Exosomes in Cancer Metastasis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 6268

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Cancer Center, Department of Pathology, University of Pittsburgh School of Medicine and UPMC Hillman, Pittsburgh, PA 15213, USA
Interests: exosomes; tumor immunology; immunotherapy
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Dear Colleagues,

In 1889, Stephen Paget formulated his “seed and soil” hypothesis that compared tumor cells to “the seed”, requiring a supportive tissue environment, “the soil”, for establishing organotropic metastasis (Paget S. The distribution of secondary growths in cancer of the breast. Lancer 133, 571–673, 1889). Since then, research on the mechanisms responsible for metastasis has been largely focused on interactions between the tumor and the host. Over the years, these interactions under the general label of the “tumor–host cell crosstalk” focused on various modes of intercellular communication mediated by growth factors, cytokines/chemokines, integrins, immune cells or a broad variety of other signals that promoted metastasis (Müller A et al, 2001 [1]; Hoshino a et al, 2015 [2]; Sun L et al, 2021 [3]). As our understanding of intercellular communication increased, it became clear that no one factor or mechanism could explain organotropic metastases. A broad variety of mechanisms that have been described largely failed to explain who or what prepared the “soil’’ in various organs and what exactly was the “seed” delivered to the prepared soil that resulted in metastasis. Who or what regulated the metastatic spread? Was it the growing tumor or the host fighting for survival?

These and other questions remain unaswered today. However, research progress has changed, mainly due to the emergence of extracellular vesicles (EVs) as the prime mediators of intercellular communication that is more efficient and more closely and specifically targeted than any other cellular interaction (Kalluri R et al, 2020 [4]; Wortzel I et al, 2019 [5]). EVs are present in all body fluids and are capable of crossing all organ barriers (Banks WA et al, 2022 [6]).

They carry their cargo in the lumen, where it is protected from exogenous degradation by the surface membrane, and deliver it to recipient cells in the native form. The surface of EVs is not biologically idle; it is decorated by a host of receptor/ligands that can engage recipient cells. Thus, freely circulating tumor-derived EVs aspire to be an almost perfect mechanism for conveying signals from tumor cells to near or distant sites in preparation for metastasis.

While this view of circulating tumor-derived EVs as a mechanism for converting distant normal tissues and cells into pro-tumor facilitators is attractive, many unanswered questions exist. For one, we have no information about how tumor-derived EVs are directed to an organ and how exactly they arrive there. Additionally, once at the site, how do the EVs engage specific tissue cells? Once engaged, which components of the exosome cargo, i.e., proteins, lipids or nucleic acids, delivered to recipient cells are responsible for inducing pro-metastatic changes? Can microvesicles (MVs) be more effective in shaping pre-metastatic changes than small EVs? Are the direct effects of tumor-derived EVs the only or the major pro-metastatic mechanism? Can the indirect interactions of EVs with immune or neural systems be involved in creating the pro-metastatic niche? Answering these questions is of prime importance for unraveling the complex mesh of molecular interactions that underlie metastasis. Much effort is needed, and it is encouraging to see that research into Paget’s hypothesis is rapidly embracing the subcellular interactions mediated by nanovesicles.

It is expected that this Special Issue will provide a forum for exchange of new knowledge about cell–cell communication via EVs that will shape future therapeutic initiatives. We are especially interested in exosomes as biomarkers of metastasis. Metastasis must be stopped or eliminated to save lives, and the understanding of its basic molecular insights is the surest way to future clinical success.

References

1. Müller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M.E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S.N.; et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410, 50–56.

2. Hoshino, A.; Costa-Silva, B.; Shen, T.-L.; Rodrigues, G.; Hashimoto, A.; Mark, M.T.; Molina, H.; Kohsaka, S.; Di Giannatale, A.; Ceder, S.; et al. Tumour exosome integrins determine organotropic metastasis. Nature 2015, 527, 329–335.

3. Sun, L.; Kees, T.; Almeida, A.S.; Liu, B.; He, X.-Y.; Ng, D.; Han, X.; Spector, D.L.; McNeish, I.A.; Gimotty, P.; et al. Available online: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00445-1 (accessed on 7 August 2023).

4. Kalluri, R.; Lebleu, V.S. The biology, function, and biomedical applications of exosomes. Science 2020, 367, 6478.

5. Wortzel, I.; Dror, S.; Kenific, C.M.; Lyden, D. Available online: https://www.cell.com/developmental-cell/fulltext/S1534-5807(19)30281-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1534580719302813%3Fshowall%3Dtrue (accessed on 7 August 2023).

6. Banks, W.A.; Sharma, P.; Hansen, K.M.; Ludwig, N.; Whiteside, T.L. Characteristics of Exosomes and the Vascular Landscape Regulate Exosome Sequestration by Peripheral Tissues and Brain. Int. J. Mol. Sci. 2022, 23, 12513.

