Interleukin 11 is upregulated in uterine lavage and endometrial cancer cells in women with endometrial carcinoma
© Yap et al; licensee BioMed Central Ltd. 2010
Received: 12 April 2010
Accepted: 17 June 2010
Published: 17 June 2010
Interleukin (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.
IL11 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.
IL11 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.
The 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.
Endometrial cancer is the most common gynaecological malignancy . Since it typically affects postmenopausal women, a significantly increased risk occurs in women from age 40 and thus endometrial cancer is increasingly frequent in many advanced countries . The invasion of endometrial cancer cells through the myometrium and their migration to the nearby lymph nodes are key factors related to its poor prognosis . Despite a relatively high incidence of uterine cancer, particularly in postmenopausal women, a suitable screening test is not available . Additionally, despite advances in the treatment of endometrial cancer, the increasing death rate associated with the disease is increasing demonstrating new treatments are required . Endometrial cancer or adenocarcinoma (type 1), which accounts for about 90% of endometrial cancers, begins in the glandular epithelial cells of the endometrium. Factors that influence endometrial epithelial cell function and are upregulated early in the disease may therefore prove to be critical potential diagnostic and therapeutic targets.
Interleukin (IL) 11 belongs to the IL6 family of cytokines and signals via a heterodimeric complex of IL11 receptor (R) α and gp130. The cellular responses of IL11 are induced by the activation of downstream Janus kinases (JAK) that phosphorylate the latent cytoplasmic transcription factors, signal transducer and activator of transcription (STAT) . Phosphorylated (p) or activated STAT proteins translocate to the nucleus to modulate gene transcription . Cytokine signalling is tightly regulated by a variety of mechanisms . The inducible suppressor of cytokine signalling (SOCS) proteins, a family with 8 members (SOCS1-SOCS7 and CIS), are expressed in response to cytokine stimulation of STAT phosphorylation acting in a negative feedback mechanism to hinder the activities of cytokine receptors [8, 9]. IL11 signals via pSTAT3 in human endometrial epithelial cells [10, 11] and stimulates SOCS3 in human endometrial cells . IL11 is expressed by endometrial glandular epithelium in women during the menstrual cycle . A recent study had identified that IL11 and IL11Rα are expressed in endometrial cancer , although there are no studies comparing the levels of IL11 protein in endometrial cancer and postmenopausal women in whom the vast majority of endometrial cancers develop. It is also not knownswhether IL11 downstream signalling is active in endometrial cancer, which would suggest a role for IL11 in carcinogenesis.
Numerous studies have suggested that IL11 has roles in human gastric, prostate and bone cancer [14–17]. 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 . We recently showed that IL11 regulates human endometrial epithelial cell adhesion and the migration and invasion of human trophoblast cells [10, 21, 22]. It has also been suggested that factors present in uterine lavage fluid correlate with the presence of endometrial cancer .
In the current study, we determined the levels of IL11 in uterine lavage in women with endometrial cancer and postmenopausal controls. We compared IL11, IL11Rα, pSTAT3 and SOCS3 protein in human endometrial carcinomas of varying histologic grades with endometrium from postmenopausal and cycling women. We determined the effect of IL11 on its downstream signaling molecules in endometrial cancer and non-cancer endometrial epithelial cells.
Patients and tissues
Clinical characteristics of the patients used in this study
Features of patients
For immunohistochemistry studies: There were 16 cancer patients, with an age range of 34-88 years (mean age = 64.4 years with standard deviation = 14.1) (Table 1), while the postmenopausal women had an age range of 51-60 years with a mean age of 54.4 years and a standard deviation of 4.0. Normal cycling women were aged between (29-41). All four of the postmenopausal women had "active" endometrium. Five or six biopsies were collected from each histologic Grades 1, 2 and 3 carcinomas. All patients were diagnosed with endometrioid adenocarcinoma tumors. Myometrial invasion was present in 85.7% of patients; of these, 66.7% had invasion to less than 50% of the myometrium, and 33.3% had invasion to 50% or more of the myometrium (Table 1). The presence of vascular/lymphatic invasion, as assessed by tumor histopathology, was apparent in 56% of patients (data not shown).
Uterine lavage were collected from a subgroup of the women with endometrial carcinoma (Grade 1 N = 4, Grade 2 N = 5, Grade 3 N = 6; mean age = 69.3 years with standard deviation = 12.9) and postmenopausal controls (N = 4, mean age = 73.7 and a standard deviation of 11.1).
