Cancer exodus hypothesis explained

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.

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.

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

• Higher metastatic efficiency: CTC clusters have been shown to possess superior seeding capabilities at distant sites compared to single CTCs.^[2]
• Survival and proliferation: The collective nature of CTC clusters allows them to share resources and offer intercellular support, improving their overall survival rates in the bloodstream.^{[3] [4]}
• Resistance to treatment: CTC clusters exhibit unique gene expression profiles that contribute to their ability to evade certain cancer therapies, making them more resistant than individual tumor cells.^{[5] [6]}

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.^{[7] [8]} This information is particularly useful for identifying patients who may benefit from more aggressive treatment strategies.^{[9] [10]}

Characterization

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

• Intravasate and travel as clusters: Research has shown that CTC clusters can enter the bloodstream as a group, travel through the circulatory system intact, and maintain their cluster phenotype during transit.^{[11] [12]}
• Extravasate through angiopellosis: A key finding of the hypothesis is that CTC clusters do not need to disaggregate to exit the bloodstream. Instead, they can undergo a process called angiopellosis, in which entire clusters migrate out of the blood vessels as a group, retaining their multicellular form. ^[13]

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.^[14] 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 . Biology, vulnerabilities and clinical applications of circulating tumour cells . Nature Reviews. Cancer . 23 . 2 . 95–111 . February 2023 . 36494603 . 9734934 . 10.1038/s41568-022-00536-4 .
2. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis . Cell . 158 . 5 . 1110–1122 . August 2014 . 25171411 . 4149753 . 10.1016/j.cell.2014.07.013 .
3. Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H . Better together: circulating tumor cell clustering in metastatic cancer . Trends in Cancer . 7 . 11 . 1020–1032 . November 2021 . 34481763 . 8541931 . 10.1016/j.trecan.2021.07.001 .
4. Aceto N, Toner M, Maheswaran S, Haber DA . En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition . Trends in Cancer . 1 . 1 . 44–52 . September 2015 . 28741562 . 10.1016/j.trecan.2015.07.006 .
5. Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, Engstrom A, Zhu H, Sundaresan TK, Miyamoto DT, Luo X, Bardia A, Wittner BS, Ramaswamy S, Shioda T, Ting DT, Stott SL, Kapur R, Maheswaran S, Haber DA, Toner M . A microfluidic device for label-free, physical capture of circulating tumor cell clusters . Nature Methods . 12 . 7 . 685–691 . July 2015 . 25984697 . 4490017 . 10.1038/nmeth.3404 .
6. Allen TA, Cullen MM, Hawkey N, Mochizuki H, Nguyen L, Schechter E, Borst L, Yoder JA, Freedman JA, Patierno SR, Cheng K, Eward WC, Somarelli JA . A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation . Frontiers in Oncology . 11 . 641187 . 2021 . 34631514 . 8495265 . 10.3389/fonc.2021.641187 . free .
7. Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, Engstrom A, Zhu H, Sundaresan TK, Miyamoto DT, Luo X, Bardia A, Wittner BS, Ramaswamy S, Shioda T, Ting DT, Stott SL, Kapur R, Maheswaran S, Haber DA, Toner M . A microfluidic device for label-free, physical capture of circulating tumor cell clusters . Nature Methods . 12 . 7 . 685–691 . July 2015 . 25984697 . 4490017 . 10.1038/nmeth.3404 .
8. Amintas S, Bedel A, Moreau-Gaudry F, Boutin J, Buscail L, Merlio JP, Vendrely V, Dabernat S, Buscail E . Circulating Tumor Cell Clusters: United We Stand Divided We Fall . International Journal of Molecular Sciences . 21 . 7 . 2653 . April 2020 . 32290245 . 7177734 . 10.3390/ijms21072653 . free .
9. Allen TA, Asad D, Amu E, Hensley MT, Cores J, Vandergriff A, Tang J, Dinh PU, Shen D, Qiao L, Su T, Hu S, Liang H, Shive H, Harrell E, Campbell C, Peng X, Yoder JA, Cheng K . Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential . Journal of Cell Science . 132 . 17 . September 2019 . jcs231563 . 31409692 . 6771143 . 10.1242/jcs.231563 .
10. Lawrence R, Watters M, Davies CR, Pantel K, Lu YJ . Circulating tumour cells for early detection of clinically relevant cancer . Nature Reviews. Clinical Oncology . 20 . 7 . 487–500 . July 2023 . 37268719 . 10237083 . 10.1038/s41571-023-00781-y .
11. Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, Gorin MA, Verdone JE, Pienta KJ, Bader JS, Ewald AJ . 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 . February 2016 . 26831077 . 4763783 . 10.1073/pnas.1508541113 . free . 2016PNAS..113E.854C .
12. Au SH, Storey BD, Moore JC, Tang Q, Chen YL, Javaid S, Sarioglu AF, Sullivan R, Madden MW, O'Keefe R, Haber DA, Maheswaran S, Langenau DM, Stott SL, Toner M . 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 . May 2016 . 27091969 . 4983862 . 10.1073/pnas.1524448113 . free . 2016PNAS..113.4947A .
13. Allen TA, Gracieux D, Talib M, Tokarz DA, Hensley MT, Cores J, Vandergriff A, Tang J, de Andrade JB, Dinh PU, Yoder JA, Cheng K . Angiopellosis as an Alternative Mechanism of Cell Extravasation . Stem Cells . 35 . 1 . 170–180 . January 2017 . 27350343 . 5376103 . 10.1002/stem.2451 .
14. Sayed ZS, Khattap MG, Madkour MA, Yasen NS, Elbary HA, Elsayed RA, Abdelkawy DA, Wadan AS, Omar I, Nafady MH . Circulating tumor cells clusters and their role in Breast cancer metastasis; a review of literature . Discover Oncology . 15 . 1 . 94 . April 2024 . 38557916 . 10984915 . 10.1007/s12672-024-00949-7 .
15. Taftaf R, Liu X, Singh S, Jia Y, Dashzeveg NK, Hoffmann AD, El-Shennawy L, Ramos EK, Adorno-Cruz V, Schuster EJ, Scholten D, Patel D, Zhang Y, Davis AA, Reduzzi C, Cao Y, D'Amico P, Shen Y, Cristofanilli M, Muller WA, Varadan V, Liu H . ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer . Nature Communications . 12 . 1 . 4867 . August 2021 . 34381029 . 8358026 . 10.1038/s41467-021-25189-z . 2021NatCo..12.4867T .
16. Allen TA . The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance . Cancers . 16 . 7 . 1377 . March 2024 . 38611055 . 11010957 . 10.3390/cancers16071377 . free .
17. Khoo BL, Grenci G, Lim YB, Lee SC, Han J, Lim CT . Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device . Nature Protocols . 13 . 1 . 34–58 . January 2018 . 29215634 . 10.1038/nprot.2017.125 .