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Mol Cancer Res. 2018 Dec;16(12):1844-1854. doi: 10.1158/1541-7786.MCR-18-0302. Epub 2018 Aug 16.

Impeding Circulating Tumor Cell Reseeding Decelerates Metastatic Progression and Potentiates Chemotherapy.

Author information

1
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
2
Oncology Discovery, Janssen Pharmaceuticals, Spring House, Pennsylvania.
3
Department of Medicine-Hematology and Oncology, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois.
4
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania. af39@drexel.edu.
5
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Abstract

Circulating tumor cells (CTCs) are commonly detected in the systemic blood of patients with cancer with metastatic tumors. However, the mechanisms controlling the viability of cancer cells in blood and length of time spent in circulation, as well as their potential for generating additional tumors are still undefined. Here, it is demonstrated that CX3CR1, a chemokine receptor, drives reseeding of breast CTCs to multiple organs. Antagonizing this receptor dramatically impairs the progression of breast cancer cells in a relevant model of human metastatic disease, by affecting both tumor growth and numerical expansion. Notably, therapeutic targeting of CX3CR1 prolongs CTC permanence in the blood, both promoting their spontaneous demise by apoptosis and counteracting metastatic reseeding. These effects lead to containment of metastatic progression and extended survival. Finally, targeting CX3CR1 improves blood exposure of CTCs to doxorubicin and in combination with docetaxel shows synergistic effects in containing overall tumor burden. IMPLICATIONS: The current findings shed light on CTCs reseeding dynamics and support the development of CX3CR1 antagonism as a viable strategy to counteract metastatic progression.

PMID:
30115759
PMCID:
PMC6279516
[Available on 2019-12-01]
DOI:
10.1158/1541-7786.MCR-18-0302

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