Prof. Dr. Theresa L. Whiteside
Guest Editor

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Published Papers (4 papers)

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Research

30 pages, 4418 KiB  
Article
Beyond Exosomes: An Ultrapurified Phospholipoproteic Complex (PLPC) as a Scalable Immunomodulatory Platform for Reprogramming Immune Suppression in Metastatic Cancer
by Ramon Gutierrez-Sandoval, Francisco Gutiérrez-Castro, Natalia Muñoz-Godoy, Ider Rivadeneira, Adolay Sobarzo, Jordan Iturra, Francisco Krakowiak, Luis Alarcón, Wilson Dorado, Andy Lagos, Diego Montenegro, Ignacio Muñoz, Rodrigo Aguilera and Andres Toledo
Cancers 2025, 17(10), 1658; https://doi.org/10.3390/cancers17101658 - 14 May 2025
Viewed by 321
Abstract
Background/Objectives: Dendritic-cell-derived exosomes (DEXs) have demonstrated immunostimulatory potential in cancer immunotherapy, yet their clinical application remains constrained by their cryodependence, compositional heterogeneity, and limited scalability. To address these limitations, we developed an ultrapurified phospholipoproteic complex (PLPC), a dendritic-secretome-derived formulation stabilized through ultracentrifugation and [...] Read more.
Background/Objectives: Dendritic-cell-derived exosomes (DEXs) have demonstrated immunostimulatory potential in cancer immunotherapy, yet their clinical application remains constrained by their cryodependence, compositional heterogeneity, and limited scalability. To address these limitations, we developed an ultrapurified phospholipoproteic complex (PLPC), a dendritic-secretome-derived formulation stabilized through ultracentrifugation and lyophilization that has been engineered to preserve its immunological function and structural integrity. Methods: Secretomes were processed under four conditions (fresh, concentrated, cryopreserved, and lyophilized PLPC) and compared through proteomic and functional profiling. Mass spectrometry (LC-MS/MS) analysis revealed that the PLPC retained a significantly enriched set of immunoregulatory proteins—including QSOX1, CCL22, and SDCBP—and exhibited superior preservation of post-translational modifications. Results: Ex vivo co-culture assays with human peripheral blood mononuclear cells (PBMCs) demonstrated that the PLPC induced robust secretion of IFN-γ, TNF-α, and IL-6 while concurrently suppressing IL-10, achieving an IFN-γ/IL-10 ratio exceeding 3.5. Flow cytometry confirmed the substantial activation of both CD4⁺ and CD8⁺ T cells, while apoptosis assays showed selective tumor cytotoxicity (>55% tumor apoptosis) with minimal impact on non-malignant cells (>92% viability). Conclusions: These findings establish the PLPC as a reproducible, Th1-polarizing immunomodulator with selective antitumor activity, ambient-temperature stability, and compatibility with non-invasive administration. Overall, the PLPC emerges as a scalable, cell-free immunotherapeutic platform with translational potential to reprogram immune suppression in metastatic therapy-resistant cancer settings. Full article
(This article belongs to the Special Issue Exosomes in Cancer Metastasis)
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19 pages, 6330 KiB  
Article
Characterisation of Castration-Resistant Cell-Derived Exosomes and Their Effect on the Metastatic Phenotype
by Jorge Recio-Aldavero, Lorena Parra-Gutiérrez, Laura Muñoz-Moreno, Irene D. Román, María Isabel Arenas and Ana M. Bajo
Cancers 2025, 17(1), 141; https://doi.org/10.3390/cancers17010141 - 4 Jan 2025
Viewed by 1064
Abstract
Background/Objectives: Prostate cancer (PCa) is characterised by its progression to a metastatic and castration-resistant phase. Prostate tumour cells release small extracellular vesicles or exosomes which are taken up by target cells and can potentially facilitate tumour growth and metastasis. The present work studies [...] Read more.
Background/Objectives: Prostate cancer (PCa) is characterised by its progression to a metastatic and castration-resistant phase. Prostate tumour cells release small extracellular vesicles or exosomes which are taken up by target cells and can potentially facilitate tumour growth and metastasis. The present work studies the effect of exosomes from cell lines that are representative of the different stages of the disease on the tumoral phenotype of PC3 cells. Methods: Exosomes were isolated by ultracentrifugation from human prostate epithelial cells (RWPE-1) and androgen-dependent PCa cells (LNCaP) and castration-resistant PCa cells (CRPC) with moderate (DU145) or high (PC3) metastatic capacity. The biophysical and biochemical properties of the exosomes were characterised as well as their effects on PC3 cell viability and migration. Results: The study of the exosomes of prostate cell lines shows heterogeneity in their size, presenting in some of them two types of populations; in both populations, a larger size in those derived from PC3 cells and a smaller size in those derived from non-tumourigenic prostate cells were detected. Differences were found in the physical properties of those derived from healthy and PCa cells, as well as between cells representative of the most aggressive stages of the disease. The highest gamma-glutamyl transferase (GGT) activity was observed in androgen-dependent cells and differences in the pro-metalloproteinases (MMP) activity were detected in healthy cells and in castration-resistant cells with moderate metastatic capacity with respect to PC3 cells. The treatment of PC3 cells with their own exosomes increased PC3 cell viability and migration. Conclusion: Exosomes represent a promising field of research in the diagnosis, prognosis, and treatment of prostate cancer. Full article
