Role of Annexin A1 Secreted by Neutrophils in Melanoma Metastasis

Cells. 2023 Jan 27;12(3):425. doi: 10.3390/cells12030425.

Abstract

Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil-lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL/6; i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM; 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1-/-) neutrophils. The depletion of peripheral neutrophils during lung melanoma metastasis development (anti-Gr1; i.p. every 48 h for 21 days) reduced the number of metastases and AnxA1 serum levels in mice. Our findings show that AnxA1 secreted by neutrophils favors melanoma metastasis evolution via FPR pathways, addressing AnxA1 as a potential biomarker for the detection or progression of melanoma.

Keywords: B16F10 cells; FPR antagonists; melanoma patients; neutrophil-depleted mice; neutrophil–lymphocyte ratio (NLR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1* / metabolism
  • Melanoma* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / metabolism
  • Phagocytosis
  • Tumor Microenvironment

Substances

  • Annexin A1
  • annexin A1, mouse

Grants and funding

This work was supported by FAPESP (Fundação de Amparo á Pesquisa do Estado de São Paulo), grant number 2014/07328-4. S.H.P.F. is a fellow researcher of the CNPq (Conselho Nacional de Pesquisa); C.B.H. and S.S. were post-doctoral fellows of CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior); M.F.B. is a PhD fellow of the FAPESP, grant number 2018/26383-7.