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Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.

ABSTRACT: INTRODUCTION: Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. METHODS: Morphological changes were assessed using fluorescence microscopy. Changes in gene expression were assessed using Agilent microarray and qRT-PCR. GeneSpring 12.1 and DAVID tools were used for bioinformatic and signaling pathway analyses. Cell migration was assessed using a transwell migration system. SB-431542, PF-573228 and PD98059 were used to inhibit transforming growth factor ? (TGF?), focal adhesion kinase (FAK), and mitogen activated protein kinase kinase (MAPKK) pathways, respectively. Interleukin-1? (IL1?) was measured using ELISA. RESULTS: MSCs exposed to secreted factors present in conditioned media (CM) from FaDu, MDA-MB-231, PC-3 and NCI-H522, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (approximately 80% to 99%, and 55% to 88% inhibition, respectively), while inhibition of the TGF? pathway was found to promote the pro-inflammatory response (approximately 3-fold increase). In addition, bioinformatics and pathway analysis of gene expression data from tumor cell lines combined with experimental validation revealed tumor-derived IL1? as one mediator of the pro-inflammatory phenotype observed in MSCs exposed to tumor CM. CONCLUSIONS: Our data revealed tumor-derived IL1? as one mediator of the pro-inflammatory response in MSCs exposed to tumor CM, which was found to be positively regulated by FAK and MAPK signaling and negatively regulated by TGF? signaling. Thus, our data support a model where MSCs could promote cancer progression through becoming pro-inflammatory cells within the cancer stroma.

SUBMITTER: Al-toub M

PROVIDER: S-EPMC3854757 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.

Al-toub Mashael M Almusa Abdulaziz A Almajed Mohammed M Al-Nbaheen May M Kassem Moustapha M Aldahmash Abdullah A Alajez Nehad M NM

Stem cell research & therapy 20130917 5

<h4>Introduction</h4>Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological ...[more]

PMID: 24405819

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Project description:BackgroundHuman Wharton's jelly-derived mesenchymal stromal/stem cells (hWJ-MSCs) have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them. Recently, we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential. This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AimTo understand the radioprotective mechanism of soluble factors secreted by hWJ-MSCs and identification of their unique genes.MethodsPropidium iodide staining, endogenous spleen colony-forming assay, and survival study were carried out for radioprotection studies. Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation. Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells, embryonic stem cells, and human fibroblasts. Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.ResultsCo-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes. WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes. Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection. Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin (IL)1-α, IL1-β, IL-6, CXCL3, CXCL5, CXCL8, CXCL2, CCL2, FLT-1, and IL-33. It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources. Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.ConclusionSystemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims.

Project description:BackgroundPatients with muscle-invasive bladder cancer face a poor prognosis due to rapid disease progression and chemoresistance. Thus, there is an urgent need for a new therapeutic treatment. The tumor microenvironment (TME) has crucial roles in tumor development, growth, progression, and therapy resistance. TME cells may also survive standard treatment of care and fire up disease recurrence. However, whether specific TME components have tumor-promoting or tumor-inhibitory properties depends on cell type and cancer entity. Thus, a deeper understanding of the interaction mechanisms between the TME and cancer cells is needed to develop new cancer treatment approaches that overcome therapy resistance. Little is known about the function and interaction between mesenchymal stromal cells (MSC) or fibroblasts (FB) as TME components and bladder cancer cells.MethodsWe investigated the functional impact of conditioned media (CM) from primary cultures of different donors of MSC or FB on urothelial carcinoma cell lines (UCC) representing advanced disease stages, namely, BFTC-905, VMCUB-1, and UMUC-3. Underlying mechanisms were identified by RNA sequencing and protein analyses of cancer cells and of conditioned media by oncoarrays.ResultsBoth FB- and MSC-CM had tumor-promoting effects on UCC. In some experiments, the impact of MSC-CM was more pronounced. CM augmented the aggressive phenotype of UCC, particularly of those with epithelial phenotype. Proliferation and migratory and invasive capacity were significantly increased; cisplatin sensitivity was reduced. RNA sequencing identified underlying mechanisms and molecules contributing to the observed phenotype changes. NRF2 and NF-κB signaling was affected, contributing to improved cisplatin detoxification. Likewise, interferon type I signaling was downregulated and regulators of epithelial mesenchymal transition (EMT) were increased. Altered protein abundance of CXCR4, hyaluronan receptor CD44, or TGFβ-signaling was induced by CM in cancer cells and may contribute to phenotypical changes. CM contained high levels of CCL2/MCP-1, MMPs, and interleukins which are well known for their impact on other cancer entities.ConclusionsThe CM of two different TME components had overlapping tumor-promoting effects and increased chemoresistance. We identified underlying mechanisms and molecules contributing to the aggressiveness of bladder cancer cells. These need to be further investigated for targeting the TME to improve cancer therapy.

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Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.

Publications

Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.

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