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Cancer exodus hypothesis
open-in-new
<h2 id="mechanism">Mechanism</h2> <p>Traditionally, it was believed that CTC clusters needed to dissociate into individual cells during their journey through the bloodstream to seed <a href="/facts/Secondary_tumor/4dadbm6z">secondary tumors</a>. However, recent studies show that CTC clusters can travel through the <a href="/facts/Circulatory_system/WXwudzzc">bloodstream</a> intact, enabling them to perform every step of metastasis while maintaining their group/cluster structure.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p>The cancer exodus hypothesis asserts that CTC clusters have several distinct advantages that increase their metastatic potential: </p> <ul><li>Higher metastatic efficiency: CTC clusters have been shown to possess superior seeding capabilities at distant sites compared to single CTCs.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li> <li>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.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li> <li>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.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a></li></ul> <h2 id="clinical-relevance">Clinical relevance</h2> <p>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 <a href="/facts/Liquid_biopsy/1HMoPqmH">liquid biopsies</a> could offer valuable information about the aggressiveness and metastatic potential of cancers.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This information is particularly useful for identifying patients who may benefit from more aggressive treatment strategies.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="characterization">Characterization</h2> <p>The hypothesis was developed due to several key studies, which have demonstrated the ability of CTC clusters to: </p> <ul><li>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.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></li> <li>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 <a href="/facts/Angiopellosis/t9qq99NV">angiopellosis</a>, in which entire clusters migrate out of the blood vessels as a group, retaining their multicellular form. <a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></li></ul> <p>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.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> 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.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="future-directions">Future directions</h2> <p>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 <a href="/facts/Cancer_treatment/dezlwmAe">treatment interventions</a>.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9734934" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9734934</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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). doi:10.1242/jcs.231563. PMC 6771143. PMID 31409692. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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). doi:10.1242/jcs.231563. PMC 6771143. PMID 31409692. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983862" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983862</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149753</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984915" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984915</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Schuster E, Taftaf R, Reduzzi C, Albert MK, Romero-Calvo I, Liu H (November 2021). "Better together: circulating tumor cell clustering in metastatic cancer". 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PMID 31409692. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771143</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10237083" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10237083</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763783" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763783</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>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. 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