Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma.

Autor:	Riedel A; Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.; The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Helal M; Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany., Pedro L; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Swietlik JJ; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Shorthouse D; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Schmitz W; Institute for Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany., Haas L; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Young T; Department of Medicine, University of Cambridge, Cambridge, United Kingdom., da Costa ASH; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Davidson S; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Bhandare P; Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany., Wolf E; Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany.; Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Würzburg, Germany., Hall BA; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Frezza C; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom., Oskarsson T; The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Shields JD; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 Apr 01; Vol. 10 (4), pp. 482-497.
DOI:	10.1158/2326-6066.CIR-21-0778
Abstrakt:	Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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