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

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.

• Authors: Chen Qian, Asurayya Worrede-Mahdi, Fei Shen, Anthony DiNatale, Ramanpreet Kaur, Qiang Zhang, Massimo Cristofanilli, Olimpia Meucci, Alessandro Fatatis
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 16 Issue 12 Pg. 1844-1854 (12 2018) ISSN: 1557-3125 [Electronic] United States
• PMID: 30115759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• CX3C Chemokine Receptor 1
• CX3CR1 protein, human
• Small Molecule Libraries
• Docetaxel
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• CX3C Chemokine Receptor 1 (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Progression
• Docetaxel (administration & dosage, pharmacology)
• Doxorubicin (administration & dosage, pharmacology)
• Drug Synergism
• Female
• Humans
• Neoplasm Metastasis (drug therapy)
• Neoplasm Transplantation
• Neoplastic Cells, Circulating (drug effects, metabolism)
• Prognosis
• Small Molecule Libraries (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays