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

被引:95
作者
Bruno, Antonino [1 ]
Bassani, Barbara [1 ]
D'Urso, Davide Giuseppe [1 ]
Pitaku, Ilvana [2 ]
Cassinotti, Elisa [2 ]
Pelosi, Giuseppe [4 ]
Boni, Luigi [5 ]
Dominioni, Lorenzo [2 ]
Noonan, Douglas M. [1 ,3 ]
Mortara, Lorenzo [3 ]
Albini, Adriana [1 ,6 ]
机构
[1] Ist Ricovero & Cura Carattere Sci IRCCS MultiMed, Vasc Biol & Angiogenesis Lab, Sci & Technol Pole PST, Milan, Italy
[2] Univ Insubria, Dept Surg & Morphol Sci, Varese, Italy
[3] Univ Insubria, Dept Biotechnol & Life Sci, Via Dunant 3, I-21100 Varese, Italy
[4] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy
[5] Univ Milan, Polyclin Hosp, Dept Med Surg Physiopathol & Transplantat, IRCCS, Milan, Italy
[6] Univ Milano Bicocca, Dept Med & Surg, Monza, Italy
关键词
angiogenesis; STAT signaling; VEGF; STAT3; STAT5; NATURAL-KILLER-CELLS; MATRIX METALLOPROTEINASES; TUMOR MICROENVIRONMENT; PERIPHERAL-BLOOD; TISSUE INHIBITOR; EXPRESSION; MMP-9; INFLAMMATION; STAT5; CYTOTOXICITY;
D O I
10.1096/fj.201701103R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in 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-like NK polarization toward the CD56(bright)CD16(dim/-)CD9(+)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; among which, angiogenin and invasion-associated enzymes related to the MMP9-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 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.
引用
收藏
页码:5365 / 5377
页数:13
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