Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma

Milosavljević, Mirjana; Jovanović, Ivan; Pejnović, Nada; Mitrović, Slobodanka; Arsenijević, Nebojša; Marković, Bojana; Lukic, Miodrag L.

doi:10.18632/oncotarget.7635

Cited by 29 publications

(22 citation statements)

References 48 publications

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“…The size of primary 4T1 mammary tumors was assessed morphometrically using electronic calipers in two dimensions. Using a below formula the tumor volumes (mm 3 ) were calculated [ 56 ]: tumor volume (mm 3 )=L (major axis of the tumor) x W(minor axis) 2 /2.…”

Section: Methodsmentioning

confidence: 99%

The organic esterO,O’-diethyl-(S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate dihydrochloride attenuates murine breast cancer growth and metastasis

et al. 2018

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Pharmacological treatment of cancer is mostly limited by drug-toxicity and resistance. It has been noticed that new organic ester ligand, O,O’-diethyl-(S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate dihydrochloride (named DE-EDCP) showed effective cytotoxic capacities against several human and mouse cancer cell lines. However, its effects on tumor growth and metastasis are unexplored. The aim of present study was to examine the ability of DE-EDCP to inhibit 4T1 murine breast cancer growth and progression and to explore possible molecular mechanisms. DE-EDCP exhibited significant tumoricidal activity on human and murine breast cancer cell lines. Further, marked reduction of murine breast cancer growth and progression by DE-EDCP was shown. DE-EDCP exhibits fewer side-effects compared to cisplatin as a conventional chemotherapeutic. Results obtained from in vivo and in vitro experiments indicate that DE-EDCP induces apoptosis and inhibits proliferation of 4T1 cells. DE-EDCP increases percentage of 4T1 cells in late apoptosis, expression of pro-apoptotic Bax and caspase-3, while decreases expression of anti-apoptotic Bcl-2. DE-EDCP treatment increased the percentage of TUNEL-positive nuclei and reduced Ki-67 expression in breast cancer tissue. DE-EDCP decreased expression of cyclin D3 and Ki-67, increased expression of cyclin-dependent kinase inhibitors p16, p21 and p27 and arrested 4T1 cells in G0/G1 cell cycle phase. Expression of STAT3 and downstream regulated molecules, NANOG and SOX2, was reduced in 4T1 cells after DE-EDCP treatment.In conclusion, DE-EDCP impairs breast cancer growth and progression by triggering cancer cell death and inhibition of cancer cell proliferation. DE-EDCP might be of interest in the development of the new anticancer agent.

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Section: Methodsmentioning

confidence: 99%

The organic esterO,O’-diethyl-(S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate dihydrochloride attenuates murine breast cancer growth and metastasis

et al. 2018

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“…Studies in ST2 −/− Balb/c mice provided evidence that IL-33/ST2 signaling plays an important role in tumor angiogenesis and necrosis [ 56 ]. Orthotopically implanted 4T1 breast cancer cells showed a significant reduction in vascular endothelial growth factor (VEGF) and IL-33 expression as compared to tumors in wild type mice.…”

Section: The Role Of Il33/st2 In Tumorigenesismentioning

confidence: 99%

“…Consistent with these observations, patient tumors with no necrosis expressed higher levels of IL-33, ST2, and VEGF as compared to necrotic tumors. However, increased microvascular density (MVD) in necrotic tumors positively correlated only with VEGF but not with IL-33 and ST2 expression [ 56 ]. Recently, Kim et al [ 57 ] proposed a novel intracellular mechanism by which IL-33 might induce cell proliferation in breast tumor cells based on studies showing that administration of IL-33 increased the phosphorylation of Cancer Osaka Thyroid (COT) protein via a dose- and time-dependent interaction between ST2 and COT.…”

Section: The Role Of Il33/st2 In Tumorigenesismentioning

confidence: 99%

The Role of IL-33/ST2 Pathway in Tumorigenesis

Larsen

Minaya

Vaish

et al. 2018

IJMS

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Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that also acts as a nuclear factor. IL-33 typically resides in the nucleus of the cells where it is expressed. However, upon tissue damage, necrosis, or injury, it is quickly released into extracellular space where it binds to its cognate receptor suppression of tumorigenicity 2 (ST2)L found on the membrane of target cells to potently activate a T Helper 2 (Th2) immune response, thus, it is classified as an alarmin. While its role in immunity and immune-related disorders has been extensively studied, its role in tumorigenesis is only beginning to be elucidated and has revealed opposing roles in tumor development. The IL-33/ST2 axis is emerging as a potent modulator of the TME. By recruiting a cohort of immune cells, it can remodel the TME to promote malignancy or impose tumor regression. Here, we review its multiple functions in various cancers to better understand its potential as a therapeutic target to block tumor progression or as adjuvant therapy to enhance the efficacy of anticancer immunotherapies.

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“…The impact of IL-33 on the TME encompasses angiogenesis, matrix remodeling and cytokine/growth factor production by non-epithelial cell components. The IL-33/ST2 signaling pathway, favoring pro-angiogenic VEGF expression in tumor cells and reducing tumor necrosis, is highly involved in mammary tumor growth ( 77 ). Concerning matrix modeling, human subepithelial myofibroblasts stimulated in vitro with IL-33 induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression ( 78 ).…”

Section: Il-33 As a Pro-tumorigenic Cytokine Through Actions On Cancementioning

confidence: 99%

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

Fournié

Poupot

2018

Front. Immunol.

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Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 immune responses through the activation of T helper 2 (TH2) cells and mast cells, IL-33 is now also known as an effective stimulator of TH1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying TH1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution.

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Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma

Cited by 29 publications

References 48 publications

The organic esterO,O’-diethyl-(S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate dihydrochloride attenuates murine breast cancer growth and metastasis

The organic esterO,O’-diethyl-(S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate dihydrochloride attenuates murine breast cancer growth and metastasis

The Role of IL-33/ST2 Pathway in Tumorigenesis

The Pro-tumorigenic IL-33 Involved in Antitumor Immunity: A Yin and Yang Cytokine

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