The time-dependent prognostic value of intratumoral cytokine expression profiles in a natural course of primary breast cancer with a long-term follow-up

Todorović‐Raković, Nataša; Radulović, Marko; Vujasinović, Tijana; Milovanović, Jelena; Nikolić‐Vukosavljević, Dragica

doi:10.1016/j.cyto.2017.11.020

Cited by 5 publications

(4 citation statements)

References 48 publications

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“…TQ significantly inhibited caspase-1 expression in PBMCs of HR+ and TNBC ( Figure 8 A), which came in accordance with distinct in vivo and in vitro studies [ 101 , 103 , 104 ]. In BC, high levels of IL-1β showed various tumor-promoting impacts [ 144 , 145 , 146 ]. Peripheral blood cells of invasive BC patients produced high levels of IL-1β, leading to metastasis [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients

Elgohary,

Eissa,

El Tayebi

2023

IJMS

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Breast cancer (BC) is not only a mass of malignant cells but also a systemic inflammatory disease. BC pro-tumorigenic inflammation has been shown to promote immune evasion and provoke BC progression. The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated when pattern recognition receptors (PRRs) sense danger signals such as calreticulin (CALR) from damaged/dying cells, leading to the secretion of interleukin-1β (IL-1β). CALR is a novel BC biological marker, and its high levels are associated with advanced tumors. NLRP3 expression is strongly correlated with an elevated proliferative index Ki67, BC progression, metastasis, and recurrence in patients with hormone receptor-positive (HR+) and triple-negative BC (TNBC). Tumor-associated macrophages (TAMs) secrete high levels of IL-1β promoting endocrine resistance in HR+ BC. Recently, an immunosuppressive soluble form of programmed death ligand 1 (sPD-L1) has been identified as a novel prognostic biomarker in triple-negative breast cancer (TNBC) patients. Interestingly, IL-1β induces sPD-L1 release. BC Patients with elevated IL-1β and sPD-L1 levels show significantly short progression-free survival. For the first time, this study aims to investigate the inhibitory impact of thymoquinone (TQ) on CALR, the NLRP3 pathway and sPD-L1 in HR+ and TNBC. Blood samples were collected from 45 patients with BC. The effect of differing TQ concentrations for different durations on the expression of CALR, NLRP3 complex components and IL-1β as well as the protein levels of sPD-L1 and IL-1β were investigated in the peripheral blood mononuclear cells (PBMCs) and TAMs of TNBC and HR+ BC patients, respectively. The findings showed that TQ significantly downregulated the expression of CALR, NLRP3 components and IL-1β together with the protein levels of secreted IL-1β and sPD-L1. The current findings demonstrated novel immunomodulatory effects of TQ, highlighting its potential role not only as an excellent adjuvant but also as a possible immunotherapeutic agent in HR+ and TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients

Elgohary,

Eissa,

El Tayebi

2023

IJMS

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“…Interestingly, various chemotherapeutics led to secretion of danger signals(96) that are reported to be activators of in ammasome pathway (97). In BC, In ammasome pathway showed various tumor promoting effects (36-38, 98) such as enhanced invasiveness in radiotherapy resistant BC cells (98), immune system dysfunction (37), BC growth, angiogenesis(36) and migration (38).The downstream IL-1β itself enhanced BC proliferation (42) metastasis (43), invasion (44) as well as chemotherapy resistance (45,46). NLRP3 required two signals for activation; the rst one was the priming step that required the transcription of NLRP3 components and Pro-IL-1β via NF-κB (99,100) while the second signal was through various danger signals that led to oligomerization of in ammasome components and formation of NLRP3 active complex then nally secretion of IL-1β (99-101).…”

Section: Discussionmentioning

confidence: 99%

“…In BC, high levels of IL-1β showed various tumor promoting impacts (42)(43)(44) and contributed to decrease of the Estrogen receptor (ERα) and chemo-resistance via epigenetic modi cation (47). Remarkably, IL-1β is not only secreted via in ammasome pathway (125).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo and in vitro studies showed that NLRP3 activation enhanced tumor growth, modulated apoptosis and enhanced cell cycle progression in BC (41). The high levels of the downstream IL-1β enhanced BC proliferation (42), metastasis (43) and invasion (44). Moreover, IL-1β contributed to cisplatin (45) and Doxorubicin resistance in BC cells (46).…”

Section: Introductionmentioning

confidence: 99%

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Suppressive effect of Thymoquinone on NLRP3 pathway in breast cancer: a novel multi-strike CALR and sec-PD-L1 inhibitor

Elgohary

Eissa²,

Tayebi

2022

Preprint

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Inflammasome is activated when pattern recognition receptor (PRR) senses danger signals such as Calreticulin (CALR) from damaged\dying cells leading to secretion of Interleukin-1β (IL-1β). High levels of CALR mediated invasive breast cancer (BC) phenotype. The NOD-like receptor (NLR) family Pyrin domain-containing protein3 (NLRP3) inflammasome showed various tumor promoting effects in BC. Interestingly, IL-1β led to endocrine resistance in Estrogen receptor positive (ER+) BC patients and enhanced production of matrix metalloproteinases (MMP), which provoked cleavage and secretion of programmed death ligand-1 (PD-L1) from surface of tumor cells. Recently, studies reported that high levels of secreted PD-L1 (sec-PD-L1) were associated with poor prognosis in triple negative breast cancer (TNBC). The current study searched for a natural product that can target sec-PD-L1 and NLRP3 pathway in TNBC and hormone receptor positive (HR+) subtypes. Thymoquinone (TQ); a natural phytochemical derived from Nigella Sativa seeds was an excellent candidate since it inhibited NLRP3 inflammasome in human and mouse melanoma. Blood samples were collected from forty-five BC patients, comprising TNBC and HR + BC subtypes. The present study investigated the impact of different TQ concentrations for distinct durations on expression of CALR, NLRP3 complex components and IL-1β as well as the protein levels of sec-PD-L1 and IL-1β in peripheral blood mononuclear cells (PBMCs) and Tumor associated macrophages (TAMs), respectively. The current findings showed that TQ significantly downregulated expression of CALR, NLRP3 components and IL-1β together with protein levels of secreted IL-1β and sec-PD-L1. Thus, collectively TQ is a novel multi-strike inhibitor highlighting its potential roles as an excellent adjuvant and a promising immunotherapeutic agent in HR + and TNBC patients.

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The role of cytokines in the evolution of cancer: IFN-γ paradigm

Todorović‐Raković

2022

Cytokine

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The time-dependent prognostic value of intratumoral cytokine expression profiles in a natural course of primary breast cancer with a long-term follow-up

Cited by 5 publications

References 48 publications

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients

Thymoquinone, a Novel Multi-Strike Inhibitor of Pro-Tumorigenic Breast Cancer (BC) Markers: CALR, NLRP3 Pathway and sPD-L1 in PBMCs of HR+ and TNBC Patients

Suppressive effect of Thymoquinone on NLRP3 pathway in breast cancer: a novel multi-strike CALR and sec-PD-L1 inhibitor

The role of cytokines in the evolution of cancer: IFN-γ paradigm

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