Mesenchymal Stem Cells in Gastric Cancer: History
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Contributor:
Fawzy Akad
,
Veronica Mocanu
,
Sorin Nicolae Peiu
,
Viorel Scripcariu
,
Bogdan Filip
,
Daniel Timofte
,
Florin Zugun-Eloae
,
Magdalena Cuciureanu
,
Monica Hancianu
,
Teodor Oboroceanu
,
Laura Condur
,
Radu Florin Popa

Bone marrow-derived mesenchymal stem cells (MSCs) naturally present in the stomach have been reported to carry a malignancy risk, but their effect in gastric cancer (GC) is still being researched. The pro- and antiangiogenic effects of MSCs derived from various sources complement their role in immune regulation and tissue regeneration and provide further understanding into the heterogeneous biology of GC, the aberrant morphology of tumor vasculature and the mechanisms of resistance to antiangiogenic drugs.

  • gastric cancer
  • angiogenesis
  • neovascularization
  • tumor microenvironment

1. Introduction

Gastric cancer (GC) is highly heterogeneous and its molecular classification is based on the location, histology and immunohistochemical evaluation of human epidermal growth factor receptor 2 (HER2) expression and the replication error (RER) phenotype of tumors and their molecular and genetic profiles. Blood markers proposed for the detection of patients at risk of GC or those likely to benefit from specific treatments include pepsinogen I, ghrelin and various microRNAs [1]. DNA methylation, histone modifications and non-coding RNA molecules (microRNAs and long non-coding RNAs) regulate gene expression in gastric tumors [2]. MicroRNAs (miRNAs) produced by exosomes in the tumor microenvironment have been proposed as biomarkers for the early diagnosis of and for disease progression in GC, as they regulate cell differentiation, proliferation and apoptosis. The prognostic role of miRNA-34a expression in the serum or tissues of GC patients is supported by a negative relationship between miRNA-34a and GC progression, with significantly lower levels in GC tissues and metastases [3]. Decreased miR-539 miRNA in GC tissues is associated with poor 5-year survival [4]. On the other hand, miR-17-5p miRNA is upregulated in surgically retrieved GC tissues and in the plasma of GC patients, and it increases the proliferation of GC cells in vitro by inhibiting GC cell apoptosis and by downregulating the expresion of genes that act as tumor suppressors [5]. Exosomal miR-155 derived from GC cells has been found to suppress adipogenesis in adipose (AD)-MSCs, leading to cancer-associated cachexia [6].
MiRNAs are widespread in mesenchymal stem cells (MSCs). The exosomes secreted by MSCs (MSC-exos) isolated from bone marrow (BM), adipose tissue (AD), dental pulp (DP), umbilical cords (UCs), amniotic fluid (AF) or the placenta could be used as miRNA delivery systems in malignancies [7].
MSC-exos have either a pro- or antiangiogenic effect on tumors through various mechanisms: the ERK1/2 pathway, AKT (protein kinase B)/eNOS pathway or miRNA transport [8]. Exome sequencing studies have provided genetic findings important to the understanding of the development of atrophic gastritis and gastric intestinal metaplasia into cancer and GC resistance to chemotherapeutic agents.
Deregulated angiogenesis promotes gastric tumor growth through the expansion of capillaries that provide nutrients and oxygen to the tumor microenvironment. Tumor growth is supported by the transition from an avascular dormant phase to a vascular expanding one. The leaky tumor endothelial cells of the tumor microenvironment increase the interstitial pressure and interact with various growth factors. Some of these growth factors (vascular endothelial growth factors—VEGFs) are angiogenesis mediators found in hypoxic, acidic areas, created by fast proliferating cancer cells due to their high dividing rate [9][10][11]. GC patients with a high expression of VEGF-A and VEGF-C have been shown to have a worse prognosis, with larger tumor sizes and increased metastatic activity [12].
The goal of genome-guided personalized therapy in gastric cancer has required a study of the relationship between MSC-exos and angiogenesis. A literature search was performed on Pubmed/Medline, Google Scholar and Embase with the keywords “(mesenchymal stem cells OR exosomes OR mesenchymal stem cell-derived exosomes OR MSC-exos) AND (angiogenesis OR angiogenic OR neovascularization OR vascular endothelial growth factors) AND (gastric cancer OR stomach neoplasm)”.
Anti-angiogenic agents—such as apatinib, ramucirumab and bevacizumab—have been so far used in GC treatment, but the results have not been as expected [13]. MSCs support angiogenesis and yet the functions of transplanted stem cells are affected by hypoxia and inflammation in the receiving tissues. MSCs lead to a significant increase in VEGF production and MSCs can be used as an important source of VEGFs [14].

