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Cited by 57Mesenchymal stem cell researchCancer Cells and MetastasisImmune cells in cancer

The DOI matches its Crossref record; 355 of the 356 references it cites were found in a registry or an index.

The Dual Role of Mesenchymal Stem Cells in Cancer Pathophysiology: Pro-Tumorigenic Effects versus Therapeutic Potential

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Slama, Youssef, Ah-Pine, Franck, Khettab, Mohamed, Arcambal, Angelique, Begue, Mickael, Dutheil, Fabien, Gasque, Philippe·2023·International Journal of Molecular Sciences
DOI 10.3390/ijms241713511PMC PMC10488262
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Abstract

Mesenchymal stem/stromal cells (MSCs) are multipotent cells involved in numerous physiological events, including organogenesis, the maintenance of tissue homeostasis, regeneration, or tissue repair. MSCs are increasingly recognized as playing a major, dual, and complex role in cancer pathophysiology through their ability to limit or promote tumor progression. Indeed, these cells are known to interact with the tumor microenvironment, modulate the behavior of tumor cells, influence their functions, and promote distant metastasis formation through the secretion of mediators, the regulation of cell–cell interactions, and the modulation of the immune response. This dynamic network can lead to the establishment of immunoprivileged tissue niches or the formation of new tumors through the proliferation/differentiation of MSCs into cancer-associated fibroblasts as well as cancer stem cells. However, MSCs exhibit also therapeutic effects including anti-tumor, anti-proliferative, anti-inflammatory, or anti-oxidative effects. The therapeutic interest in MSCs is currently growing, mainly due to their ability to selectively migrate and penetrate tumor sites, which would make them relevant as vectors for advanced therapies. Therefore, this review aims to provide an overview of the double-edged sword implications of MSCs in tumor processes. The therapeutic potential of MSCs will be reviewed in melanoma and lung cancers.

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Crossref · 10.3390/ijms241713511

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Figures

Figure 1 The proliferation and differentiation of perivascular (p) MSCs in cancer can give rise either to pericytes, perivascular fibroblasts, cancer-associated fibroblasts, as well as cancer stem cells. The vascular unit is formed by endothelial cells (CD93+), peridentothelial pericytes (PCs, CD248high) embedded into the extracellular matrix (ECM, e.g., multimerin-2) of the basement membrane, and perivascular mesenchymal stem cells (pMSCs CD248low/CD90+). Single-cell RNA profiling experiments have indicated that PCs (e.g., in the CNS) may give rise to subsets of pMSCs, which can proliferate, particularly in response to PDGF, and differentiate into either fibroblasts subsets (ECMhigh or VEGFhigh), cancer-associated fibroblasts (CAFs to support tumor growth), or cancer stem cells (CSCs), as recently evidenced in glioblastoma [63,73]. Fibroblasts stimulated by TGF-β1 may give rise to myofibroblasts (Smooth Muscle cell Actin/SMAhigh/ECMhigh). TAMs: tumor-associated macrophages. (Figure designed by BioRender).
Figure 1 The proliferation and differentiation of perivascular (p) MSCs in cancer can give rise either to pericytes, perivascular fibroblasts, cancer-associated fibroblasts, as well as cancer stem cells. The vascular unit is formed by endothelial cells (CD93+), peridentothelial pericytes (PCs, CD248high) embedded into the extracellular matrix (ECM, e.g., multimerin-2) of the basement membrane, and perivascular mesenchymal stem cells (pMSCs CD248low/CD90+). Single-cell RNA profiling experiments have indicated that PCs (e.g., in the CNS) may give rise to subsets of pMSCs, which can proliferate, particularly in response to PDGF, and differentiate into either fibroblasts subsets (ECMhigh or VEGFhigh), cancer-associated fibroblasts (CAFs to support tumor growth), or cancer stem cells (CSCs), as recently evidenced in glioblastoma [63,73]. Fibroblasts stimulated by TGF-β1 may give rise to myofibroblasts (Smooth Muscle cell Actin/SMAhigh/ECMhigh). TAMs: tumor-associated macrophages. (Figure designed by BioRender).CC BY · PubMed Central
Figure 2 Recruitment of distant (BM)/resident MSCs, activation via diverse mechanisms, and differentiation to CAFs of the TME. Perivascular cells (MSCs/fibroblasts) as well as pericytes (blue) are resident cells, while MSCs from the bone marrow can be recruited in tumor sites. Factors derived mainly from necrotic tissues (notably in response to therapies) and infiltrating immune cells such as macrophages may contribute to the recruitment, proliferation, and activation of MSCs/Fib. MSCs will differentiate into CAFs with either restraining or promoting activities towards cancer cells. (Figure designed by BioRender).
Figure 2 Recruitment of distant (BM)/resident MSCs, activation via diverse mechanisms, and differentiation to CAFs of the TME. Perivascular cells (MSCs/fibroblasts) as well as pericytes (blue) are resident cells, while MSCs from the bone marrow can be recruited in tumor sites. Factors derived mainly from necrotic tissues (notably in response to therapies) and infiltrating immune cells such as macrophages may contribute to the recruitment, proliferation, and activation of MSCs/Fib. MSCs will differentiate into CAFs with either restraining or promoting activities towards cancer cells. (Figure designed by BioRender).CC BY · PubMed Central
Figure 3 Mesenchymal stem cells are highly plastic and exhibit multipotency (transdifferentiation) in the tumor microenvironment. CAFs: cancer-associated fibroblasts; EMT: epithelial–mesenchymal transition; EndMT: endothelial–mesenchymal transition; MSCs: mesenchymal stem cells. (Figure designed by BioRender).
Figure 3 Mesenchymal stem cells are highly plastic and exhibit multipotency (transdifferentiation) in the tumor microenvironment. CAFs: cancer-associated fibroblasts; EMT: epithelial–mesenchymal transition; EndMT: endothelial–mesenchymal transition; MSCs: mesenchymal stem cells. (Figure designed by BioRender).CC BY · PubMed Central
Figure 4 Interactions and regulations involving mesenchymal stem cells in the tumor microenvironment. AKT: protein kinase B; α-SMA: α-smooth muscle actin; C3a: complement component 3 anaphylatoxins; CAF: cancer-associated fibroblast; CCL: CC chemokine ligand; COL: collagen; Cox-2: cyclooxygenase-2; CSC: cancer stem cell; CXCL: C-X-C motif ligand; CXCR: C-X-C motif chemokine receptor; DDR2: discoidin domain receptor tyrosine kinase 2; ERK: extracellular signal-regulated kinase; FASL: fas ligand; FSP1: fibroblast-specific protein 1; HGF: hepatocyte growth factor; HIF-1: hypoxia-inducible factor-1; IDO: indoleamine-2,3-dioxygenase; IFN-γ: interferon-γ; IGF: insulin growth factor; IL: interleukin; iNOS: inducible nitric oxide synthase; JAK/STAT: janus kinase-signal transducer and activator of transcription; MMPs: matrix metalloproteinases; MSCs: mesenchymal stem cells; mTOR: mammalian target of rapamycin; NFκB: nuclear factor-κB; NK: natural killer; NO: nitric oxide; PD-1: programmed cell death protein 1; PDGF: platelet-derived growth factor; PD-L1: programmed cell death ligand 1; PGE2: prostaglandin E2; PI3K: phosphoinositide 3-kinase; RANTES: regulated on activation, normal T cell expressed and secreted; SDF-1: stromal cell-derived factor 1; Smad: small mothers against decapentaplegic; Src: proto-oncogene tyrosine-protein kinase; STAT: signal transducer and activator of transcription; TAM: tumor-associated macrophage; TAN: tumor-associated neutrophil; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; TNFR: tumor necrosis factor receptor; TRAIL: tumor-necrosis-factor-related apoptosis-inducing ligand; VEGF: vascular endothelial growth factor. (Figure designed by BioRender).
Figure 4 Interactions and regulations involving mesenchymal stem cells in the tumor microenvironment. AKT: protein kinase B; α-SMA: α-smooth muscle actin; C3a: complement component 3 anaphylatoxins; CAF: cancer-associated fibroblast; CCL: CC chemokine ligand; COL: collagen; Cox-2: cyclooxygenase-2; CSC: cancer stem cell; CXCL: C-X-C motif ligand; CXCR: C-X-C motif chemokine receptor; DDR2: discoidin domain receptor tyrosine kinase 2; ERK: extracellular signal-regulated kinase; FASL: fas ligand; FSP1: fibroblast-specific protein 1; HGF: hepatocyte growth factor; HIF-1: hypoxia-inducible factor-1; IDO: indoleamine-2,3-dioxygenase; IFN-γ: interferon-γ; IGF: insulin growth factor; IL: interleukin; iNOS: inducible nitric oxide synthase; JAK/STAT: janus kinase-signal transducer and activator of transcription; MMPs: matrix metalloproteinases; MSCs: mesenchymal stem cells; mTOR: mammalian target of rapamycin; NFκB: nuclear factor-κB; NK: natural killer; NO: nitric oxide; PD-1: programmed cell death protein 1; PDGF: platelet-derived growth factor; PD-L1: programmed cell death ligand 1; PGE2: prostaglandin E2; PI3K: phosphoinositide 3-kinase; RANTES: regulated on activation, normal T cell expressed and secreted; SDF-1: stromal cell-derived factor 1; Smad: small mothers against decapentaplegic; Src: proto-oncogene tyrosine-protein kinase; STAT: signal transducer and activator of transcription; TAM: tumor-associated macrophage; TAN: tumor-associated neutrophil; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; TNFR: tumor necrosis factor receptor; TRAIL: tumor-necrosis-factor-related apoptosis-inducing ligand; VEGF: vascular endothelial growth factor. (Figure designed by BioRender).CC BY · PubMed Central
Figure 5 Tumor support functions of mesenchymal stem cells. Adapted from Frisbie et al. [143]. CAAs: cancer-associated adipocytes; CAFs: cancer-associated fibroblasts; CAMs: cancer-associated myofibroblasts; CSCs: cancer stem cells; EMT: epithelial–mesenchymal transition; IL: interleukin; MSCs: mesenchymal stem cells; NK cells: natural killer cells; TME: tumor microenvironment; TNF-α: tumor necrosis factor-α. (Figure designed by BioRender).
Figure 5 Tumor support functions of mesenchymal stem cells. Adapted from Frisbie et al. [143]. CAAs: cancer-associated adipocytes; CAFs: cancer-associated fibroblasts; CAMs: cancer-associated myofibroblasts; CSCs: cancer stem cells; EMT: epithelial–mesenchymal transition; IL: interleukin; MSCs: mesenchymal stem cells; NK cells: natural killer cells; TME: tumor microenvironment; TNF-α: tumor necrosis factor-α. (Figure designed by BioRender).CC BY · PubMed Central
Figure 6 Mesenchymal stem cells as vectors for therapeutic agents. Ag: silver; Au: gold; CX3CL1: C-X3-C motif chemokine ligand 1; EMT: epithelial–mesenchymal transition; Fe: iron; Hf: hafnium; HSV-tk: herpes simplex virus thymidine kinase; IFN: interferon; IL: interleukin; MSC: mesenchymal stem cell; NK cell: natural killer cell; TNF-α: tumor necrosis factor-α; TRAIL: TNF-related apoptosis-inducing ligand; TSP-1: thrombospondin-1. (Figure designed by BioRender).
Figure 6 Mesenchymal stem cells as vectors for therapeutic agents. Ag: silver; Au: gold; CX3CL1: C-X3-C motif chemokine ligand 1; EMT: epithelial–mesenchymal transition; Fe: iron; Hf: hafnium; HSV-tk: herpes simplex virus thymidine kinase; IFN: interferon; IL: interleukin; MSC: mesenchymal stem cell; NK cell: natural killer cell; TNF-α: tumor necrosis factor-α; TRAIL: TNF-related apoptosis-inducing ligand; TSP-1: thrombospondin-1. (Figure designed by BioRender).CC BY · PubMed Central

