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Inhibition of dendritic cell migration by transforming growth factor-?1 increases tumor-draining lymph node metastasis.

ABSTRACT: BACKGROUND: Transforming growth factor (TGF)-? is known to be produced by progressor tumors and to immobilize dendritic cells (DCs) within those tumors. Moreover, although TGF-?1 has been shown to promote tumor progression, there is still no direct, in vivo evidence as to whether TGF-?1 is able to directly induce distant metastasis. METHODS: To address that issue and investigate the mechanism by which TGF-?1 suppresses DC activity, we subdermally inoculated mouse ears with squamous cell carcinoma cells stably expressing TGF-?1 or empty vector (mock). RESULTS: The numbers of DCs within lymph nodes draining the resultant TGF-?1-expressing tumors was significantly lower than within nodes draining tumors not expressing TGF-?1. We then injected fluorescently labeled bone marrow-derived dendritic cells into the tumors, and subsequent analysis confirmed that the tumors were the source of the DCs within the tumor-draining lymph nodes, and that there were significantly fewer immature DCs within the nodes draining TGF-?1-expressing tumors than within nodes draining tumors not expressing TGF-?1. In addition, 14 days after tumor cell inoculation, lymph node metastasis occurred more frequently in mice inoculated with TGF-?1 transfectants than in those inoculated with the mock transfectants. CONCLUSIONS: These findings provide new evidence that tumor-derived TGF-?1 inhibits migration of DCs from tumors to their draining lymph nodes, and this immunosuppressive effect of TGF-?1 increases the likelihood of metastasis in the affected nodes.

SUBMITTER: Imai K

PROVIDER: S-EPMC3298529 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis.

Imai Kazuhiro K Minamiya Yoshihiro Y Koyota Souichi S Ito Manabu M Saito Hajime H Sato Yusuke Y Motoyama Satoru S Sugiyama Toshihiro T Ogawa Jun-Ichi J

Journal of experimental & clinical cancer research : CR 20120110

<h4>Background</h4>Transforming growth factor (TGF)-β is known to be produced by progressor tumors and to immobilize dendritic cells (DCs) within those tumors. Moreover, although TGF-β1 has been shown to promote tumor progression, there is still no direct, in vivo evidence as to whether TGF-β1 is able to directly induce distant metastasis.<h4>Methods</h4>To address that issue and investigate the mechanism by which TGF-β1 suppresses DC activity, we subdermally inoculated mouse ears with squamous ...[more]

PMID: 22233831

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Project description:Although the primary organ has been the subject of intense investigation in the field of organ fibrosis over the past several decades, the presence of lymph node fibrosis due to persistent activation of the immune response in its partner organ remains largely unknown. Previously, we demonstrated that activation of the immune response following ischemia-reperfusion injury (IRI) and crescentic glomerulonephritis (CGN) in the kidney was associated with extracellular matrix (ECM) production by fibroblastic reticular cells (FRCs) of the kidney-draining lymph node (KLN). Here, we sought to determine whether FRCs in the KLN become similarly fibrogenic following unilateral ureteral obstruction (UUO) of the kidney. We subjected 6-8-week-old C57BL/6J mice to UUO for 2, 7, and 14 days. We examined the microarchitecture of the kidney and KLN by immunofluorescence staining at each timepoint, and we quantified immune cell populations in the KLN by flow cytometry. The contralateral kidney unaffected by UUO and its partner KLN were used as controls. We found through immunofluorescence staining that FRCs increased production of ECM fibers and remodeled the microarchitecture of the UUO KLN, contributing to fibrosis that mirrored the changes in the kidney. We also observed by flow cytometry that the populations of CD11b+ antigen-presenting cells, CD11c+ dendritic cells, and activated CD4+ and CD8+ T cells were significantly higher in the UUO KLN than the KLN draining the unaffected contralateral kidney. Expression of the TGFβ/TGFβR signaling pathway was upregulated and colocalized with FRCs in the UUO KLNs, suggesting a possible mechanism behind the fibrosis. Both release of ureteral ligation at 2 days following UUO and depletion of FRCs at the time of injury onset halted the progression of fibrosis in both the kidney and the KLN. These findings for the first time highlight the association between fibrosis both in the kidney and the KLN during UUO, and they lay the groundwork for future studies that will investigate more deeply the mechanisms behind the connection between FRCs and KLN fibrosis.

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Inhibition of dendritic cell migration by transforming growth factor-?1 increases tumor-draining lymph node metastasis.

Publications

Inhibition of dendritic cell migration by transforming growth factor-β1 increases tumor-draining lymph node metastasis.

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