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

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

doi:10.1096/fj.201701103r

Cited by 93 publications

(124 citation statements)

References 87 publications

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“…MMPs, the family of metal matrix enzymes function to digest collagen, which makes cancer cells move to other sites, and are often found upregulated during cancer progression . MMP9 primarily degrades collagen type IV, the main component of the basement membrane . MMP2 is associated with cancer invasion .…”

Section: Discussionmentioning

confidence: 99%

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Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

et al. 2019

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Background No effective treatment is currently available for poorly differentiated thyroid cancer which is resistant to radioiodine, especially with migration and invasion. A great number of researches have revealed the anticancer effects of salidroside, but none have studied the effects of salidroside on thyroid cancer. This study aimed to investigate the effect of salidroside on migration and invasion of poorly differentiated thyroid cancer cells. Methods The effects of salidroside on migration, invasion and apoptosis of poorly differentiated thyroid cancer WRO cells and normal thyroid follicular epithelial Nthy‐ori 3‐1 cells were measured by wound‐healing assay, transwell migration/invasion assay and flow cytometry, respectively. The expression levels of MMP2 and MMP9 at RNA and protein levels in WRO cells were detected by qRT‐PCR and western blot. The phosphorylation levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and the apoptosis‐related protein levels of Bax, cleaved caspase 3 and Bcl‐2 were assessed by western blot. Results Salidroside significantly suppressed migration/invasion and induced apoptosis in poorly differentiated thyroid cancer WRO cells. We further illustrated that salidroside significantly inhibited expressions of MMP2 and MMP9 at mRNA and protein levels and the phosphorylation activation of JAK2/STAT3 in WRO cells. In addition, salidroside increased expressions of pro‐apoptotic factors (Bax and cleaved caspase 3) and decreased expression of anti‐apoptotic factor (Bcl‐2) significantly in WRO cells. Conclusion The present study demonstrates that salidroside inhibits migration and invasion of WRO cells (a kind of poorly differentiated cancer cell line) significantly, which might be via suppressing JAK2‐STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…31 MMP9 primarily degrades collagen type IV, the main component of the basement membrane. 32 MMP2 is associated with cancer invasion. 17 Figure 2 indicates that intracellular expression of MMP2 and MMP9 at mRNA and protein levels was repressed by salidroside.…”

Section: Discussionmentioning

confidence: 99%

Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

et al. 2019

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“…Peripheral blood and tumor-infiltrated NK cells in cancer patients express the CD56 bright CD16 − CD49a + CD9 + phenotype (54,(58)(59)(60)(61), and they have compromised cytotoxicity (54,58,59,(61)(62)(63)(64). We have described a proangiogenic function in NK cells isolated from the peripheral blood and tumorinfiltrated cells of cancer patients (54,(58)(59)(60) and the expression of angiogenin, CXCR4/CXCL12, MMP2, MMP9, and tissue inhibitor for MMP (TIMP)-1 and TIMP-2 in NK cells from the peripheral blood and tumor-infiltrated cells of patients with colon cancer (59), which are molecules also secreted by dNK cells (55,(65)(66)(67). NK cells have been detected at low levels in the EC microenvironment (68); this study found significantly high levels of IL-1β and CXCL10 in the tumor, but low levels CXCL12, CCL27, and CCL21 as compared to the surrounding healthy tissue, and the NK cells in EC were compromised in cytotoxicity.…”

Section: Natural Killer Cellsmentioning

confidence: 99%

“…Another excellent example within the uterine environment is NK cells "tuning" into dNK, which represent a major source of angiogenic factors supporting placentation (52). On the other hand, EC TME reshapes NK-cell phenotype and function to promote tumor progression (68) and acquire a decidual-like and proangiogenic phenotype/function (53,59,146) in patients with various cancers.…”

Section: Pregnancy and Ec Shared Interplay Between The Immune And Angmentioning

confidence: 99%

Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal–Maternal Interface

Bruno¹,

Corrado

Baci

et al. 2020

Front. Oncol.

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The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal-fetal interface. The biological and immunological processes behind the maternal-fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal-fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal-fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific "immune clock" in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.

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“…We characterised also NK cells in the peripheral blood (tumour associated NK cells, pTA-NKs) and tissue infiltrate (tumour-infiltrating NK cells, TI-NKs) in colorectal cancer patients, these cell subsets also display pro-angiogenic feature as those in NSCLC patients [12]. NK cells in the peripheral blood, in particular the CD56 bright CD16 low/-, reflect the TI-NKs, and are present both in male and female cancer patients [11,12,24,25].…”

Section: Introductionmentioning

confidence: 96%

Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production, and secrete monocyte-recruiting and polarizing factors

Baci

Gallazzi

Mortara

et al. 2020

Preprint

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ABSTRACTBackgroundNatural killer (NK) cells are effector lymphocytes of the innate immunity. Two major NK cell subsets are mostly present in the peripheral blood (pNKs): the cytotoxic CD56dimCD16+ NK cell subset (90-95% of pNKs), and the low cytotoxic, highly cytokine-producing CD56brightCD16-/low NK cell subset (5-10% of pNKs). It has been demonstrated that NK cells in peripheral blood of patients with several tumors are altered. We have shown that in NSCLC and colon cancer, tumor associated circulating NK (pTA-NK) and tumor infiltrating NK (TI-NK) are skewed towards the CD56brightCD16-/low phenotype. We have detected the production of pro-inflammatory and pro-angiogenic cytokines and chemokines. Other groups are reporting similar observations. There is still a lack of knowledge concerning the phenotype of pNK cells in prostate cancer (PCa). Here, we phenotypically and functionally characterized peripheral blood NK (pNK) from PCa patients (PCa pTA-NKs) and investigated their production of soluble factors, with endothelial cells and macrophage stimulatory action.MethodsNK cell subset distribution was investigated in the peripheral blood of PCa patients, by multicolor flow cytometry (FC) for surface antigens expression. Protein arrays were performed to characterize the secretome on FACS-sorted pNK cells. Secreted products from FACS-sorted PCa TA-NKs were used to characterize their production of pro-inflammatory molecules. Secreted products from FACS-sorted PCa pTA-NKs were also used to stimulate endothelial cells and monocytes and macrophages, determining their ability to recruit and polarize them. Alterations of endothelial cells and monocytes, following exposure to secreted products from FACS-sorted PCa pTA-NKs, was assessed by RT-PCR. To confirm these observations, secreted products from 3 different PCa (PC-3, DU-145, LNCaP) cell lines were used to assess their effects on human NK cell polarization, by multicolor flow cytometry.ResultsCirculating NK cells from prostate cancer patients have been studied before, mostly for their impaired lytic functions. However, here we are the first to report that circulating pNK cells from PCa patients acquire a CD56brightCD9+CD49a+CXCR4+ phenotype with pro-inflammatory properties. We observed a similar polarization of heathy-donor derived pNK cells exposed to secreted products of three different PCa cell lines. Increased production of CXCL8, CXCR4, MMP-9, pro-inflammatory and reduced production of TNFα, IFNγ and Granzyme-B was detected. PCa TA-NKs released factors able to support angiogenesis in vitro and increased the expression of CXCL8, ICAM-1 and VCAM-1 mRNA in endothelial cells, confirming a pro-inflammatory signature. Secretome analysis revealed the ability of PCa pTA-NKs to release pro-angiogenic cytokines/chemokines involved in monocyte recruitment and M2-like polarization. In experimental setting, secreted products from PCa pTA-NKs can recruit THP-1 monocyte and polarize THP-1-differentiated macrophage towards CD206/Arginase1/IL-10/CXCL8-expressing M2-like/TAMs.ConclusionsOur results show that PCa pTA-NKs are effector cells able to produce pro-inflammatory angiogenesis factors able to stimulate endothelial cells, attract monocytes and polarize macrophage to an M2-like type. Our data provides a rationale for the possible use of pNK profiling in clinical studies on PCaGRAPHICAL ABSTRACTGraphical Abstract:Representative cartoon illustrating the pro-angiogenic features of PCa pTA-NKs.A) direct effects of PCa pTA-NKs in supporting angiogenesis by interacting with endothelial cells. B) Proposed model for PCa pTA-NK pro-angiogenic activities via macrophage recruitment and polarization.

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

Cited by 93 publications

References 87 publications

Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal–Maternal Interface

Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production, and secrete monocyte-recruiting and polarizing factors

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