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  1. Birbrair, A. (2020). Tumor Microenvironment: Non-Hematopoietic Cells, Springer International Publishing. Advances in Experimental Medicine and Biology. · DOI

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Metadata

Authors
Slama, Y., Ah-Pine, F., Khettab, M., Arcambal, A., Begue, M., Dutheil, F., & Gasque, P.
Affiliations
  • University of Reunion Island (RE)
  • Laboratoire Interdisciplinaire de Recherche en Santé (LIRS), RunResearch, Clinique Sainte-Clotilde, 127 Route de Bois de Nèfles, 97400 Saint-Denis, La Réunion, France
  • Clinifutur (RE)
Corresponding author
Slama, Youssef
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2023-08-31
Volume
24
Issue
17
Pages
13511
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms241713511
PMC
PMC10488262
OpenAlex
W4386331467
Cited by
57
References
356
Citations by year
2026: 13 · 2025: 22 · 2024: 21 · 2023: 1
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
EPIGEN project research (CPER FEDER 2019221-0022768)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
mesenchymal stem cells, tumor microenvironment, tumor progression, metastasis, cancer-associated fibroblasts, cancer stem cells, tumor immunomodulation, melanoma, lung cancer, cell-cell interactions
MeSH terms
Humans, Lung Neoplasms, Melanoma, Multipotent Stem Cells, Tumor Microenvironment, Mesenchymal Stem Cells, Carcinogenesis

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