Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer

Antonino Bruno, Barbara Bassani, Davide Giuseppe D'Urso, Ilvana Pitaku, Elisa Cassinotti, Giuseppe Pelosi, Luigi Boni, Lorenzo Dominioni, Douglas M. Noonan, Lorenzo Mortara, Adriana Albini

Research output: Contribution to journalArticlepeer-review


NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solidmalignancies,NKcells have compromised functions.Wehave previously reported that lung tumor-associated NKcells (TANKs; peripheralblood) andtumor-infiltratingNKcells (TINKs) showproangiogenic,decidualNK-like (dNK) phenotype. In this study, we functionally andmolecularly investigated TINKs and TANKs fromblood and tissue samples of patients with colorectal cancer (CRC), a neoplasmin which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-likeNKpolarization toward the CD56brightCD16dim/-2CD9+CD49+ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; amongwhich, angiogenin and invasion-associated enzymes related to theMMP9-TIMP1/2 axis.Here,we describe, for the first time, to our knowledge, the expression of angiogenin,MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 orMMP inhibitors with immunotherapy could help repolarizeCRCTINKs and TANKs to anti-tumor antimetastatic ones.

Original languageEnglish
Pages (from-to)5365-5377
Number of pages13
JournalFASEB Journal
Issue number10
Publication statusPublished - Oct 1 2018


  • Angiogenesis
  • STAT signaling
  • STAT3
  • STAT5
  • VEGF

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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