Key Characteristics of Circulating Tumor Cell Clusters and Implications for Cancer Metastases

Authors

  • Yakov Perlov Belmont High School
  • Dean Lee Scientist in HiFiBiO Therapeutics, a local (Cambridge) biotechnology company

DOI:

https://doi.org/10.47611/jsrhs.v10i2.1470

Keywords:

Cancer, Circulating Tumor Cells, CTC, Circulating Tumor Cell Clusters, Chemotherapy, Chemoresistance, Apoptosis, Anoikis, Reduced Apoptosis, Necrosis, Quiescence, Stemness, Cancer Stem Cells, CSCs, Cancer Epigenetics, Polycomb, Tumor Spheroids, Tumorospheres, CTC Clusters, Single CTCs, Metastasis

Abstract

Primary tumors generate metastases by shedding tumor cells into the circulation; these circulating tumor cells (CTCs) implant at distant sites to develop into metastatic lesions. CTCs can travel either as clusters or as single CTCs. Previous studies revealed that the frequency of CTC clusters in a cancer patient positively correlates with the likelihood of developing metastatic lesions. Three key characteristics of CTC clusters - chemoresistance, reduced apoptosis, and epigenetically programmed stemness - enhance their metastatic potential relative to single CTCs:

  1. CTC clusters seem to be more resistant to chemotherapy due to their quiescent and necrotic cores, making drug penetration difficult. Their chemoresistance also correlates with specific molecular components of the extracellular matrix.

  2. CTC clusters suffer lower rates of apoptosis. This might be attributed to autocrine factors that protect against immune attack and the epithelial-mesenchymal transition.

  3. The DNA methylation landscape of CTC clusters closely resembles that of embryonic stem cells. It features hypomethylation of four critical transcription factors associated with stemness and hypermethylation of a set of pro-differentiation genes.

Further research might focus on the interdependence of these three characteristics and whether they precede or follow the clustering of CTCs. The answers to these research questions will help drug developers define specific mechanisms that can curb the metastatic potential of CTC clusters.

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Author Biographies

Yakov Perlov, Belmont High School

Yakov is a senior from Belmont, Massachusetts. Yakov is focused on cancer research and has a niche interest in the steps leading up to cancer metastasis, such as the epithelial-mesenchymal transition. He hopes to continue his studies in the life sciences at the undergraduate and graduate levels.

Dean Lee, Scientist in HiFiBiO Therapeutics, a local (Cambridge) biotechnology company

Dean is a scientist for computational biology at HiFiBiO Therapeutics. He collaborates with immunologists and cancer biologists to discover and validate promising targets for antibody-based drugs. He is interested in using classical machine learning methods as well as newly described deep learning methods to better mine large genomics and transcriptomics datasets.

References or Bibliography

Klameth, L., Rath, B., Hochmaier, M., Moser, D., Redl, M., Mungenast, F., Gelles, K., Ulsperger, E., Zeillinger, R., & Hamilton, G. (2017). Small cell lung cancer: model of circulating tumor cell tumorospheres in chemoresistance. Scientific reports, 7(1), 5337. https://doi.org/10.1038/s41598-017-05562-z

Laurent, J., Frongia, C., Cazales, M., Mondesert, O., Ducommun, B., & Lobjois, V. (2013). Multicellular tumor spheroid models to explore cell cycle checkpoints in 3D. BMC cancer, 13, 73. https://doi.org/10.1186/1471-2407-13-73

Hamilton, G., Rath, B., Holzer, S., & Hochmair, M. (2016). Second-line therapy for small cell lung cancer: exploring the potential role of circulating tumor cells. Translational lung cancer research, 5(1), 71–77. https://doi.org/10.3978/j.issn.2218-6751.2015.12.12

Tannock, I. F., Lee, C. M., Tunggal, J. K., Cowan, D. S., & Egorin, M. J. (2002). Limited penetration of anticancer drugs through tumor tissue: a potential cause of resistance of solid tumors to chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research, 8(3), 878–884.

Däster, S., Amatruda, N., Calabrese, D., Ivanek, R., Turrini, E., Droeser, R. A., Zajac, P., Fimognari, C., Spagnoli, G. C., Iezzi, G., Mele, V., & Muraro, M. G. (2017). Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment. Oncotarget, 8(1), 1725–1736. https://doi.org/10.18632/oncotarget.13857

Zschenker, O., Streichert, T., Hehlgans, S., & Cordes, N. (2012). Genome-wide gene expression analysis in cancer cells reveals 3D growth to affect ECM and processes associated with cell adhesion but not DNA repair. PloS one, 7(4), e34279. https://doi.org/10.1371/journal.pone.0034279

Pease, J.C., Brewer, M., & Tirnauer, J. (2012). Spontaneous spheroid budding from monolayers: a potential contribution to ovarian cancer dissemination. Biology Open, 1, 622 - 628. https://doi.org/10.1242/bio.2012653

