Cancer exodus hypothesis

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The cancer exodus hypothesis establishes that circulating tumor cell clusters (CTC clusters) maintain their multicellular structure throughout the metastatic process. It was previously thought that these clusters must dissociate into single cells during metastasis. [1] According to the hypothesis, CTC clusters intravasate (enter the bloodstream), travel through circulation as a cohesive unit, and extravasate (exit the bloodstream) at distant sites without disaggregating, significantly enhancing their metastatic potential. This concept is considered a key advancement in understanding of cancer biology and CTCs role in cancer metastasis. [2] [3]

Contents

Mechanism

Traditionally, it was believed that CTC clusters needed to dissociate into individual cells during their journey through the bloodstream to seed secondary tumors. However, recent studies show that CTC clusters can travel through the bloodstream intact, enabling them to perform every step of metastasis while maintaining their group/cluster structure. [3] [2] [4]

The cancer exodus hypothesis asserts that CTC clusters have several distinct advantages that increase their metastatic potential:

Clinical relevance

The cancer exodus hypothesis offers important insights into how metastasis occurs and highlights the significance of CTC clusters in cancer progression. Detecting and analyzing CTC clusters through liquid biopsies could offer valuable information about the aggressiveness and metastatic potential of cancers. [10] [11] This information is particularly useful for identifying patients who may benefit from more aggressive treatment strategies. [2] [12]

Characterization

The hypothesis was developed due to several key studies, which have demonstrated the ability of CTC clusters to:

These findings underscore the critical role of CTC clusters in driving the metastatic cascade and suggest that CTC clusters could serve as important biomarkers in cancer diagnosis, prognosis, and treatment planning. [5] Additionally, understanding the mechanisms that allow CTC clusters to retain their structure and survive in circulation opens new avenues for targeted cancer therapies designed to disrupt this process. [15]

Future directions

As research into the cancer exodus hypothesis progresses, new therapeutic strategies could emerge to specifically target CTC clusters. Blocking their formation, disrupting their cohesion, or preventing their ability to survive in the bloodstream could offer new ways to prevent metastasis in aggressive cancers. Continued studies will be essential to further elucidate the biological pathways involved in CTC cluster-mediated metastasis and develop potential treatment interventions. [16] [17]

References

  1. ↑ Ring A, Nguyen-Sträuli BD, Wicki A, Aceto N (February 2023). "Biology, vulnerabilities and clinical applications of circulating tumour cells". Nature Reviews. Cancer. 23 (2): 95–111. doi:10.1038/s41568-022-00536-4. PMC   9734934 . PMID   36494603.
  2. 1 2 3 4 Allen TA, Asad D, Amu E, Hensley MT, Cores J, Vandergriff A, et al. (September 2019). "Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential". Journal of Cell Science. 132 (17) jcs231563. doi:10.1242/jcs.231563. PMC   6771143 . PMID   31409692.
  3. 1 2 3 4 Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. (August 2014). "Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis". Cell. 158 (5): 1110–1122. doi:10.1016/j.cell.2014.07.013. PMC   4149753 . PMID   25171411.
  4. 1 2 Au SH, Storey BD, Moore JC, Tang Q, Chen YL, Javaid S, et al. (May 2016). "Clusters of circulating tumor cells traverse capillary-sized vessels". Proceedings of the National Academy of Sciences of the United States of America. 113 (18): 4947–4952. Bibcode:2016PNAS..113.4947A. doi: 10.1073/pnas.1524448113 . PMC   4983862 . PMID   27091969.
  5. 1 2 Sayed ZS, Khattap MG, Madkour MA, Yasen NS, Elbary HA, Elsayed RA, et al. (April 2024). "Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature". Discover Oncology. 15 (1) 94. doi:10.1007/s12672-024-00949-7. PMC   10984915 . PMID   38557916.
  6. ↑ Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H (November 2021). "Better together: circulating tumor cell clustering in metastatic cancer". Trends in Cancer. 7 (11): 1020–1032. doi:10.1016/j.trecan.2021.07.001. PMC   8541931 . PMID   34481763.
  7. ↑ Aceto N, Toner M, Maheswaran S, Haber DA (September 2015). "En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition". Trends in Cancer. 1 (1): 44–52. doi:10.1016/j.trecan.2015.07.006. PMID   28741562.
  8. ↑ Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–691. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  9. ↑ Allen TA, Cullen MM, Hawkey N, Mochizuki H, Nguyen L, Schechter E, et al. (2021). "A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation". Frontiers in Oncology. 11 641187. doi: 10.3389/fonc.2021.641187 . PMC   8495265 . PMID   34631514.
  10. ↑ Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–691. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  11. ↑ Amintas S, Bedel A, Moreau-Gaudry F, Boutin J, Buscail L, Merlio JP, et al. (April 2020). "Circulating Tumor Cell Clusters: United We Stand Divided We Fall". International Journal of Molecular Sciences. 21 (7): 2653. doi: 10.3390/ijms21072653 . PMC   7177734 . PMID   32290245.
  12. ↑ Lawrence R, Watters M, Davies CR, Pantel K, Lu YJ (July 2023). "Circulating tumour cells for early detection of clinically relevant cancer". Nature Reviews. Clinical Oncology. 20 (7): 487–500. doi:10.1038/s41571-023-00781-y. PMC   10237083 . PMID   37268719.
  13. ↑ Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, et al. (February 2016). "Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters". Proceedings of the National Academy of Sciences of the United States of America. 113 (7): E854 –E863. Bibcode:2016PNAS..113E.854C. doi: 10.1073/pnas.1508541113 . PMC   4763783 . PMID   26831077.
  14. ↑ Allen TA, Gracieux D, Talib M, Tokarz DA, Hensley MT, Cores J, et al. (January 2017). "Angiopellosis as an Alternative Mechanism of Cell Extravasation". Stem Cells. 35 (1): 170–180. doi:10.1002/stem.2451. PMC   5376103 . PMID   27350343.
  15. ↑ Taftaf R, Liu X, Singh S, Jia Y, Dashzeveg NK, Hoffmann AD, et al. (August 2021). "ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer". Nature Communications. 12 (1) 4867. Bibcode:2021NatCo..12.4867T. doi:10.1038/s41467-021-25189-z. PMC   8358026 . PMID   34381029.
  16. ↑ Allen TA (March 2024). "The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance". Cancers. 16 (7): 1377. doi: 10.3390/cancers16071377 . PMC   11010957 . PMID   38611055.
  17. ↑ Khoo BL, Grenci G, Lim YB, Lee SC, Han J, Lim CT (January 2018). "Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device". Nature Protocols. 13 (1): 34–58. doi:10.1038/nprot.2017.125. PMID   29215634.
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