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Review
. 2021 Mar 2:9:625221.
doi: 10.3389/fcell.2021.625221. eCollection 2021.

Could Extracellular Vesicles Contribute to Generation or Awakening of "Sleepy" Metastatic Niches?

Affiliations
Review

Could Extracellular Vesicles Contribute to Generation or Awakening of "Sleepy" Metastatic Niches?

Alberto Hernández-Barranco et al. Front Cell Dev Biol. .

Abstract

Pre-metastatic niches provide favorable conditions for tumor cells to disseminate, home to and grow in otherwise unfamiliar and distal microenvironments. Tumor-derived extracellular vesicles are now recognized as carriers of key messengers secreted by primary tumors, signals that induce the formation of pre-metastatic niches. Recent evidence suggests that tumor cells can disseminate from the very earliest stages of primary tumor development. However, once they reach distal sites, tumor cells can persist in a dormant state for long periods of time until their growth is reactivated and they produce metastatic lesions. In this new scenario, the question arises as to whether extracellular vesicles could influence the formation of these metastatic niches with dormant tumor cells? (here defined as "sleepy niches"). If so, what are the molecular mechanisms involved? In this perspective-review article, we discuss the possible influence of extracellular vesicles in early metastatic dissemination and whether they might play a role in tumor cell dormancy. In addition, we comment whether extracellular vesicle-mediated signals may be involved in tumor cell awakening, considering the possibility that extracellular vesicles might serve as biomarkers to detect early metastasis and/or minimal residual disease (MRD) monitoring.

Keywords: disseminated tumor cells; dormancy; exosome; extracellular vesicle; metastasis.

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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
The influence of stromal-derived EVs in tumor cell dormancy. EVs generated in different stromal cells may have the ability to induce DTC dormancy in diverse tumor types. The transport of miRNA in these EVs outstand as one of the main mechanism potentially involved in this process: In the bone marrow, MSCs-derived EVs contain different miRNAs capable of modulating several pro-dormant features (e.g., quiescence, reduced proliferation, etc.) in breast cancer cells, whereas miRNAs in BMSCs-derived EVs suppress progression of bladder cancer. In the liver, several miRNAs in hepatic niche-derived EVs reduced breast cancer cell proliferation. Finally, miRNAs in EVs derived from fibroblasts induce a stem cell like phenotype and resistance to therapy in breast and colorectal cancer cells.
FIGURE 2
FIGURE 2
Tumor-derived EVs influence stromal populations. Rather than inducing DTC dormancy, tumor-derived EVs could contribute to their re-awakening through different mechanisms. (A) Neuroblastoma, glioblastoma, lung, and ovarian cancer generate EVs capable of inducing a pro-tumoral phenotype in MSCs which usually involves a myofibroblastic conversion. These modified MSCs eventually upregulate the secretion of pro-tumoral cytokines and chemokines such as IL-8, IL6, and VEGF. (B) Similarly, melanoma or leukemia cells release EVs that are captured by BMSCs which induces the secretion of IL8, CXCL12 among other soluble factors. This tumor EV-mediated release of cytokines and chemokines has an effect on the bone marrow physiology suppressing hematopoiesis and disturbing several features of the bone marrow progenitors, which favor the growth of tumor cells at dormant niches.
FIGURE 3
FIGURE 3
Influence of endothelial cell-derived EVs in tumor cells. The crosstalk between tumor and endothelial cells via EVs modulate several biological processes that could influence DTC awakening. (A) Tumor-derived exosomes induce vascular leakiness, endothelium activation and angiogenesis, key processes in metastasis development, directly by transferring different molecules and miRNAs to the endothelial cells or indirectly by affecting other cell populations in the microenvironment as stromal or immune cells. (B) The altered endothelium is also capable of generating EVs, which induce pro-metastatic features (e.g., cell survival, neoangiogenesis, invasion) in a variety of cancer types (as Lung cancer, glioma, or hepatocellular carcinoma), these signals may be similar to those involved in tumor DTC awakening.
FIGURE 4
FIGURE 4
Potential contribution of tumor-EVs to DTC awakening. The processes regulated by tumor derived EVs in formation of PMNs could be involved in DTC awakening. Tumor exosomes induce the mobilization of bone marrow precursors, which eventually contribute to the generation of pro-inflammatory and immunosuppressive niches. Similarly, alterations in the stromal cells of the liver result in the generation of a fibrotic and pro-tumorigenic microenvironment. Moreover, both PMN and sleepy niches are organotropic processes that occur at specific locations along the body depending on the tumor type. Interestingly, the expression of different integrins on the EVs surface seems to mediate metastatic organotropism. Overall, tumor derived exosomes trigger different processes as the induction of pro-inflammatory microenvironments, vascular modification, and EMC remodeling which result into the generation of optimal pre-metastatic niches. These processes may affect the equilibrium between dormancy and awakening in the DTCs.

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