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]

Related Research Articles

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<span class="mw-page-title-main">Biopsy</span> Medical test involving extraction of sample cells or tissues for examination

A biopsy is a medical test commonly performed by a surgeon, an interventional radiologist, or an interventional cardiologist. The process involves the extraction of sample cells or tissues for examination to determine the presence or extent of a disease. The tissue is then fixed, dehydrated, embedded, sectioned, stained and mounted before it is generally examined under a microscope by a pathologist; it may also be analyzed chemically. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. An incisional biopsy or core biopsy samples a portion of the abnormal tissue without attempting to remove the entire lesion or tumor. When a sample of tissue or fluid is removed with a needle in such a way that cells are removed without preserving the histological architecture of the tissue cells, the procedure is called a needle aspiration biopsy. Biopsies are most commonly performed for insight into possible cancerous or inflammatory conditions.

<span class="mw-page-title-main">Cancer stem cell</span> Cancer cells with features of normal cells

Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are hypothesized to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

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Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.

<span class="mw-page-title-main">E-selectin</span> Mammalian protein found in Homo sapiens

E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.

<span class="mw-page-title-main">Exosome (vesicle)</span> Membrane-bound extracellular vesicles

Exosomes, ranging in size from 30 to 150 nanometers, are membrane-bound extracellular vesicles (EVs) that are produced in the endosomal compartment of most eukaryotic cells. In multicellular organisms, exosomes and other EVs are found in biological fluids including saliva, blood, urine and cerebrospinal fluid. EVs have specialized functions in physiological processes, from coagulation and waste management to intercellular communication.

<span class="mw-page-title-main">Adrenal tumor</span> Tumors of the adrenal gland, usually resulting in hormone overproduction

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<span class="mw-page-title-main">Circulating tumor cell</span> Cell from a primary tumor carried by blood circulation

A circulating tumor cell (CTC) is a cancer cell from a primary tumor that has shed into the blood of the circulatory system, or the lymph of the lymphatic system. CTCs are carried around the body to other organs where they may leave the circulation and become the seeds for the subsequent growth of secondary tumors. This is known as metastasis, responsible for most cancer-related deaths.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

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<span class="mw-page-title-main">Joan Massagué</span> Spanish biologist

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<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

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<span class="mw-page-title-main">Circulating tumor DNA</span> Tumor-derived fragmented DNA in the bloodstream

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References

  1. ↑ Ring, Alexander; Nguyen-Sträuli, Bich Doan; Wicki, Andreas; Aceto, Nicola (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. ISSN   1474-1768. PMC   9734934 . PMID   36494603.
  2. 1 2 3 4 Allen, TA (2019). "Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential". Journal of Cell Science. 132 (17). doi:10.1242/jcs.231563. PMC   6771143 . PMID   31409692.
  3. 1 2 3 4 Aceto, N (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; Sarioglu, AF; Sullivan, R; Madden, MW; O'Keefe, R; Haber, DA; Maheswaran, S; Langenau, DM; Stott, SL; Toner, M (3 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): 4947–52. Bibcode:2016PNAS..113.4947A. doi: 10.1073/pnas.1524448113 . PMC   4983862 . PMID   27091969.
  5. 1 2 Sayed, Zeinab S.; Khattap, Mohamed G.; Madkour, Mostafa A.; Yasen, Noha S.; Elbary, Hanan A.; Elsayed, Reem A.; Abdelkawy, Dalia A.; Wadan, Al-Hassan Soliman; Omar, Islam; Nafady, Mohamed H. (2024-04-01). "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. ISSN   2730-6011. PMC   10984915 . PMID   38557916.
  6. ↑ Schuster, Emma; Taftaf, Rokana; Reduzzi, Carolina; Albert, Mary K.; Romero-Calvo, Isabel; Liu, Huiping (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. ISSN   2405-8033. PMC   8541931 . PMID   34481763.
  7. ↑ Aceto, Nicola; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A. (May 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. ISSN   2405-8025. PMID   28741562.
  8. ↑ 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 (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–91. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  9. ↑ Allen, Tyler A.; Cullen, Mark M.; Hawkey, Nathan; Mochizuki, Hiroyuki; Nguyen, Lan; Schechter, Elyse; Borst, Luke; Yoder, Jeffrey A.; Freedman, Jennifer A.; Patierno, Steven R.; Cheng, Ke; Eward, William C.; Somarelli, Jason A. (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 . ISSN   2234-943X. PMC   8495265 . PMID   34631514.
  10. ↑ 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 (July 2015). "A microfluidic device for label-free, physical capture of circulating tumor cell clusters". Nature Methods. 12 (7): 685–91. doi:10.1038/nmeth.3404. PMC   4490017 . PMID   25984697.
  11. ↑ Amintas, Samuel; Bedel, Aurélie; Moreau-Gaudry, François; Boutin, Julian; Buscail, Louis; Merlio, Jean-Philippe; Vendrely, Véronique; Dabernat, Sandrine; Buscail, Etienne (2020-04-10). "Circulating Tumor Cell Clusters: United We Stand Divided We Fall". International Journal of Molecular Sciences. 21 (7): 2653. doi: 10.3390/ijms21072653 . ISSN   1422-0067. PMC   7177734 . PMID   32290245.
  12. ↑ Lawrence, Rachel; Watters, Melissa; Davies, Caitlin R.; Pantel, Klaus; Lu, Yong-Jie (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. ISSN   1759-4782. PMC   10237083 . PMID   37268719.
  13. ↑ Cheung, Kevin J.; Padmanaban, Veena; Silvestri, Vanesa; Schipper, Koen; Cohen, Joshua D.; Fairchild, Amanda N.; Gorin, Michael A.; Verdone, James E.; Pienta, Kenneth J.; Bader, Joel S.; Ewald, Andrew J. (2016-02-16). "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): E854–863. Bibcode:2016PNAS..113E.854C. doi: 10.1073/pnas.1508541113 . ISSN   1091-6490. PMC   4763783 . PMID   26831077.
  14. ↑ 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 (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, Rokana; Liu, Xia; Singh, Salendra; Jia, Yuzhi; Dashzeveg, Nurmaa K.; Hoffmann, Andrew D.; El-Shennawy, Lamiaa; Ramos, Erika K.; Adorno-Cruz, Valery; Schuster, Emma J.; Scholten, David; Patel, Dhwani; Zhang, Youbin; Davis, Andrew A.; Reduzzi, Carolina (2021-08-11). "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. ISSN   2041-1723. PMC   8358026 . PMID   34381029.
  16. ↑ Allen, TA (31 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, Bee Luan; Grenci, Gianluca; Lim, Ying Bena; Lee, Soo Chin; Han, Jongyoon; Lim, Chwee Teck (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. ISSN   1750-2799. PMID   29215634.
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