Bring Along Your Friends: Homotypic and Heterotypic Circulating Tumor Cell Clustering to Accelerate Metastasis

Overview

Journal Biomed J

Publisher Elsevier

Specialty General Medicine

Date 2020 Mar 24

PMID 32200952

Citations 45

Authors

Nicola Aceto

Affiliations

Soon will be listed here.

Abstract

Metastasis formation is a hallmark of invasive cancers and it is achieved through the shedding of circulating tumor cells (CTCs) from the primary site into the blood circulation. There, CTCs are found as single cells or as multicellular clusters, with clusters carrying an elevated ability to survive within the bloodstream and initiate new metastatic lesions at distant sites. Clusters of CTCs include homotypic clusters made of cancer cells only, as well as heterotypic clusters that incorporate stromal or immune cells along with cancer cells. Both homotypic and heterotypic CTC clusters are characterized by a high metastasis-forming capability, high proliferation rate and by distinct molecular features compared to single CTCs, and their presence in the peripheral circulation of cancer patients is generally associated with a poor prognosis. In this short review, we summarize the current literature that describes homotypic and heterotypic CTC clusters, both in the context of their molecular characteristics as well as their value in the clinical setting. While CTC clusters have only recently emerged as key players in the metastatic process and many aspects of their biology remain to be investigated, a detailed understanding of their vulnerabilities may pave the way towards the generation of new metastasis-suppressing agents.

Citing Articles

Mechanical signatures in cancer metastasis.

Agrawal A, Javanmardi Y, Watson S, Serwinski B, Djordjevic B, Li W NPJ Biol Phys Mech. 2025; 2(1):3.

PMID: 39917412 PMC: 11794153. DOI: 10.1038/s44341-024-00007-x.

Tumour hypoxia in driving genomic instability and tumour evolution.

Suvac A, Ashton J, Bristow R Nat Rev Cancer. 2025; 25(3):167-188.

PMID: 39875616 DOI: 10.1038/s41568-024-00781-9.

A Melanoma Brain Metastasis CTC Signature and CTC:B-cell Clusters Associate with Secondary Liver Metastasis: A Melanoma Brain-Liver Metastasis Axis.

Bowley T, Ortiz M, Lagutina I, Steinkamp M, Fahy B, Tawfik B Cancer Res Commun. 2025; 5(2):295-308.

PMID: 39831781 PMC: 11816052. DOI: 10.1158/2767-9764.CRC-24-0498.

Excess shed mesothelin disrupts pancreatic cancer cell clustering to impair peritoneal colonization.

Ewa T, Panchwagh N, Tai C, Avula L, Joseph S, Rudloff M FASEB J. 2024; 38(24):e70247.

PMID: 39673668 PMC: 11646052. DOI: 10.1096/fj.202400446R.

Multi-scale transcriptomics reveals that specific tumor cells promote lung adenocarcinoma metastasis through crosstalk with the microenvironment.

Cai Q, Shi L, Zhang M, Chen P Discov Oncol. 2024; 15(1):520.

PMID: 39363121 PMC: 11450129. DOI: 10.1007/s12672-024-01306-4.

References

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

Suo Y, Xie C, Zhu X, Fan Z, Yang Z, He H . Proportion of circulating tumor cell clusters increases during cancer metastasis. Cytometry A. 2016; 91(3):250-253. DOI: 10.1002/cyto.a.23037. View

Virchow R . Cellular pathology. As based upon physiological and pathological histology. Lecture XVI--Atheromatous affection of arteries. 1858. Nutr Rev. 1989; 47(1):23-5. DOI: 10.1111/j.1753-4887.1989.tb02747.x. View

Szczerba B, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J . Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019; 566(7745):553-557. DOI: 10.1038/s41586-019-0915-y. View

ZEIDMAN I, BUSS J . Transpulmonary passage of tumor cell emboli. Cancer Res. 1952; 12(10):731-3. View

Ting D, Wittner B, Ligorio M, Vincent Jordan N, Shah A, Miyamoto D . Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep. 2014; 8(6):1905-1918. PMC: 4230325. DOI: 10.1016/j.celrep.2014.08.029. View

Cheung K, Padmanaban V, Silvestri V, Schipper K, Cohen J, Fairchild A . Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A. 2016; 113(7):E854-63. PMC: 4763783. DOI: 10.1073/pnas.1508541113. View

Vetter M, Landin J, Szczerba B, Castro-Giner F, Gkountela S, Donato C . Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer. Breast Cancer Res. 2018; 20(1):141. PMC: 6247738. DOI: 10.1186/s13058-018-1067-y. View

Liotta L, Saidel M, KLEINERMAN J . The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 1976; 36(3):889-94. View

10.

Cho H, Kim J, Song H, Sohn K, Jeon M, Han K . Microfluidic technologies for circulating tumor cell isolation. Analyst. 2018; 143(13):2936-2970. DOI: 10.1039/c7an01979c. View

11.

Chan C, Hutcheon M, Hyland R, Smith G, Patterson B, Matthay R . Pulmonary tumor embolism: a critical review of clinical, imaging, and hemodynamic features. J Thorac Imaging. 1987; 2(4):4-14. View

12.

Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B . Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res. 2007; 13(3):920-8. DOI: 10.1158/1078-0432.CCR-06-1695. View

13.

Pieters T, van Roy F . Role of cell-cell adhesion complexes in embryonic stem cell biology. J Cell Sci. 2014; 127(Pt 12):2603-13. DOI: 10.1242/jcs.146720. View

14.

Ramasamy S, Saez B, Mukhopadhyay S, Ding D, Ahmed A, Chen X . Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway. Proc Natl Acad Sci U S A. 2016; 113(7):1871-6. PMC: 4763742. DOI: 10.1073/pnas.1511380113. View

15.

Giuliano M, Shaikh A, Lo H, Arpino G, De Placido S, Zhang X . Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize. Cancer Res. 2018; 78(4):845-852. DOI: 10.1158/0008-5472.CAN-17-2748. View

16.

Sprouse M, Welte T, Boral D, Liu H, Yin W, Vishnoi M . PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling. Int J Mol Sci. 2019; 20(8). PMC: 6514876. DOI: 10.3390/ijms20081916. View

17.

Roberts K, Hamele-Bena D, Saqi A, Stein C, Cole R . Pulmonary tumor embolism: a review of the literature. Am J Med. 2003; 115(3):228-32. DOI: 10.1016/s0002-9343(03)00305-x. View

18.

Hayes D, Cristofanilli M, Budd G, Ellis M, Stopeck A, Miller M . Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006; 12(14 Pt 1):4218-24. DOI: 10.1158/1078-0432.CCR-05-2821. View

19.

King M, Harmon K . Unusual forms of pulmonary embolism. Clin Chest Med. 1994; 15(3):561-80. View

20.

Aceto N, Toner M, Maheswaran S, Haber D . En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition. Trends Cancer. 2017; 1(1):44-52. DOI: 10.1016/j.trecan.2015.07.006. View