IL11 in uterine fluid
Uterine lavages (uterine washings) were collected from postmenopausal women (N = 4) and women with endometrial cancer above except for women with Grade 1 carcinoma where washings were collected from 4 women instead of 5 women (Grade 1-3 (N = 4; 5; 6 respectively) as previously described . Uterine fluid from all women was concentrated 3-4 fold using Nanosep microconcentration devices with a 3 K cut-off (Pall Life Sciences, East Hills, NY). IL11 was then measured in the samples by ELISA as previously described .
IL-11 and IL-11Rα immunohistochemistry
Immunohistochemistry for IL11 and IL11Rα was performed as described previously  using a monoclonal anti-huIL-11 (5E3) and antihuIL-11Rα (4D12) antibodies (generous gifts from Dr. Lorraine Robb). Briefly, paraffin sections (5 μm) were dewaxed in histosol and rehydrated in a graded series of ethanol. Endogenous peroxidase activity was quenched by immersion in 3% H2O2 in methanol for 10 min. Non-specific staining was blocked using a blocking solution of 10% normal horse serum (Sigma-Aldrich Inc., Missouri, USA) and 2% normal human serum, diluted in 1× Tris-buffered saline (TBS) for 30 min. Primary antibodies were diluted to 4 μg/ml in blocking solution and applied for 18 h at 4°C. A non-immune isotype IgG negative control (R&D Systems Inc., Minneapolis, MN, USA) diluted to a matching concentration as the primary antibody, was also included for each tissue. Antibody localisation was detected by sequential application of biotinylated horse anti-mouse IgG (Vector Laboratories, Burlingame, CA, USA) diluted 1:200 in blocking solution for 30 min and an avidin-biotin complex conjugated to HRP (Vectastain ABC Elite kit; Vector Laboratories, Burlingame, CA, USA). The substrate used was diaminobenzidine (DAB) (Zymed, San Francisco, USA) forming an insoluble brown precipitate. Sections were then counterstained in Harris hematoxylin (Sigma Diagnostics, St. Louis, USA). Sections from normal endometrium were used as positive controls and included in each immunostaining run to provide quality control.
pSTAT3 and SOCS3 immunohistochemistry
Immunohistochemistry for pSTAT3 and SOCS3 was conducted using polyclonal rabbit anti-mouse (Cell Signalling Technology Inc., MA, USA) and monoclonal rabbit anti-human (Clone C204) (Immuno-Biological Laboratories Inc., MN, USA) antibodies respectively as previously shown , at final concentration of 0.09 μg/ml and 1 μg/ml respectively.
Formalin fixed sections were deparaffinized in histosol and rehydrated in a graded series of ethanol. Endogenous activity was blocked by incubation in 3% H2O2 in methanol for 10 min. Non-specific staining was blocked using blocking solutions consisting of 10% normal swine serum (in-house) and 2% normal human serum for pSTAT3 and 10% normal goat serum (Vector Laboratories) and 2% normal human serum for SOCS3, each diluted in 1×TBS for 30 min. Primary antibodies were diluted in the appropriate blocking solution and applied for 18 h at 4°C. A non-immune isotype IgG negative control (R&D Systems) diluted to a matching concentration as the primary antibody, was also included for each tissue. Antibody localisation was detected by sequential application of biotinylated swine anti rabbit IgG (DAKO, Glostrup, Denmark) or biotinylated goat anti-rabbit IgG (Vector Laboratories) diluted 1:200 in blocking solution correspondingly for 30 min and an avidin-biotin complex conjugated to HRP (Vectastain ABC Elite kit, Vector Laboratories). The substrate used was diaminobenzidine (DAB) (Zymed), which forms an insoluble brown precipitate. Sections were then counterstained in Harris hematoxylin (Sigma Diagnostics). Sections from normal pre-menopausal endometrium were used as positive controls and included in each immunostaining run to provide quality control.
