Reduced inducibility of SOCS3 by interferon gamma associates with higher resistance of human breast cancer lines as compared to normal mammary epithelial cells

Součková, Kamila; Kovařı́k, Aleš; Dušek, Ladislav; Humpolikova-Adamkova, L; Lauerová, L; Krejčí, Eva; Matoušková, Eva; Buršíková, Eva; Fojtová, Miloslava; Kovařík, J

doi:10.4149/neo_2009_05_379

Cited by 3 publications

(3 citation statements)

References 32 publications

(33 reference statements)

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“…In normal breast epithelial cells SOCS3 is induced, while in several breast cancer cell lines SOCS3 is weakly activated. In breast tumour cells, it has been postulated that the IFNγ induced anti-proliferative effects are reduced due to a lower sensitivity to SOCS3 induction [19]. Our in vitro studies identified that IL11 (from 1 ng/ml) stimulated SOCS3 protein abundance in non-carcinoma HES cells.…”

Section: Discussionmentioning

confidence: 54%

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Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

Yap¹,

Salamonsen²,

Jobling

et al. 2010

Reprod Biol Endocrinol

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BackgroundInterleukin (IL) 11 is produced by human endometrium and endometrial cancer tissue. It has roles in endometrial epithelial cell adhesion and trophoblast cell invasion, two important processes in cancer progression. This study aimed to determine the levels of IL11 in uterine lavage fluid in women with endometrial cancer and postmenopausal women. It further aimed to determine the levels of IL11 protein and its signaling molecules in human endometrial cancer of varying grades, and endometrium from postmenopausal women and IL11 signalling mechanisms in endometrial cancer cell lines.MethodsIL11 levels in uterine lavage were measured by ELISA. IL11, IL11 receptor(R) α, phosphorylated (p) STAT3 and SOCS3 were examined by immunohistochemistry in endometrial carcinomas and in control endometrium from postmenopausal women and normal cycling women. The effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance in endometrial cancer cell lines and non-cancer endometrial epithelial cells was determined by Western blot.ResultsIL11 was present in uterine flushings and was significantly higher in women with Grade 1 carcinomas compared to postmenopausal women (p < 0.05). IL11 immunostaining was significantly elevated in the endometrial tumour epithelial cells from Grade 1 and 3 compared to endometrial epithelium from postmenopausal and cycling women. IL11Rα immunostaining intensity was increased in cancer epithelium in the Grades 1 and 2 tumours compared to epithelium from postmenopausal women. Both IL11 and IL11Rα localized to vascular endothelial and smooth muscle cells while IL11 also localized to subsets of leucocytes in the cancer tissues. pSTAT3 was found in both the tumour epithelial and stromal compartments but was maximal in the tumour epithelial cells, while SOCS3 was predominantly found in the tumour epithelial cells. pSTAT3 staining intensity was significantly higher in Grade 1 and 2 tumour epithelial cells compared to epithelial cells from cycling and postmenopausal women. SOCS3 staining intensity did not differ between between each tumour and postmenopausal endometrial epithelium but SOCS3 in cycling endometrium was significantly higher compared to postmonopausal and Tumour Grades 2 and 3. IL11 increased pSTAT3/STAT3 in all tumour cell lines, while SOCS3 abundance was increased only in one tumour cell line.ConclusionsThe present study suggests that IL11 in uterine washings may be useful as a diagnostic marker for early stage endometrial cancer. It indicates that IL11, along with its specific receptor, IL11Rα, and downstream signalling molecules, STAT3 and SOCS3, are likely to play a role in the progression of endometrial carcinoma. The precise role of IL11 in endometrial cancer remains to be elucidated.

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Section: Discussionmentioning

confidence: 54%

“…In addition critical roles for pSTAT3 and SOCS3 in cancer have also been proposed [8,18,19]. Tumor cell survival depends on the cells' ability to adhere to, migrate and invade through the tissue and to metastasize into other organs and tissues [20].…”

Section: Introductionmentioning

confidence: 99%

Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

Yap¹,

Salamonsen²,

Jobling

et al. 2010

Reprod Biol Endocrinol

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show abstract

“…Human IFNγ‐secreting MDA‐MB‐231 tumour cell lines (MDA‐hIFNγ) were constructed, with MDA‐m cells as a control. MDA‐MB‐231 cells were IFNγ‐resistant ; thus, the action of local hIFNγ on HUVECs could be analysed in vivo . MDA‐hIFNγ (or MDA‐m) with HUVEC‐Dll4 (or HUVEC‐m) cells were co‐injected into SCID mice, with MDA‐m as a control.…”

Section: Resultsmentioning

confidence: 99%

IFNγ‐responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down‐regulation of Dll4

Deng

Liu

Rong

et al. 2014

The Journal of Pathology

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Although IFNγ is regarded as a key cytokine in angiostatic response, our poor understanding of its effective cellular target drastically limits its clinical trials against angiogenesis-related disorders. Here, we investigated the effect of IFNγ on endothelial cells (ECs) and possible molecular mechanisms in angiostasis. By employing Tie2(IFNγR) mice, in which IFNγR expression was reconstituted under the control of Tie2 promoter in IFNγR-deficient mice, we found that the response of ECs to IFNγ was highly effective in inhibiting blood supply and retarding tumour growth. Interestingly, the expression of IFNγR on Tie2(-) cells did not inhibit, but promoted tumour growth in control wild-type mice. Mechanism studies showed that IFNγ reacting on ECs down-regulated the delta-like ligand 4 (Dll4)/Notch signalling pathway. Accordingly, overexpression of Dll4 in human ECs diminished the effect of IFNγ on ECs. This study demonstrates that the action of IFNγ on ECs, but not other cells, is highly effective for tumour angiostasis, which involves down-regulating Dll4. It provides insights for EC-targeted angiostatic therapy in treating angiogenesis-associated disorders in the clinic.

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The untold story of IFN-γ in cancer biology

Kursunel

Esendağlı

2016

Cytokine & Growth Factor Reviews

151

103

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Reduced inducibility of SOCS3 by interferon gamma associates with higher resistance of human breast cancer lines as compared to normal mammary epithelial cells

Cited by 3 publications

References 32 publications

Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma

IFNγ‐responsiveness of endothelial cells leads to efficient angiostasis in tumours involving down‐regulation of Dll4

The untold story of IFN-γ in cancer biology

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