Exosomes in Cancer Metastasis

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. 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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