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IL-1? inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

ABSTRACT: 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? (IL-1?)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1? 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? 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.

SUBMITTER: Castano Z

PROVIDER: S-EPMC6511979 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

Castaño Zafira Z San Juan Beatriz P BP Spiegel Asaf A Pant Ayush A DeCristo Molly J MJ Laszewski Tyler T Ubellacker Jessalyn M JM Janssen Susanne R SR Dongre Anushka A Reinhardt Ferenc F Henderson Ayana A Del Rio Ana Garcia AG Gifford Ann M AM Herbert Zachary T ZT Hutchinson John N JN Weinberg Robert A RA Chaffer Christine L CL McAllister Sandra S SS

Nature cell biology 20180827 9

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-1β (IL-1β)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic ...[more]

PMID: 30154549

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Project description:BACKGROUND: The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis. METHODS: Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC). RESULTS: Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor ? (ER?)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 103 cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear ? catenin and fibronectin but were negative for ER? and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and ? catenin to the membrane of tumor cells was observed. ER? was re-expressed in lung metastatic cells in two of five samples. CONCLUSIONS: Tumorspheres isolated under defined culture conditions from patient core biopsies were tumorigenic when transplanted into the mammary fat pad of NUDE mice, and metastasized to multiple mouse organs. Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. The development of macrometastases with organ-specific phenotypic distinctions provides a superior model for the investigation of organ-specific effects on metastatic cancer cell survival and growth.

Dataset Information

IL-1? inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

Publications

IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

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