Dataset Information

Mesenchymal stem cell infiltration during neoplastic transformation of the human prostate.

ABSTRACT: Mesenchymal Stem Cells (MSCs) have been identified in prostate cancer, raising the critical question of their physical and temporal source. Therefore, MSCs were quantified and characterized in benign and malignant prostate tissue representing different disease states and a wide range of age groups from fetal development through adult death using analytical and functional methodologies. In contrast to lineage-restricted Mesenchymal Progenitor Cells (MPCs) found in normal prostate tissue, MSCs with tri-lineage differentiation potential (adipogenesis, osteogenesis, and chondrogenesis) are identified in prostate tissue from a subset of men with prostate cancer, consistent with an influx of more stem-like progenitors (i.e. MSCs) from the bone marrow. Additionally, prostate tissue from a subset of these patients is highly enriched in MSCs, suggesting their enumeration may have prognostic value for identifying men with aggressive disease. This influx is an ongoing process continuing throughout disease progression as documented by the presence of MSCs in metastatic lesions from multiple organ sites harvested at the time of death in metastatic castration-resistant prostate cancer (mCRPC) patients. This infiltration of MSCs from systemic circulation provides the rationale for their use as a cell-based vector to deliver therapeutic agents.

SUBMITTER: Brennen WN

PROVIDER: S-EPMC5564518 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mesenchymal stem cell infiltration during neoplastic transformation of the human prostate.

Brennen W Nathaniel WN Zhang Baohui B Kulac Ibrahim I Kisteman L Nelleke LN Antony Lizamma L Wang Hao H Meeker Alan K AK De Marzo Angelo M AM Garraway Isla P IP Denmeade Samuel R SR Isaacs John T JT

Oncotarget 20170701 29

Mesenchymal Stem Cells (MSCs) have been identified in prostate cancer, raising the critical question of their physical and temporal source. Therefore, MSCs were quantified and characterized in benign and malignant prostate tissue representing different disease states and a wide range of age groups from fetal development through adult death using analytical and functional methodologies. In contrast to lineage-restricted Mesenchymal Progenitor Cells (MPCs) found in normal prostate tissue, MSCs wit ...[more]

PMID: 28493842

Similar Datasets

Project description:Comprehensive analysis of alterations in gene expression along with neoplastic transformation in human cells provides valuable information about the molecular mechanisms underlying transformation. To further address these questions, we performed whole transcriptome analysis to the human mesenchymal stem cell line, UE6E7T-3, which was immortalized with hTERT and human papillomavirus type 16 E6/E7 genes, in association with progress of transformation in these cells. At early stages of culture, UE6E7T-3 cells preferentially lost one copy of chromosome 13, as previously described; in addition, tumor suppressor genes, DNA repair genes, and apoptosis-activating genes were overexpressed. After the loss of chromosome 13, additional aneuploidy and genetic alterations that drove progressive transformation, were observed. At this stage, the cell line expressed oncogenes as well as genes related to anti-apoptotic functions, cell-cycle progression, and chromosome instability (CIN); these pro-tumorigenic changes were concomitant with a decrease in tumor suppressor gene expression. At later stages after prolong culture, the cells exhibited chromosome translocations, acquired anchorage-independent growth and tumorigenicity in nude mice, (sarcoma) and exhibited increased expression of genes encoding growth factor and DNA repair genes, and decreased expression of adhesion genes. In particular, glypican-5 (GPC5), which encodes a cell-surface proteoglycan that might be a biomarker for sarcoma, was expressed at high levels in association with transformation. Patched (Ptc1), the cell surface receptor for hedgehog (Hh) signaling, was also significantly overexpressed and co-localized with GPC5. Knockdown of GPC5 expression decreased cell proliferation, suggesting that it plays a key role in growth in U3-DT cells (transformants derived from UE6E7T-3 cells) through the Hh signaling pathway. Thus, the UE6E7T-3 cell culture model is a useful tool for assessing the functional contribution of genes showed by expression profiling to the neoplastic transformation of human fibroblasts and human mesenchymal stem cells (hMSC).

Project description:BACKGROUND:Mesenchymal stromal cells isolated from bone marrow (MSC) represent an attractive source of adult stem cells for regenerative medicine. However, thorough research is required into their clinical application safety issues concerning a risk of potential neoplastic degeneration in a process of MSC propagation in cell culture for therapeutic applications. Expansion protocols could preselect MSC with elevated levels of growth-promoting transcription factors with oncogenic potential, such as c-MYC. We addressed the question whether c-MYC expression affects the growth and differentiation potential of human MSC upon extensive passaging in cell culture and assessed a risk of tumorigenic transformation caused by MSC overexpressing c-MYC in vivo. METHODS:MSC were subjected to retroviral transduction to induce expression of c-MYC, or GFP, as a control. Cells were expanded, and effects of c-MYC overexpression on osteogenesis, adipogenesis, and chondrogenesis were monitored. Ectopic bone formation properties were tested in SCID mice. A potential risk of tumorigenesis imposed by MSC with c-MYC overexpression was evaluated. RESULTS:C-MYC levels accumulated during ex vivo passaging, and overexpression enabled the transformed MSC to significantly overgrow competing control cells in culture. C-MYC-MSC acquired enhanced biological functions of c-MYC: its increased DNA-binding activity, elevated expression of the c-MYC-binding partner MAX, and induction of antagonists P19ARF/P16INK4A. Overexpression of c-MYC stimulated MSC proliferation and reduced osteogenic, adipogenic, and chondrogenic differentiation. Surprisingly, c-MYC overexpression also caused an increased COL10A1/COL2A1 expression ratio upon chondrogenesis, suggesting a role in hypertrophic degeneration. However, the in vivo ectopic bone formation ability of c-MYC-transduced MSC remained comparable to control GFP-MSC. There was no indication of tumor growth in any tissue after transplantation of c-MYC-MSC in mice. CONCLUSIONS:C-MYC expression promoted high proliferation rates of MSC, attenuated but not abrogated their differentiation capacity, and did not immediately lead to tumor formation in the tested in vivo mouse model. However, upregulation of MYC antagonists P19ARF/P16INK4A promoting apoptosis and senescence, as well as an observed shift towards a hypertrophic collagen phenotype and cartilage degeneration, point to lack of safety for clinical application of MSC that were manipulated to overexpress c-MYC for their better expansion.

Dataset Information

Mesenchymal stem cell infiltration during neoplastic transformation of the human prostate.

Publications

Mesenchymal stem cell infiltration during neoplastic transformation of the human prostate.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets