How Circulating Tumor Cluster Biology Contributes to the Metastatic Cascade: from Invasion to Dissemination and Dormancy

Overview

Journal Cancer Metastasis Rev

Specialty Oncology

Date 2023 Jul 13

PMID 37442876

Authors

Mostafa M Nasr

Conor C Lynch

Affiliations

Soon will be listed here.

Abstract

Circulating tumor cells (CTCs) are known to be prognostic for metastatic relapse and are detected in patients as solitary cells or cell clusters. Circulating tumor cell clusters (CTC clusters) have been observed clinically for decades and are of significantly higher metastatic potential compared to solitary CTCs. Recent studies suggest distinct differences in CTC cluster biology regarding invasion and survival in circulation. However, differences regarding dissemination, dormancy, and reawakening require more investigations compared to solitary CTCs. Here, we review the current state of CTC cluster research and consider their clinical significance. In addition, we discuss the concept of collective invasion by CTC clusters and molecular evidence as to how cluster survival in circulation compares to that of solitary CTCs. Molecular differences between solitary and clustered CTCs during dormancy and reawakening programs will also be discussed. We also highlight future directions to advance our current understanding of CTC cluster biology.

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References

Hurtado P, Martinez-Pena I, Pineiro R . Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs). Cancers (Basel). 2020; 12(10). PMC: 7599894. DOI: 10.3390/cancers12102861. View

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

Allgayer H, Aguirre-Ghiso J . The urokinase receptor (u-PAR)--a link between tumor cell dormancy and minimal residual disease in bone marrow?. APMIS. 2008; 116(7-8):602-14. PMC: 2821075. DOI: 10.1111/j.1600-0463.2008.00997.x. View

Egan K, Cooke N, Kenny D . Living in shear: platelets protect cancer cells from shear induced damage. Clin Exp Metastasis. 2014; 31(6):697-704. DOI: 10.1007/s10585-014-9660-7. View

Albrengues J, Shields M, Ng D, Park C, Ambrico A, Poindexter M . Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018; 361(6409). PMC: 6777850. DOI: 10.1126/science.aao4227. View

Risson E, Nobre A, Maguer-Satta V, Aguirre-Ghiso J . The current paradigm and challenges ahead for the dormancy of disseminated tumor cells. Nat Cancer. 2021; 1(7):672-680. PMC: 7929485. DOI: 10.1038/s43018-020-0088-5. View

Sarioglu A, Aceto N, Kojic N, Donaldson M, Zeinali M, Hamza B . A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods. 2015; 12(7):685-91. PMC: 4490017. DOI: 10.1038/nmeth.3404. View

Herath S, Razavi Bazaz S, Monkman J, Warkiani M, Richard D, OByrne K . Circulating tumor cell clusters: Insights into tumour dissemination and metastasis. Expert Rev Mol Diagn. 2020; 20(11):1139-1147. DOI: 10.1080/14737159.2020.1846523. View

Friedlander T, Ngo V, Dong H, Premasekharan G, Weinberg V, Doty S . Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. Int J Cancer. 2013; 134(10):2284-93. DOI: 10.1002/ijc.28561. View

10.

Kondapaneni R, Rao S . Matrix stiffness and cluster size collectively regulate dormancy versus proliferation in brain metastatic breast cancer cell clusters. Biomater Sci. 2020; 8(23):6637-6646. DOI: 10.1039/d0bm00969e. View

11.

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

12.

Xiao Q, Ge G . Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenviron. 2012; 5(3):261-73. PMC: 3460045. DOI: 10.1007/s12307-012-0105-z. View

13.

Hansel G, Schonlebe J, Haroske G, Wollina U . Late recurrence (10 years or more) of malignant melanoma in south-east Germany (Saxony). A single-centre analysis of 1881 patients with a follow-up of 10 years or more. J Eur Acad Dermatol Venereol. 2010; 24(7):833-6. DOI: 10.1111/j.1468-3083.2009.03536.x. View

14.

Kamyabi N, Huang J, Lee J, Bernard V, Semaan A, Stephens B . A microfluidic device for label-free isolation of tumor cell clusters from unprocessed blood samples. Biomicrofluidics. 2019; 13(4):044111. PMC: 6701978. DOI: 10.1063/1.5111888. View

15.

Francescangeli F, Contavalli P, De Angelis M, Careccia S, Signore M, Haas T . A pre-existing population of ZEB2 quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer. J Exp Clin Cancer Res. 2020; 39(1):2. PMC: 6947904. DOI: 10.1186/s13046-019-1505-4. View

16.

Gorgoulis V, Adams P, Alimonti A, Bennett D, Bischof O, Bishop C . Cellular Senescence: Defining a Path Forward. Cell. 2019; 179(4):813-827. DOI: 10.1016/j.cell.2019.10.005. View

17.

Chang M, Chang Y, Chen J, Jeng Y, Yang C, Tien Y . Clinical Significance of Circulating Tumor Microemboli as a Prognostic Marker in Patients with Pancreatic Ductal Adenocarcinoma. Clin Chem. 2016; 62(3):505-13. DOI: 10.1373/clinchem.2015.248260. View

18.

Di Mauro C, Pesapane A, Formisano L, Rosa R, Damato V, Ciciola P . Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. Sci Rep. 2017; 7(1):9388. PMC: 5571185. DOI: 10.1038/s41598-017-10062-1. View

19.

Kopp H, Placke T, Salih H . Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res. 2009; 69(19):7775-83. DOI: 10.1158/0008-5472.CAN-09-2123. View

20.

Chen H, Cao B, Sun B, Cao Y, Yang K, Lin Y . Author Correction: Highly-sensitive capture of circulating tumor cells using micro-ellipse filters. Sci Rep. 2018; 8(1):5269. PMC: 5864916. DOI: 10.1038/s41598-018-22955-w. View