2. MSCs in GC

The gastric epithelium renews itself incessantly with the help of adult stem cells, derived either from the base or the neck of antral glands or from the isthmus. Similarly to the gut epithelium, two gastric stem cell populations with a different plasticity, longevity and cycling rate have been hypothesized [15]. MSCs play various anti-inflammatory and immunoregulatory roles, with a regenerative potential based on secretion and modulation rather than the direct replacement of tissues [16].
The presence of MSC-like cells has been confirmed in human GC tissues and they share similar characteristics to BM-MSCs [17], but have a different phenotype and function [18]. BM-MSCs, which are usually found in inflammed tissues, have been previously linked to GC development in Helicobacter felis-infected mice [19]. Helicobacter pylori infection increases MSC proliferation and migration and activates the PI3K-AKT signaling pathway, due to the reduction of glutamine and the metabolite alpha-ketoglutarate (α-kg), produced by the gamma-glutamyltransferase enzyme secreted by Helicobacter pylori—as shown by an in vivo study on nude mice [20]. BM-MSCs are considered to be the precursors of GC-MSCs. BM-MSCs show a GC-MSC-like phenotype and function through NF-κB activation following knockdown of miR-155-5p, which is downregulated in GC-MSCs [18]. BM-MSCs promote GC angiogenesis by releasing VEGFs, fibroblast-derived growth factors, platelet-derived growth factors, stromal cell derived factors-1 (SDF-1s) and cytokines [21].
MSC-like cells are also found in adjacent non-cancerous gastric tissues, sharing the same fibroblast-like appearance as normal BM-MSCs and being different in respect to their gene profiles [22].
GC-MSCs have a higher inflammatory response, with increased levels of IL-6, MCP-1 and VEGF [18]. GC-MSCs show an osteoblastic differentiation potential in vitro [23]. GC-MSCs are also characterized by high levels of fibroblast proteins, α-smooth muscle actin (α-SMA) and vimentin [24]. GC-MSCs create an immunosuppressive tumor microenvironment by impairing the anti-tumor immunity mechanisms mediated by peripheral blood mononuclear cells through Treg/Th17 imbalance, with increased levels of Treg cells and decreased levels of Th17 cells [25].
The effect of GC-MSCs on GC progression, migration and angiogenesis is superior to those of adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and BM-MSCs in vitro. A list of the pro-angiogenic effects of GC-MSCs is provided in Table 1.
GC-MSCs have the highest levels of the pro-angiogenic factors VEGF, MIP-2, transforming growth factor TGF-β1, IL-6, and—especially—IL-8, showing the ability of GC-MSCs to enhance GC angiogenesis—mostly by secreting the inflammatory cytokine IL-8. GC cells cultured with GC-MSCs achieve a highly branched structure, suggesting an increased capacity to form tube-like structures [23]. MSC-derived IL-6 induces endothelin-1 (ET-1) secretion from cancer cells, which activates the AKT and ERK pathways in endothelial cells to promote endothelial cell recruitment and tumor neovascularization in gastrointestinal cancer cells. In tumors with diameters higher than 7 mm, angiogenesis plays an important role in tumor growth. MSCs increase tumor angiogenesis within the first 14 days—the earliest stage of tumor development [26]. The trans-differentiation of GC-MSCs into endothelial cells also modifies the entire GC vascular network [27].
GC angiogenesis is stimulated by IL-8 cytokines secreted by GC-MSCs and by the interaction of GC-MSCs with neutrophils that produce pro-angiogenic factors [28]. IL-8 has been shown to enhance the angiogenic effects of human BM-MSCs by stimulating VEGF production through PI3K/AKT and mitogen-activated protein kinase (MAPK)/ERK signaling pathways in cancer cells [14]. The interaction between GC-MSCs and GC-infiltrating neutrophils promotes angiogenesis. The pro-angiogenic activity of neutrophils stimulated with GC-MSCs in a conditioned medium obtained from cultured GC cells has been confirmed by the increased formation of tube-like structures as compared with control neutrophils, as shown by an in vitro endothelial cell tube formation assay performed on human umbilical vein endothelial cells (HUVECs) [29]. GC-MSC-derived angiogenesis can be suppressed by inhibiting the NF-κB/VEGF signaling pathways, which are responsible for the promotion of angiogenesis and the stimulation of VEGF expression in vitro and in vivo in the tumor environment. HUVECs showed decreased tube-formation ability when exposed to GC-MSCs treated with NF-κB inhibitors or a VEGF-neutralization antibody [24].
The miRNAs expressed in GC tissue are not unique to a specific cell type, as tumor stroma contains various mesenchymal cell types. MiRNAs packaged into GC-MSC-exos are delivered to GC cells and mediate GC progression. GC-MSCs promote GC progression by transporting these exosomal miRNAs to GC cells. Aberrant miRNA expression found in miR-214, miR-221 and miR-222 was found to be significantly higher in GC-MSCs and in GC tissues as compared to non-GC-MSCs and non-GC tissues. These increased miRNAs help GC-MSCs to promote lymph node metastasis, venous invasion and tumor node metastasis (TNM) staging in vitro and in vivo. GC-MSCs alter miR-221 expression in GC cells by delivering exosomal miRNAs to target cells [30][31].
MiR-15b-3p packed into exosomes (exo-miR-15b-3p) secreted by BGC-823 cells is increased in GC cells, tissues and serum and promote the malignant transformation of normal gastric mucosa epithelium cells GES-1 by regulating the dynein light chain Tctex-type 1 (DYNLT1)/Caspase-3/Caspase-9 signaling pathway, with decreased expression of the DYNLT1 gene [32].
Table 1. Mesenchymal stem cells derived from gastric cancer tissues promote tumor angiogenesis.
Pro-Angiogenic Factors Secreted by GC-MSCs Pro-Angiogenic Signaling Pathways Activated by GC-MSCs Interactions of GC-MSCs with Tumor Microenvironment Reference
VEGF, MIP-2, TGF-β1, IL-6, IL-8     [23]
IL-6, ET-1 AKT/ERK   [26]
IL-6, IL-8      
JAK2/STAT3 Neutrophils, macrophages [28][29]
PDGF-DD β-catenin, notch-1, NFκB, AKT   [21]
VEGF, bFGF   Carcinoma-associated fibroblasts, endothelial cells [33]

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11041031

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