) donors were expanded under hypoxic (5% O₂) and normal (20% O₂) culture conditions. MSC from old donors exhibited a reduction in proliferation rate and differentiation potential together with the accumulation of senescence features compared to that of young donors. However, MSC cultured under hypoxic condition showed enhanced self-renewing and proliferation capacity in both age groups as compared to normal condition. Bioinformatic analysis of the gene ontology (GO) and KEGG pathway under hypoxic culture condition identified hypoxia-inducible miRNAs that were found to target transcriptional activity leading to enhanced cell proliferation, migration as well as decrease in growth arrest and apoptosis through the activation of multiple signaling pathways. Overall, differentially expressed miRNA provided additional information to describe the biological changes of young and aged MSCs expansion under hypoxic culture condition at the molecular level. Based on our findings, the therapeutic potential hierarchy of MSC according to donor’s age group and culture conditions can be categorized in the following order: young (hypoxia) > young (normoxia) > old aged (hypoxia) > old aged (normoxia).

• Age
• Bone-marrow
• Differentiation
• Hypoxia
• Mesenchymal stem cells
• MicroRNA
• Next generation sequencing
• Proliferation

Schematic illustration of the combination of NPs and MSCs drug delivery systems for cancer therapy.

• cell therapy
• clinical trials
• fibrosis
• liver disease
• progenitor cells
• stem cells

• cell fusion
• hepatocytes
• mesenchymal stem cells
• paracrine effect
• transdifferention

• Adipose Tissue/cytology
• Bone Marrow Cells/cytology
• Cell Differentiation/physiology
• Cell Transdifferentiation/physiology
• Cytokines/metabolism
• Epidermal Growth Factor/pharmacology
• Fetal Blood/cytology
• Fibroblast Growth Factors/pharmacology
• Hepatocytes/cytology
• Humans
• Liver Diseases/therapy
• Liver Regeneration/physiology
• Liver Transplantation
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Signal Transduction

• Dopamine D2 receptors
• Endothelial progenitor cells
• Mesenchymal stem cells
• Mobilization

Prostate cancer (PC) is one of the most common cancers arising in men and has a high propensity for bone metastasis, particularly to the spine. At this stage, it often causes severe morbidity due to pathological fracture and/or metastatic epidural spinal cord compression which, if untreated, inevitably leads to intractable pain, neurological deficit, and paralysis. Unfortunately, the underlying molecular mechanisms driving growth of secondary PC in the bony vertebral column remain largely unknown. Further investigation is warranted in order to identify therapeutic targets in the future. This review summarizes the current understanding of PC bone metastasis in the spine, highlighting interactions between key tumor and bone-derived factors which influence tumor progression, especially the functional roles of osteoblasts and osteoclasts in the bone microenvironment through their interactions with metastatic PC cells and the critical pathway RANK/RANKL/OPG in bone destruction.

• OPG bone microenvironment
• RANK
• RANKL
• metastasis
• osteoblasts
• osteoclasts
• prostate cancer
• spine