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Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy.

ABSTRACT: The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using ¹²³I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of ¹²³I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated ¹³¹I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

SUBMITTER: Tutter M

PROVIDER: S-EPMC7854278 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAs a type of high-frequency electrotherapy, a short-wave can promote the fracture healing process; yet, its underlying therapeutic mechanisms remain unclear.PurposeTo observe the effect of Short-Wave therapy on mesenchymal stem cell (MSC) homing and relative mechanisms associated with fracture healing.Materials and methodsFor in vivo study, the effect of Short-Wave therapy to fracture healing was examined in a stabilized femur fracture model of 40 SD rats. Radiography was used to analyze the morphology and microarchitecture of the callus. Additionally, fluorescence assays were used to analyze the GFP-labeled MSC homing after treatment in 20 nude mice with a femoral fracture. For in vitro study, osteoblast from newborn rats simulated fracture site was first irradiated by the Short-Wave; siRNA targeting HIF-1 was used to investigate the role of HIF-1. Osteoblast culture medium was then collected as chemotaxis content of MSC, and the migration of MSC from rats was evaluated using wound healing assay and trans-well chamber test. The expression of HIF-1 and its related factors were quantified by q RT-PCR, ELISA, and Western blot.ResultsOur in vivo experiment indicated that Short-Wave therapy could promote MSC migration, increase local and serum HIF-1 and SDF-1 levels, induce changes in callus formation, and improve callus microarchitecture and mechanical properties, thus speeding up the healing process of the fracture site. Moreover, the in vitro results further indicated that Short-Wave therapy upregulated HIF-1 and SDF-1 expression in osteoblast and its cultured medium, as well as the expression of CXCR-4, β-catenin, F-actin, and phosphorylation levels of FAK in MSC. On the other hand, the inhibition of HIF-1α was significantly restrained by the inhibition of HIF-1α in osteoblast, and it partially inhibited the migration of MSC.ConclusionsThese results suggested that Short-Wave therapy could increase HIF-1 in callus, which is one of the crucial mechanisms of chemotaxis MSC homing in fracture healing.

Project description:Tumor‑stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast‑activating protein‑positive staining around the cancer cells was increased in SPARC‑positive compared with SPARC‑negative cases. Proliferation and wound healing assays in SPARC‑silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription‑quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild‑type (WT) cells. However, it was markedly reduced when co‑cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC‑transplanted tumors compared with WT‑transplanted tumors, with a more marked suppression observed following shSPARC co‑transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial‑mesenchymal transition (EMT) were markedly suppressed in tumors co‑transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.

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Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy.

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