Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, actively contribute to the formation of the tumour microenvironment, wherein they are converted into tumour-associated MSCs (TA-MSCs).
TA-MSCs regulate tumour growth, metastasis and responses to chemotherapy and radiotherapy by producing growth factors, chemokines and cytokines.
TA-MSCs have an important role in regulating tumour immunity. Blocking TA-MSC-associated immunosuppressive factors could unleash antitumour immune responses.
Novel antitumour therapeutic strategies can be developed by targeting TA-MSC-produced factors that promote tumour growth, metastasis and drug resistance.
Owing to their tumour-tropic nature, in vitro-expanded MSCs can be genetically engineered to express antitumour agents at the tumour site to specifically kill tumour cells or to enhance antitumour immune responses.
Mesenchymal stem cells, also known as mesenchymal stromal cells (MSCs), exist in many tissues and are known to actively migrate to sites of tissue injury, where they participate in wound repair. Tumours can be considered “wounds that never heal” and, in response to cues from a tumour, MSCs are continuously recruited to and become integral components of the tumour microenvironment. Recently, it has become apparent that such tumour-associated MSCs (TA-MSCs) have an active role in tumour initiation, promotion, progression and metastasis. In this Review, we discuss recent advances in our understanding of the pathogenic role of TA-MSCs in regulating the survival, proliferation, migration and drug resistance of tumour cells, as well as the influence of MSCs on the immune status of the tumour microenvironment. Moreover, we discuss therapeutic approaches that target TA-MSC upstream or downstream modulators or use MSCs as vehicles for the delivery of tumoricidal agents. It is anticipated that new insights into the functions of TA-MSCs will lead to the development of novel therapeutic strategies against tumours.
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We thank A. I. Roberts for critically reviewing and discussing the manuscript. We are indebted to those whose work is not discussed owing to space limitations. This work is supported by National Natural Science Foundation of China (81530043, 81330046), the Ministry of Science and Technology of China (2015CB964500), the Scientific Innovation Project of the Chinese Academy of Science (XDA01040100), the Suzhou Science and Technology Program (SZS201616), the Shanghai Rising-Star Program (14QA1404200), the Youth Innovation Promotion Association research fund from the Chinese Acadmey of Sciences (2060206),and the Department of Science and Technology of Jiangsu Province research fund (BE2016671).
The authors declare no competing financial interests.
- Inducible nitric oxide synthase
(iNOS). One of the key enzymes generating nitric oxide from L-arginine. The expression of iNOS is usually regulated by inflammatory cytokines.
- Indoleamine 2,3-dioxygenase
(IDO). A rate-limiting enzyme that catalyses L-tryptophan catabolism through the kynurenine pathway.
- ARE/poly(U)-binding/degradation factor 1
(AUF1). A regulatory protein that controls mRNA stability through its interaction with the adenosine- and uridine-rich regions of the target mRNA.
All of the factors secreted by cells, tissues, organs and organisms in a given biological setting.
(5-FU). A drug used for the treatment of tumours. 5-FU can inhibit the synthesis of thymidylate and thus induce the cell death of tumour cells.
(1-MT). A competitive inhibitor of indoleamine 2, 3-dioxygenase.
- Cytosine deaminase
(CD). A hydrolase acting on carbon–nitrogen bonds other than peptide bonds, specifically in cyclic amidines. CD converts non-toxic prodrug 5-fluorocytosine (5-FC) to the tumour-toxic chemotherapeutic agent 5-fluorouracil (5-FU).
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Shi, Y., Du, L., Lin, L. et al. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Discov 16, 35–52 (2017). https://doi.org/10.1038/nrd.2016.193
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