Endometrial epithelial cancer and non-cancer cell lines
The endometrial carcinoma cells ECC-1, HEC-1A and Ishikawa cells were cultured in DMEM/F12 (1:1), McCoy's 5A and DMEM (Invitrogen, Victoria, Australia) respectively supplemented with 10% fetal calf serum (SAFC Biosciences, Victoria, Australia), 1% L-glutamine (Sigma-Aldrich Pty. Ltd) and 1% antibiotic-antimycotic (Invitrogen, Victoria, Australia). The non-cancer human endometrial epithelial (HES) cell line  was obtained from Dr. Douglas Kniss (Ohio State University, Columbus, OH). Cells were maintained in RPMI 1640 (Sigma-Aldrich Pty. Ltd) supplemented with 10% FCS, 1% L-glutamine and 1% antibiotic- antimycotic. Confluent cells were transferred into serum free medium for 24 hours prior to treatment
IL11 regulation of pSTAT3 and SOCS3 in human endometrial cancer cell lines
The endometrial cancer cell lines ECC-1, HEC-1A and Ishikawa and or HES cells were treated with diluents control, IL11 (1, 10, 100, 500 ng/ml) for 15 minutes or 4 hours. Phosphorylated STAT3 and total STAT3 abundance (15 min) and SOCS3 protein abundance (4 hours; treatment time was determined from previous studies in endometrial cells) were analysed by Western blot as previously described  and briefly as follows. Cells were grown to confluence, the medium aspirated and cells washed with ice-cold sterile PBS, twice on ice. Cells were lysed and scraped in ice-cold lysis buffer containing 50 mM Tris Base, 150 mM NaCl, 2 mM EDTA, 2 mM EGTA, 25 mM NaF, 25 mM β-glycerolphosphate, pH 7.5 and 2 μl/well protease inhibitors cocktail set III (AEBSF, HCl 100 mM, aprotinin 80 μM, bestatin 5 μM, E-64 1.5 mM, leupeptin hemisulfate 2 mM, pepstatin A 1 mM (Calbiochem, San Diego, CA, USA). Cell extracts were then centrifuged at 12000 rpm for 30 min at 4°C, and supernatant protein quantified using the BCA protein assay kit (Pierce, Rockford, IL, USA). Equal amounts of total protein were then resolved on SDS-PAGE gels and transferred to nitrocellulose membranes. All membranes were incubated with Ponceau S (Sigma) to ensure equal protein loading in all lanes. The membranes were blocked with 5% nonfat dry milk in Tris-buffered saline with 0.1% Tween (TBST) and probed separately with antibodies specific for phosphorylated STAT3 (Tyr705, Cell Signaling Technology Inc.) (1:1000), total STAT3 (Cell Signaling Technology), (1:1000) or SOCS3 (IBL Co. LTD, Gunma, Japan). The membranes were washed in TBST then incubated for 1 h with horseradish peroxidase (HRP)-conjugated rabbit secondary antibody (Dako Cytomation, Glostrup, Denmark) (1:1500). Finally, the HRP activity was detected using enhanced chemilluminescence reagent (Pierce, Rockford, IL, USA). To determine the specificity of IL-11 in the cells a specific IL11 antagonist was used (provided by Commonwealth serum Laboratories, Melbourne, Australia) .
All in vitro cell culture experiments were performed in two independent experiments in duplicate.
Semiquantitative analysis of immunostaining and statistical analysis
Positive staining was scored semiquantitatively by two independent observers, blind to the identity of the tissue, with an intensity score assigned as 0 (negative) to 3 (maximal staining intensity). All statistical analyses were performed using GraphPad Prism. Data was analysed by the non-parametric Kruskal-Wallis test followed by the Dunn's post-hoc test. Differences were considered significant at P < 0.05.
IL11 is upregulated in uterine fluid of women with endometrial cancer
Immunolocalisation of IL11 and its specific receptor, IL11Rα in endometrial cancer and endometrium from post-menopausal women
IL11 staining was also present in vascular endothelial and smooth muscle cells in Grade 3 tumours (Fig 3D-E). Similarly, positive staining for IL11Rα was seen in vascular smooth muscle and endothelial cells in Grade 3 tumours but not in Grades 1 and 2 (Fig 4D). No staining for IL11 and IL11Rα was seen in vascular endothelial and smooth muscle cells in postmenopausal endometrium or proliferative phase endometrium (data not shown). Intense staining for IL11 was seen in subpopulations of leukocytes infiltrating the cancer glands in four of the six Grade 3 tumours (Fig 3E). Secretory phase endometrium served as positive controls for IL11 and IL11Rα and demonstrated positive IL11 and IL11Rα staining in glandular epithelium as previously reported (Fig 3G and Fig 4F) . No immunostaining was detected in the IL11 and IL11Rα negative controls (Fig 3H and 4G).
