TY - JOUR
T1 - Impeding circulating tumor cell reseeding decelerates metastatic progression and potentiates chemotherapy
AU - Qian, Chen
AU - Worrede-Mahdi, Asurayya
AU - Shen, Fei
AU - DiNatale, Anthony
AU - Kaur, Ramanpreet
AU - Zhang, Qiang
AU - Cristofanilli, Massimo
AU - Meucci, Olimpia
AU - Fatatis, Alessandro
N1 - Funding Information:
The authors wish to thank Dr. Kenneth J. Pienta at the Brady Urological Institute of Johns Hopkins University (Baltimore, MD), and members of his laboratory for valuable discussion. The FX-68 small-molecule compound was synthesized in the laboratory of Dr. Joseph Salvino (current address: The Wistar Institute, Philadelphia, PA), which the authors wish to thank also for coordinating the efforts of Eurofins Pharma and Reaction Biology toward this project. This work was funded by grants from the NIH (CA202929), Wallace H. Coulter Foundation and Breast Cancer Alliance (to A. Fatatis and O. Meucci.) and from the Department of Defense, Breast Cancer Program Breakthrough Award Level 2 (BC150659; to A. Fatatis).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-18-0302
DO - 10.1158/1541-7786.MCR-18-0302
M3 - Article
C2 - 30115759
AN - SCOPUS:85057763922
VL - 16
SP - 1844
EP - 1854
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 12
ER -