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Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects

1
Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Via Monte Generoso, n. 71, 21100 Varese, Italy
2
School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
3
Vascular Biology and Angiogenesis Laboratory, Scientific and Technologic Park, IRCCS MultiMedica, 20138 Milan, Italy
4
UOSD Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
*
Authors to whom correspondence should be addressed.
These authors share equal contribution.
These authors share equal senior authorship.
Cancers 2019, 11(4), 461; https://doi.org/10.3390/cancers11040461
Received: 14 February 2019 / Revised: 21 March 2019 / Accepted: 26 March 2019 / Published: 1 April 2019
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
Immune cells, as a consequence of their plasticity, can acquire altered phenotype/functions within the tumor microenvironment (TME). Some of these aberrant functions include attenuation of targeting and killing of tumor cells, tolerogenic/immunosuppressive behavior and acquisition of pro-angiogenic activities. Natural killer (NK) cells are effector lymphocytes involved in tumor immunosurveillance. In solid malignancies, tumor-associated NK cells (TANK cells) in peripheral blood and tumor-infiltrating NK (TINK) cells show altered phenotypes and are characterized by either anergy or reduced cytotoxicity. Here, we aim at discussing how NK cells can support tumor progression and how induction of angiogenesis, due to TME stimuli, can be a relevant part on the NK cell-associated tumor supporting activities. We will review and discuss the contribution of the TME in shaping NK cell response favoring cancer progression. We will focus on TME-derived set of factors such as TGF-β, soluble HLA-G, prostaglandin E2, adenosine, extracellular vesicles, and miRNAs, which can exhibit a dual function. On one hand, these factors can suppress NK cell-mediated activities but, on the other hand, they can induce a pro-angiogenic polarization in NK cells. Also, we will analyze the impact on cancer progression of the interaction of NK cells with several TME-associated cells, including macrophages, neutrophils, mast cells, cancer-associated fibroblasts, and endothelial cells. Then, we will discuss the most relevant therapeutic approaches aimed at potentiating/restoring NK cell activities against tumors. Finally, supported by the literature revision and our new findings on NK cell pro-angiogenic activities, we uphold NK cells to a key host cellular paradigm in controlling tumor progression and angiogenesis; thus, we should bear in mind NK cells like a TME-associated target for anti-tumor therapeutic approaches. View Full-Text
Keywords: NK cells; tumor microenvironment; angiogenesis; tumor therapy; targeting immunotherapy; chemotherapy NK cells; tumor microenvironment; angiogenesis; tumor therapy; targeting immunotherapy; chemotherapy
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Bassani, B.; Baci, D.; Gallazzi, M.; Poggi, A.; Bruno, A.; Mortara, L. Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects. Cancers 2019, 11, 461.

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