Abstract
BackgroundMetastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood.MethodsSpecific gene contributions to lung metastasis were identified by comparing gene profiles of 4T1 tumors metastasizing to various organs via microarray. The oncogenic properties CXCL17 were examined by in vivo spontaneous metastasis mouse model. The chemotactic activity of CXCL17 on CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) was examined by both in vitro and in vivo models. The therapeutic effects of MDSC depletion and platelet-derived growth factor-BB (PDGF-BB) inhibition were examined by orthotic models.ResultsHere, we demonstrate that breast cancer cells secrete CXCL17, which increases the accumulation of CD11b+Gr-1+ MDSCs in the lungs. Metastatic lung-infiltrating CD11b+Gr-1+ MDSCs induce angiogenesis in the lungs and facilitate cancer extravasation and survival that ultimately promote lung metastases. CXCL17 increases CD11b+Gr-1+ MDSCs to express PDGF-BB, which not only contributes to CD11b+Gr-1+ MDSC-mediated angiogenesis in the lung metastatic niche, but is also involved in the colonization of breast cancer. Consequently, both CD11b+Gr-1+ MDSC depletion and PDGF receptor inhibitor effectively prevents CXCL17-driven lung metastasis in breast cancer. More importantly, patients with high levels of CXCL17 have shorter distant metastasis-free and overall survival rates, indicators of poor prognosis.ConclusionOur study reveals that MDSCs derived by CXCL17 contribute to the establishment of a lung metastatic niche by PDGF-BB secretion and provide a rationale for development of CXCL17 or PDGF-BB antagonists to inhibit or prevent lung metastasis in cases of breast cancer.
Highlights
Breast cancer is the most common malignant disease affecting women worldwide
CD11b+Gr-1+ Myeloid-derived suppressor cells (MDSCs) facilitate cancer extravasation and survival via platelet-derived growth factor-BB (PDGF-BB) Because PDGF-BB has been implicated as being an oncogenic factor for metastasis in various cancers [26, 27], and Chemokine ligand 17 (CXCL17) provokes CD11b+Gr-1+ MDSCs to express high levels of PDGF-BB, we investigated the impact of CD11b+Gr-1+ MDSC-derived PDGF-BB in cancer extravasation, as determined by transendothelial migration analysis
Our findings identify primary breast cancer-secreted CXCL17 as an important contributor that drives the formation of the lung metastatic niche (Fig. 7)
Summary
Breast cancer is the most common malignant disease affecting women worldwide. Recent statistics indicate that breast cancer is estimated to account for 30% of all new cancer diagnoses in women [1]. Hsu et al Breast Cancer Research (2019) 21:23 highly-organized cell biological process is the variation in metastatic organ-specific tropism depending on the tumor type [5, 6]. One of the reasons for organ-specific tropism of cancer cells is the formation of a permissive microenvironment, known as the metastatic niche, in target organs. Growing evidence supports the hypothesis that MDSCs exert their pro-tumorigenic effects by suppressing T and B cell functions and promoting tumor angiogenesis, proliferation, survival, and metastasis [13]. It remains unclear why and how MDSCs accumulate in the lungs, creating a permissive microenvironment for metastasizing breast cancer cells. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
