Mesenchymal stem cells as a vector for the inflammatory prostate microenvironment
ABSTRACT Mesenchymal stem cells (MSCs) have an inherent tropism for sites of inflammation, which are frequently present in sites of cancer, including prostatic lesions. MSCs have been defined as CD73/CD90/CD105 triple-positive cells in the absence of hematopoietic lineage markers with the ability to differentiate into multiple mesodermal lineages, including osteoblasts, adipocytes, and chondrocytes. Our group has previously demonstrated that MSCs represent between 0.01 and 1.1% of the total cells present in human prostatectomy tissue. In addition to their multi-lineage differentiation potential, MSCs are immunoprivileged in nature and have a range of immunomodulatory effects on both the innate and adaptive arms of the immune system. MSCs have been detected in an increasing array of tissues, and evidence suggests that they are likely present in perivascular niches throughout the body. These observations suggest that MSCs represent critical mediators of the overall immune response during physiological homeostasis and likely contribute to pathophysiological conditions as well. Chronic inflammation has been suggested as an initiating event and progression factor in prostate carcinogenesis, a process in which the immunosuppressive properties of MSCs may play a role. MSCs have also been shown to influence malignant progression through a variety of other mechanisms, including effects on tumor proliferation, angiogenesis, survival, and metastasis. Additionally, human bone marrow-derived MSCs have been shown to traffic to human prostate cancer xenografts in immunocompromised murine hosts. The trafficking properties and immunoprivileged status of MSCs suggest that they can be exploited as an allogeneic cell-based vector to deliver cytotoxic or diagnostic agents for therapy.
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ABSTRACT: Breast cancer is the most common malignancy among females throughout the world. Current treatments have unsatisfactory outcomes due to the dispersed nature of certain types of the disease. The development of a more effective therapy for breast cancer has long been one of the most elusive goals of cancer gene therapy. In the present study, human mesenchymal stem cells derived from umbilical cord (hUMSCs) genetically modified with interleukin 18 (IL-18) gene were used to study the effect of hUMSCs/IL-18 on the growth, migration and invasion of MCF-7 and HCC1937 cells in vitro. The hUMSCs could be efficiently modified by lentiviral systems and stably expressed IL-18 protein. hUMSCs/IL-18, but not hUMSCs without the IL-18 gene transduction, significantly suppressed the proliferation, migration and invasion of the MCF-7 and HCC1937 cells. The mechanism of this proliferation suppression may have involved the induction of G1- to S-phase arrest of the breast cancer cells by the hUMSCs/IL-18. In conclusion, hUMSCs/IL-18 can suppress the proliferation, migration and invasion of breast cancer cells in vitro and may provide an approach for a novel antitumor therapy in breast cancer.Experimental and therapeutic medicine 02/2015; 9(4). DOI:10.3892/etm.2015.2286 · 0.94 Impact Factor
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ABSTRACT: Recent studies have reported that bone marrow-derived cells (BMDCs), which are recruited to sites of tissue injury and inflammation, can differentiate into epithelial cells, such as liver, lung, gastrointestinal tract, and skin cells. We investigated the role of BMDCs in contributing to regeneration of injured prostate epithelium. Using chimera rats that received allogenic bone marrow grafts from green fluorescent protein (GFP) transgenic rats after lethal whole-body irradiation, we investigated the existence of epithelial marker-positive BMDCs in injured prostate tissue caused by transurethral injection of lipopolysaccharide. Prostate tissues were harvested 2 weeks after transurethral lipopolysaccharide injection. Immunofluorescence staining showed that some cells in the stroma co-expressed GFP and pan-cytokeratin, which suggested the existence of epithelial marker-positive BMDCs. To confirm the existence of such cells, we collected bone marrow-derived non-hematopoietic cells (GFP+/CD45- cells) from the prostate by fluorescence-activated cell sorter analysis and analyzed the characteristics of the GFP+/CD45- cells. The number of cells in this population significantly increased from 0.042% to 0.492% compared with normal prostate tissue. We found by immunofluorescent analysis and RT-PCR that GFP+/CD45- cells expressed cytokeratin, which suggested that these cells have some features of epithelial cells. In the prostate obtained from the chimera rats 34 weeks after lipopolysaccharide injection, GFP- and cytokeratin-positive cells were observed in the prostate gland, which suggested that some of the cells in the prostate gland regenerated after prostate inflammation derived from bone marrow. BMDCs might be able to differentiate into prostate epithelial cells after prostatic injury. Prostate 9999: 1-9, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.The Prostate 02/2015; 191(4). DOI:10.1002/pros.22962 · 3.57 Impact Factor
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ABSTRACT: Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.Frontiers in Oncology 12/2014; 4:364. DOI:10.3389/fonc.2014.00364