Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May 20:9:637675.
doi: 10.3389/fcell.2021.637675. eCollection 2021.

The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment

Yanghong Ni  1   2 , Xiaoting Zhou  1   2 , Jia Yang  1   2 , Houhui Shi  1   2 , Hongyi Li  1   2 , Xia Zhao  2 , Xuelei Ma  1
Affiliations
Review

The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment

Yanghong Ni et al. Front Cell Dev Biol. .

Abstract

Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.

Keywords: MSCs; CAFs; TAMs; antineoplastic drug resistance; cell-cell interplays; tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
A schematic overview of tumor microenvironments. Tumor microenvironment refers to the local biological environment where tumor cells exist, and are composed of tumor cells, stromal cells and immune cells. TME is involved in the initiation and maintenance of non-cell autonomous resistance by a variety of mechanisms, including hypoxia, low PH, shifts and polarizations in the immune cell population, vascular abnormalities and diverse stroma cells-derived secretomes, exosomes, soluble factors. TME serves as safeguard to tumor cells by providing mechanical support or secreting different cytokines to evade treatment. Treg, regulatory T lymphocytes; MSC, mesenchymal stem cells; T, T lymphocytes; B, B lymphocytes; DC, dendritic cells; N, neutrophils; M, macrophages; NK, natural killer cells; E, epithelial cells; F, fibroblasts; CAA, cancer-associated adipocytes; L, lymphatic endothelial cells; TEC, tumor endothelial cells; CSC, cancer stem cells; TAM, tumor-associated macrophages; CAF, cancer-associated fibroblasts; MDSC, myeloid-derived suppressor cells; EMT, epithelial-mesenchymal transition. The figure was created with BioRender.com.
FIGURE 2
FIGURE 2
Cancer-associated fibroblasts and drug resistance. The intricate mechanisms of drug resistance mediated by CAFs include secreting soluble factors, delivering exosomes, metabolic reprogramming and extracellular matrix (ECM) remodeling. CAFs can secret a broad range of cytokines or factors which enable to activate a series of signaling cascades, leading to therapeutic resistance. CAFs-derived exosomes deliver miRNAs, lncRNAs and mtDNA to cancer cells, which participate in transmitting paracrine signals of therapeutic resistance. Moreover, in order to adapt to a glucose-deficient microenvironment, CAFs coordinate with tumor cells to modulate metabolic mode. Lastly, activated signals within CAFs increased production of extracellular matrix components, resulting in changes of its physical and biochemical characteristics under therapeutic pressure. CCL1, chemokine C-C motif ligand-1; CCL5, chemokine C-C motif ligand-5; IL-6, interleukin-6; IL-8, interleukin-8;IL-11, interleukin-11; SDF1, stromal cell derived factor-1; HGF, hepatocyte growth factor; TGF-ß, transforming growth factor-β; IGF-2, insulin-like growth factor 2; PAI-1, plasminogen activator inhibitor-1, MMP, matrix metalloproteinase; HA, hyaluronan; HSPG2, heparin sulphate proteoglycan 2; LPP, lipoma-preferred partner. The figure was created with BioRender.com.
FIGURE 3
FIGURE 3
Interactions of tumor cells with parts of non-malignant cells within tumor microenvironments mediating drug resistance. Tumor microenvironment contains quantities of non-malignant stromal cells which are essential for tumor progression and drug resistance. Interactions between tumor cells and stromal cells polarize stromal cells. In turn, the stromal cells educated by tumor cells secret a variety of molecules, leading to immunosuppression, metabolic regulation and pharmacokinetics adjustment, which eventually weakens therapeutic efficacy. Arg-1, arginase-1; IL-23,interlukin-23; PNT, peroxynitrite; G-CSF, granulocyte-colony stimulating factor; PGE2, prostaglandin E2; FOXP3, forkhead box protein P3; mGlutR1, glutamate receptor 1; P-gP: P-glycoprotein, IDO1, indoleamine 2,3-dioxygenase; CAA: cancer associated adipocyte; FFAs: free fatty acids; AA: arachidonic acid; VEGF: vascular endothelial growth factor; FGF4: fibroblast growth factor 4; FAK: focal adhesion kinase. CTL, cytotoxic T lymphocytes. The figure was created with BioRender.com.
FIGURE 4
FIGURE 4
Mesenchymal stem cells and drug resistance. Mainly isolated from bone marrow, adipose tissue and umbilical cord, MSCs promote drug resistance in multiple ways, such as secreting soluble factors and exosomes, genetic mutations, direct cell-cell contact and differentiating into CAF or CSC. The diverse soluble factors and exosomes derived from MSCs could induce chemoresistance dependent on multiple pathways and downstream mechanisms, some of which relate to the inhibition of tumor cell apoptosis by regulating the expression of apoptosis-related proteins. It is noteworthy that chemoresistance properties of MSCs can be conferred via direct cell–cell contact with tumor cells as well. This interaction can enhance the expression of Bcl-2. Also, gene mutations such as p53 deficiency in MSCs could contribute to drug resistance by mediating antitumor immunity. Finally, MSCs have the potential to evolve into CAFs and CSCs, which have been reported to be involved in the development of resistance. MSC, mesenchymal stem cell; CSC, cancer stem cell; CAF, cancer-associated fibroblast; SDF-1: stromal cell-derived factor-1; TGF-β, transforming growth factor-β; PIFAs, platinum-induced fatty acids. ICAM-1, intercellular adhesion molecule-1. The figure was created with BioRender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acharyya S., Oskarsson T., Vanharanta S., Malladi S., Kim J., Morris P. G., et al. (2012). A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150 165–178. 10.1016/j.cell.2012.04.042 - DOI - PMC - PubMed
    1. Adamo A., Dal Collo G., Bazzoni R., Krampera M. (2019). Role of mesenchymal stromal cell-derived extracellular vesicles in tumour microenvironment. Biochim. Biophys. Acta Rev. Cancer 1871 192–198. 10.1016/j.bbcan.2018.12.001 - DOI - PubMed
    1. Aggen D. H., Ager C. R., Obradovic A. Z., Chowdhury N., Ghasemzadeh A., Mao W., et al. (2021). Blocking IL1 beta promotes tumor regression and remodeling of the myeloid compartment in a renal cell carcinoma model: multidimensional analyses. Clin. Cancer Res. 27 608–621. 10.1158/1078-0432.CCR-20-1610 - DOI - PMC - PubMed
    1. Akino T., Hida K., Hida Y., Tsuchiya K., Freedman D., Muraki C., et al. (2009). Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am. J. Pathol. 175 2657–2667. 10.2353/ajpath.2009.090202 - DOI - PMC - PubMed
    1. Akiyama K., Maishi N., Ohga N., Hida Y., Ohba Y., Alam M. T., et al. (2015). Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel. Am. J. Pathol. 185 572–580. 10.1016/j.ajpath.2014.10.017 - DOI - PubMed

LinkOut - more resources

  NODES
innovation 2
Note 1
twitter 2