(This article belongs to the Special Issue Exosomes in Cancer Metastasis)
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16 pages, 5674 KiB  
Article
LincRNA01703 Facilitates CD81+ Exosome Secretion to Inhibit Lung Adenocarcinoma Metastasis via the Rab27a/SYTL1/CD81 Complex
by Yun Huang, Shan Guo, Ying Lin, Liyun Huo, Hongmei Yan, Zhanwen Lin, Zishuo Chen, Junchao Cai, Jueheng Wu, Jie Yuan, Hongyu Guan, Guoyong Wu, Weibin Wu and Tianyu Tao
Cancers 2023, 15(24), 5781; https://doi.org/10.3390/cancers15245781 - 9 Dec 2023
Cited by 2 | Viewed by 2348
Abstract
Metastasis, a major cause of cancer-related mortality worldwide, frequently occurs early in the diagnosis of lung adenocarcinoma (LUAD). However, the precise molecular mechanisms governing the aggressive metastatic behavior of LUAD remain incompletely understood. In this study, we present compelling evidence indicating that the [...] Read more.
Metastasis, a major cause of cancer-related mortality worldwide, frequently occurs early in the diagnosis of lung adenocarcinoma (LUAD). However, the precise molecular mechanisms governing the aggressive metastatic behavior of LUAD remain incompletely understood. In this study, we present compelling evidence indicating that the long noncoding RNA linc01703 is significantly downregulated in metastatic lung cancer cells. Intriguingly, in vivo experiments revealed that Linc01703 exerted a profound inhibitory effect on lung cancer metastasis without discernible impact on the in vitro proliferation or invasion capacities of LUAD cells. Mechanistically, Linc01703 enhanced the interaction between Rab27a, SYTL1, and CD81, consequently promoting the secretion of CD81+ exosomes. These exosomes, in turn, suppressed the infiltration of immune cells within the tumor microenvironment, thereby impeding LUAD metastasis. Importantly, our analysis of lung cancer tissues revealed a correlation between reduced CD81 expression and an unfavorable patient prognosis. Collectively, our findings suggest that Linc01703 functions as a metastasis suppressor by facilitating the secretion of CD81+ exosomes through the formation of the Rab27a/SYTL1/CD81 complex. Full article
(This article belongs to the Special Issue Exosomes in Cancer Metastasis)
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15 pages, 2943 KiB  
Article
Arginase-1 in Plasma-Derived Exosomes as Marker of Metastasis in Patients with Head and Neck Squamous Cell Carcinoma
by Linda Hofmann, Malgorzata Harasymczuk, Diana Huber, Miroslaw J. Szczepanski, Grzegorz Dworacki, Theresa L. Whiteside and Marie-Nicole Theodoraki
Cancers 2023, 15(22), 5449; https://doi.org/10.3390/cancers15225449 - 16 Nov 2023
Cited by 2 | Viewed by 1820
Abstract
Immunoregulatory Arginase-1 (Arg-1) is present in the tumor microenvironment of solid tumors. Its association to clinicopathology and its prognostic impact are inconsistent among different tumor types and biological fluids. This study evaluated Arg-1 protein levels in tumors and the circulation of patients with [...] Read more.
Immunoregulatory Arginase-1 (Arg-1) is present in the tumor microenvironment of solid tumors. Its association to clinicopathology and its prognostic impact are inconsistent among different tumor types and biological fluids. This study evaluated Arg-1 protein levels in tumors and the circulation of patients with head and neck squamous cell carcinoma (HNSCC) in relation to clinical stage and prognosis. Tumor Arg-1 expression was monitored via immunohistochemistry while plasma Arg-1 levels via ELISA in 37 HNSCC patients. Arg-1 presence in plasma-derived exosomes was assessed using Western blots in 20 HNSCC patients. High tumor Arg-1 expression correlated with favorable clinicopathology and longer recurrence-free survival (RFS), while high plasma Arg-1 levels were associated with unfavorable clinicopathology. All patients with low tumor and high plasma Arg-1 had nodal metastases and developed recurrence. This discrepancy was attributed to the presence of Arg-1-carrying exosomes. Arg-1 was found in plasma-derived exosomes from all HNSCC patients. High exosomal Arg-1 levels were associated with positive lymph nodes and short RFS. Circulating Arg-1+ exosomes represent a mechanism of active Arg-1 export from the tumor to the periphery. Exosomes reflected biologically relevant Arg-1 levels in metastatic HNSCC and emerged as potentially more accurate biomarkers of metastatic disease and RFS than tissue or plasma Arg-1 levels. Full article
(This article belongs to the Special Issue Exosomes in Cancer Metastasis)
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