The role of IL-33/ST2 signaling pathway in development of breast carcinoma necrosis

[M. Z. Milosavljević]

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Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signalni put promoviše rast tumora i razvoj metastaza inhibicijom antitumorskog imunskog odgovora. IL-33 je protein sa anti- i proinflamatornom ulogom koji funkcioniše kao transkripcioni faktor i klasičan citokin sa ulogom alarmina. Nekrotične ćelije sekretuju imunoregulatorne citokina uključujući IL-33 koji je član IL-1 familije citokina. Prethodne studije sugerišu da IL-33 promoviše ekspresiju i oslobađanje vaskularnog endotelnog faktora rasta (VEGF) u mastocitima i ukazuju na njegovu proangiogenu ulogu aktivacijom endotelnih ćelija preko IL-33R. Međutim, značaj aktivacije IL-33/IL-33R signalnog puta u angiogenezi i tumorskoj nekrozi nije u potpunosti jasna. Cilj naše studije je bio da se ispita uloga signalnog puta IL-33/IL-33R u tumorskoj nekrozi i angiogenezi karcinoma dojke. Delecija gena za IL-33R u BALB/c miševa pojačava tumorsku nekrozu u isporava rast tumora u eksperimentalnom modelu 4T1 karcinoma dojke što je povezano sa smanjenom ekspresijom vaskularnog endotelnog faktora rasta i IL-33 u ćelijama tumora dojke. Ekspresija IL-33 u ćelijama karcinoma dojke raste tokom vremena u IL-33R+/+ ali ne i u IL-33R-/-. Rezultat ukazuje na mehanizam pozitivne povratne sprege IL-33/IL-33R osovine. Analizirali smo ekspresije IL-33. IL-33R, i VEGF.a, kao i mikrovaskularnu gustinu (MVD) u tumorima 40 pacijenkinja sa karcinomom dojke sa prisutnom ili odsutnom nekrozom u tkivu tumora. Detektovali smo značajno veću ekspresiju IL-33. IL-33R i VEGF-a u tkivu karcinoma dojke bez detektabilne nekroze. Ekspresije IL-33 i IL-33R koreliraju sa ekspresijom VEGF-a u tumorskim ćelijama. Takođe, ekspresija VEGF je bila u pozitivnoj korelaciji sa MVD u perinekrotičnom rubu tumora. IL-33 poput IL-1β pokauje proangiogenu ulogu i kontroliše produkciju VEGF-a. IL-1β pojačava ekspresiju VEGF-a i njegovih receptora na endotelnim ćelijama a zajedno sa VEGF-om promoviše tumorsku angiogenezu. Kao i IL-1, IL-33 aktivira IL-1R3 (IL-1RAcP) ukazujuć da inhibicija ovog protein primenom anti-IL-1R3 antitela inhibira angiogenezu tumora i pojačava tumorsku nekrozu u tkivu carcinoma dojke usled gubitka vaskularne podpore. Na osnovu ovih rezultata smatramo da IL-33 oslobođen iz nekrotičnih ćelija facilitira ekspresiju VEGF-a u okolnim tumorskim ćelijama promovišući angiogenezu što je potvrđeno većom MVD u perinekrotičnoj zoni humanog carcinoma dojke. Naši rezultati ukazuju da IL-33/IL-33R signalni put igra važnu ulogu u rastu tumora pojačavanjem ekspresije proangiogenog VEGF-a i inhibicijom tumorske nekroze. U dodatku na ranija istraživanja, naši rezultati ukazuju na suprotnu ulogu intracelularnog i sekretovanog IL-33. Naša studija pokazuje dodatni mehanizam kojim IL-33/IL-33R osovina učestvuje u karcinogenezi i daje racionalno objašnjenje za potencijalnu blokadu IL-33 kao terapijskog modaliteta u lečenju humanog karcinoma dojke.

Interleukin-33 (IL-33)/IL-33 receptor (IL-33R, IL-RL1, ST2) signaling pathway promotes mammary cancer growth and metastasis by inhibiting anti-tumor immunity. IL-33 is dual function protein with roles as a nuclear factor and a classical cytokine and functions as a prototypic „alarmin”. Necrotic cells release immunoregulatory cytokines, including IL-33, a member of the IL-1 family of cytokines. Previous studies suggest that IL-33 directly facilitated vascular endothelial growth factor (VEGF) expression and secretion in primed mast and showed proangiogenic role of IL-33 by inducing endothelial proangiogenic activity via IL-33R expressed on endothelial cells.However, the role of IL-33/IL-33R axis in neoangiogenesis and tumor necrosis is not elucidated. Therefore, the aim of this study was to investigate the role of IL-33/IL-33R axis in mammary tumor necrosis and angiogenesis. Deletion of IL-33R gene in BALB/c mice enhanced tumor necrosis and attenuated tumor growth in 4T1 breast cancer model, which was associated with markedly decreased expression of VEGF and IL-33 in mammary tumor cells. IL-33 expression in mammary tumor cells significantly increased over time in IL-33R+ /+ mice, but not in IL-33R-/- mice the findings that reflect positive feedback mechanism in IL-33/IL-33R axis We next analyzed IL-33, IL-33R and VEGF expression and microvascular density (MVD) in breast tumors from 40 female patients with absent or present tumor necrosis. We found significantly higher expression of IL-33, IL-33R and VEGF in breast cancer tissues with absent tumor necrosis. Both, IL-33 and IL-33R expression correlated with VEGF expression in tumor cells. Further, VEGF expression positively correlated with MVD in perinecrotic zone. IL-33 is very much like IL-1 in that both IL-1β and IL-33 are proangiogenic and control the production of VEGF. IL-1β increases expression of VEGF and its receptors on endothelial cells and acts together with VEGF in promoting tumor mediated angiogenesis. Thus, the neutralization of IL-1β reduced tumor growth and the tumor-induced angiogenesis. As IL-1 and IL- 33 both use IL-1R3 (IL-1RAcP), it may be speculated that anti-IL-1R3 antibodies may reduce angiogenesis and increase tumor necrosis in breast cancer due to loss of vascular supply. On the basis of these observations we suggest that IL-33 released by necrotic cells may facilitate VEGF expression on nearby tumor cells, which could lead to enhanced angiogenesis as demonstrated by high-grade MVD in perinecrotic zone in human breast cancer tissue. Taking together, our data indicate that IL-33/IL-33R pathway is critically involved in mammary tumor growth by facilitating expression of pro-angiogenic VEGF in tumor cells and attenuating tumor necrosis. Additionally, results indicate oposite functions of intracellular and secreted IL-33. Thus, this study revealed an additional mechanism by which IL-33/IL-33R pathway may be involved in tumorigenesis and provide rationale for blocking IL-33 as a therapeutic modality in human breast carcinoma.

IL-33, IL-33R, karcinom dojke, neoangiogeneza, nekroza

IL-33, IL-33R, breast neoplasm, neoangiogenesis, necrosis

616.18-006(043.3)

Dojka - Karcinom

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