CXCL17-derived CD11b+Gr-1+ myeloid-derived suppressor cells contribute to lung metastasis of breast cancer through platelet-derived growth factor-BB

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.Electronic supplementary materialThe online version of this article (10.1186/s13058-019-1114-3) contains supplementary material, which is available to authorized users.

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

“…These factors are hailed as alternative vasculature-creating mechanisms, but equally effective and perhaps overlapping, since they use similar signaling pathways (extracellular-related kinase (ERK)/Akt or mitogen-activated protein kinase (MAPK)), while the tumor-activated pSTAT3 pathway in MDSCs results in their generation [58,64]. Kuo et al detected that CXCL17 supported de novo angiogenesis and lung metastasis by means of PDGF expressing CD11b + Gr-1 + MDSC in mice [70].…”

The Engagement Between MDSCs and Metastases: Partners in Crime

“…In colorectal cancer mouse model, instead, high amounts of CXCL1 released by TAMs have been reported to attract CXCR2expressing MDSCs to generate liver pMNs (157). Other studies reported additional chemokines promoting MDSC transport to pMNs, such as MCP-1 (monocyte chemoattractant protein 1) (158), CCL12 (159), CCL9 (160), CCL15 (161), and CXCL17 (162), although the source of these cytokines in pMNs remains often unclear. Nowadays there are accumulating evidences that pro-metastatic molecules can be transported not only as soluble factors, but also inside tumor-derived microvesicles such as TEXs (13,163,164).…”

“…MDSCs play a critical role on initiating and sustaining the development of a new vascularization in pMN, primarily by secreting a variety of regulatory molecules such as VEGFA (173). Recently, Hsu et al demonstrated that high amount of platelet-derived growth factor BB (PDGF-BB) released by pMN-infiltrating MDSCs increases angiogenesis and chaperone tumor cells through the bloodstream to new sites of metastasis (162). Another MDSC-associated proangiogenic factor is Bv8, which is released by a STAT3-dependent pathway (174,175).…”

Stromal Platelet–Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain

“…More recently, focus has shifted towards the ligand. PDGFB is dramatically induced by TGFβ in normal mammary epithelial cells (10), and in the past year, was revealed to promote cancer associated fibroblast (CAF) invasiveness and lung metastasis in the murine mammary 4T1 tumor model (11)(12)(13). Overall, these findings led to our current study testing how PDGFRβ signaling alters BC initiation, progression, and/or metastasis.…”