학술논문
IL-1[beta] inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization
Document Type
Report
Author
Source
Nature Cell Biology. September 2018, Vol. 20 Issue 9, p1084, 4 p.
Subject
Language
English
ISSN
1465-7392
Abstract
Author(s): Zafira Castaño [sup.1] [sup.2] , Beatriz P. San Juan [sup.3] , Asaf Spiegel [sup.4] , Ayush Pant [sup.4] , Molly J. DeCristo [sup.1] [sup.2] , Tyler Laszewski [sup.1] , [...]
Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1[beta] (IL-1[beta])-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1[beta] maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1[beta] expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival. Castaño et al. show that primary breast tumours drive an IL-1[beta] -mediated inflammatory response that inhibits cellular plasticity and metastatic colonization of metastasis-initiating cells.
Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1[beta] (IL-1[beta])-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1[beta] maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1[beta] expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival. Castaño et al. show that primary breast tumours drive an IL-1[beta] -mediated inflammatory response that inhibits cellular plasticity and metastatic colonization of metastasis-initiating cells.