Pampaloni, F., Reynaud, E. G., & Stelzer, E. H. (2007). The third dimension bridges the gap between cell culture and live tissue. Nature reviews. Molecular cell biology, 8(10), 839–845. https://doi.org/10.1038/nrm2236

Hoffmann, O. I., Ilmberger, C., Magosch, S., Joka, M., Jauch, K. W., & Mayer, B. (2015). Impact of the spheroid model complexity on drug response. Journal of biotechnology, 205, 14–23. https://doi.org/10.1016/j.jbiotec.2015.02.029

Jansson, S., Bendahl, P. O., Larsson, A. M., Aaltonen, K. E., & Rydén, L. (2016). Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort. BMC cancer, 16, 433. https://doi.org/10.1186/s12885-016-2406-y

Hou, J. M., Krebs, M., Ward, T., Sloane, R., Priest, L., Hughes, A., Clack, G., Ranson, M., Blackhall, F., & Dive, C. (2011). Circulating tumor cells as a window on metastasis biology in lung cancer. The American journal of pathology, 178(3), 989–996. https://doi.org/10.1016/j.ajpath.2010.12.003

Frisch, S. M., & Francis, H. (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. The Journal of cell biology, 124(4), 619–626. https://doi.org/10.1083/jcb.124.4.619

Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging Biological Principles of Metastasis. Cell, 168(4), 670–691. https://doi.org/10.1016/j.cell.2016.11.037

Gkountela, S., Castro-Giner, F., Szczerba, B. M., Vetter, M., Landin, J., Scherrer, R., Krol, I., Scheidmann, M. C., Beisel, C., Stirnimann, C. U., Kurzeder, C., Heinzelmann-Schwarz, V., Rochlitz, C., Weber, W. P., & Aceto, N. (2019). Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell, 176(1-2), 98–112.e14. https://doi.org/10.1016/j.cell.2018.11.046

Lee, T. I., Jenner, R. G., Boyer, L. A., Guenther, M. G., Levine, S. S., Kumar, R. M., Chevalier, B., Johnstone, S. E., Cole, M. F., Isono, K., Koseki, H., Fuchikami, T., Abe, K., Murray, H. L., Zucker, J. P., Yuan, B., Bell, G. W., Herbolsheimer, E., Hannett, N. M., Sun, K., … Young, R. A. (2006). Control of developmental regulators by Polycomb in human embryonic stem cells. Cell, 125(2), 301–313. https://doi.org/10.1016/j.cell.2006.02.043

Wong, D. J., Liu, H., Ridky, T. W., Cassarino, D., Segal, E., & Chang, H. Y. (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell stem cell, 2(4), 333–344. https://doi.org/10.1016/j.stem.2008.02.009

Niwa H. (2007). How is pluripotency determined and maintained?. Development (Cambridge, England), 134(4), 635–646. https://doi.org/10.1242/dev.02787

Kim, J., Chu, J., Shen, X., Wang, J., & Orkin, S. H. (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell, 132(6), 1049–1061. https://doi.org/10.1016/j.cell.2008.02.039

Saunders, A., Huang, X., Fidalgo, M., Reimer, M. H., Jr, Faiola, F., Ding, J., Sánchez-Priego, C., Guallar, D., Sáenz, C., Li, D., & Wang, J. (2017). The SIN3A/HDAC Corepressor Complex Functionally Cooperates with NANOG to Promote Pluripotency. Cell reports, 18(7), 1713–1726. https://doi.org/10.1016/j.celrep.2017.01.055

Reddington, J. P., Sproul, D., & Meehan, R. R. (2014). DNA methylation reprogramming in cancer: does it act by re-configuring the binding landscape of Polycomb repressive complexes?. BioEssays : news and reviews in molecular, cellular and developmental biology, 36(2), 134–140. https://doi.org/10.1002/bies.201300130

Avissar-Whiting, M., Koestler, D. C., Houseman, E. A., Christensen, B. C., Kelsey, K. T., & Marsit, C. J. (2011). Polycomb group genes are targets of aberrant DNA methylation in renal cell carcinoma. Epigenetics, 6(6), 703–709. https://doi.org/10.4161/epi.6.6.16158

Dongre, A., & Weinberg, R. A. (2019). New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nature reviews. Molecular cell biology, 20(2), 69–84. https://doi.org/10.1038/s41580-018-0080-4

Amintas, S., Bedel, A., Moreau-Gaudry, F., Boutin, J., Buscail, L., Merlio, J. P., Vendrely, V., Dabernat, S., & Buscail, E. (2020). Circulating Tumor Cell Clusters: United We Stand Divided We Fall. International journal of molecular sciences, 21(7), 2653. https://doi.org/10.3390/ijms21072653

Published

07-01-2021

How to Cite

Perlov, Y., & Lee, D. (2021). Key Characteristics of Circulating Tumor Cell Clusters and Implications for Cancer Metastases. Journal of Student Research, 10(2). https://doi.org/10.47611/jsrhs.v10i2.1470

Issue

Vol. 10 No. 2 (2021)

Section

HS Review Articles

Copyright (c) 2021 Yakov Perlov; Dean Lee

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