Abstract
BackgroundChemokines are involved in multiple aspects of pathogenesis and cellular trafficking in tumorigenesis. In this study, we report that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1), recruits immature myeloid-derived cells and enhances early tumor progression.Methodology/Principal FindingsCXCL17 was preferentially expressed in some aggressive types of gastrointestinal, breast, and lung cancer cells. CXCL17 expression did not impart NIH3T3 cells with oncogenic potential in vitro, but CXCL17-expressing NIH3T3 cells could form vasculature-rich tumors in immunodeficient mice. Our data showed that CXCL17-expressing tumor cells increased immature CD11b+Gr1+ myeloid-derived cells at tumor sites in mice and promoted CD31+ tumor angiogenesis. Extensive chemotactic assays proved that CXCL17-responding cells were CD11b+Gr1highF4/80− cells (∼90%) with a neutrophil-like morphology in vitro. Although CXCL17 expression could not increase the number of CD11b+Gr1+ cells in tumor-burdened SCID mice or promote metastases of low metastatic colon cancer cells, the existence of CXCL17-responding myeloid-derived cells caused a striking enhancement of xenograft tumor formation.Conclusions/SignificanceThese results suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes tumor progression through angiogenesis.
Highlights
The tumor microenvironment is the result of an extremely complex series of biological events that depend on tumor cell interaction with the responding host cells [1]
A variety of factors produced by both tumor cells and host responding cells have been discovered that regulate angiogenesis [1,2,3,4], and data emerging from current studies demonstrate that tumor-associated macrophages (TAMs) [1,4], mesenchymal stem cells (MSCs) [5], and myeloid-derived suppressor cells (MDSCs) [4,5,6] are accumulated at tumor sites and play a pivotal role in tumor angiogenesis, as well as tumor progression and metastasis
Immunostaining of mCXCL17-3T3-derived tumor using anti-CD31 Ab revealed increased formation of vasculature (Figure 1F). These results indicate that CXCL17 does not have oncogenic transformation activity with NIH3T3 cells in vitro, but suggest that CXCL17 introduces tumorigenicity through angiogenesis in vivo
Summary
The tumor microenvironment is the result of an extremely complex series of biological events that depend on tumor cell interaction with the responding host cells [1]. The directional migration of A2056 human melanoma cells was shown by exposure of the C-X-C-type chemokine ligand (CXCL) 8 [8], and both CXCL8 and CXCL5 expression in non-small cell lung carcinoma (NSCLC) has been correlated with tumor angiogenesis [9]. It was demonstrated that the new C-X-C chemokine induces migration of CD14+ monocytes and CD11c+ immature dendritic cells (DCs) from human peripheral blood [10] and contributes to potential angiogenesis [11], the role of the chemokine in tumorigenesis remains unclear. We demonstrate that CXCL17 recruits CD11b+Gr1+ myeloid-derived cells at tumor sites and promotes angiogenesis and tumorigenesis. We report that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1), recruits immature myeloidderived cells and enhances early tumor progression
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