2. Academic Validation
  3. Inducible nitric oxide synthase (iNOS)-activated Cxcr2 signaling in myeloid cells promotes TGFβ-dependent squamous cell carcinoma lung metastasis

Inducible nitric oxide synthase (iNOS)-activated Cxcr2 signaling in myeloid cells promotes TGFβ-dependent squamous cell carcinoma lung metastasis

  • Cancer Lett. 2023 Jul 29;216330. doi: 10.1016/j.canlet.2023.216330.
Xing Li 1,  Yao Ke 2,  Ariel L Hernandez 2,  Jingjing Yu 2,  Li Bian 2,  Spencer C Hall 2,  Kyle Nolan 2,  Jing H Wang 3,  Christian D Young 4,  Xiao-Jing Wang 5
Affiliations

Affiliations

  • 1 Hospital of Stomatology, Jilin University, Changchun, 130021, PR China; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • 2 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
  • 3 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 4 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Electronic address: christian.young@cuanschutz.edu.
  • 5 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, CO, 80045, USA; Department of Pathology & Laboratory Medicine, University of California Davis, Sacramento, CA, 95817, USA. Electronic address: drxwang@ucdavis.edu.
PMID: 37524225 DOI: 10.1016/j.canlet.2023.216330
Abstract

Transforming growth factor beta (TGFβ) activity is linked to metastasis in many Cancer types, but whether TGFβ activity is necessary for squamous cell carcinoma (SCC) lung metastasis has not been studied. Here we used a lung metastatic SCC model derived from keratin 15 (K15). KrasG12D.SMAD4-/- SCC and human SCC specimens to identify metastasis drivers and test therapeutic interventions. We demonstrated that a TGFβ receptor (TGFβR) inhibitor reduced lung metastasis in mouse SCC correlating with reduced CD11b+/Ly6G+ myeloid cells positive for inducible nitric oxide synthase (iNOS). Further, TGFβ activity and iNOS were higher in primary human oral SCCs with metastasis than SCCs without metastasis. Consistently, either depleting myeloid cells with anti-Gr1 antibody or inhibiting iNOS with L-N6-(1-iminoethyl)-l-lysine (L-NIL) reduced SCC lung metastasis. L-NIL treated tumor-bearing mice exhibited reductions in tumor-infiltrating myeloid cells and in plasma Cxcl5 levels, and attenuated primary tumor growth with increased Apoptosis and decreased proliferation. Blocking Cxcl5 with an antagonist of its receptor CXCR2, SB225002, also reduced SCC lung metastasis.

Keywords

L-NIL; Myeloid-derived suppressor cells; Oral cancer; Smad4 deletion; Spontaneous lung metastasis model.

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