Immunolocalisation of pSTAT3 and SOCS3 in endometrial cancer tissue and endometrium from post-menopausal women
IL11 regulation of pSTAT3 and SOCS3 in human endometrial cancer cell lines
Overall, all the human endometrial cancer cell lines (ECC-1: 5 pg/106 cells, HEC-1A: 3 pg/106 cells, Ishikawa cells: 6 pg/106 cells) and the endometrial epithelial cell line HES, secreted very low levels of IL11 under serum free conditions. The cells were subsequently cultured in serum free conditions to examine the effect of IL11 on pSTAT3/STAT3 and SOCS3 protein abundance.
This study was the first to show that IL11 protein was increased in uterine fluid and endometrial tumour epithelial cells in women with Grade 1 endometrial carcinoma compared to postmenopausal women. It further demonstrated that IL11's main endometrial signalling molecules, pSTAT3 and SOCS3, were produced by endometrial cancer cells. IL11 was shown to signal via pSTAT3 and SOCS3 in human endometrial cancer cell lines.
Endometrial glandular epithelial products are primarily secreted apically into the uterine lumen therefore we investigated the levels of IL11 in uterine flushings. In agreement with our study, a previous study has suggested that factors present in uterine washings may confirm the presence of endometrial cancer . IL11 levels in uterine washings were very high (10-100 fold) in a cohort of women with Grade 3 cancers compared to the other tumour grades and controls. As endometrial cancer progresses, the epithelial cancer cells lose their polarity. Our study suggests that non-polarised endometrial cancer epithelial cells may also secrete products into the uterine lumen. It is also possible that IL11 may be secreted by the cancer associated leukocytes into the uterine lumen in the Grade 3 tumours thereby contributing to the IL11 levels found in the lavage fluid.
Previous studies have shown that in cycling endometrium, IL11 and IL11Rα predominantly localise to human endometrial glandular epithelium and decidualized human endometrial stromal cells [12, 28]. Endometrial IL11 protein production alters with cyclical variation; in the glandular epithelium it is low in the proliferative phase of the menstrual cycle and increases in the mid-late secretory phase . However, since endometrial cancer affects predominantly post-menopausal women, we compared the levels of IL11, IL11Rα, pSTAT3 and SOCS3 in endometrial cancer tissue to endometrial tissue from post-menopausal.
In agreement with our study, IL11 localised predominantly to cancer epithelial cells in a recent report . IL11 mRNA was reported to be higher in endometrial cancer tissue compared to endometrial tissue from proliferative phase tissue, while differences in the level of IL11 protein between the groups was not reported . Our data demonstrated that IL11 protein was significantly elevated specifically in endometrial epithelial tumor cells early in the Grade 1 tumours compared to postmenopausal controls reflecting the data in uterine washings. This suggests that IL11 levels in uterine washings may be useful as an endometrial cancer marker.
IL11Rα protein was upregulated in endometrial epithelial tumour cells compared to endometrial epithelium from postmenopausal women. Strong staining for both IL11 and IL11Rα was identified in tumour vascular endothelial and smooth muscle cells as recently reported .
IL11 localised to leukocytes only in the advanced Grade 3 tumours and not in control postmenopausal endometrium. Numerous studies report that tumour associated macrophages promote angiogenesis and correlate with poor prognosis . In endometrial cancer, tumour associated macrophages are associated with vascular space invasion and myometrial invasion . It is likely that factors produced by tumour associated leukocytes contribute to tumourigenesis.
In agreement with the present study, IL11 is significantly upregulated in several non-endometrial cancers. IL11 and IL11Rα transcript levels are linked to breast cancer prognosis - breast tumours with a poor prognostic index show a high level of IL11 . Similarly, IL11 and IL11Rα protein are highly expressed in human colorectal adenocarcinoma and IL11Rα levels correlate with clinicopathological factors . IL11 is also increased in gastric cancer . Overall, these studies indicate that IL11 may play a role in tumour formation.
Tumour development and progression depends on cell adherence to extracellular matrix, proliferation, migration and invasion of tumour cells followed by their metastasis into other tissues and on escaping immune detection and destruction. Our previous studies show that IL11 increases the adhesion of human endometrial epithelial cells to various extracellular matrix molecules and to human trophoblast, at least in part by regulating adhesion molecule mRNA expression and protein production . Endometrial extracellular matrix molecules appear to be targets of IL11 actions in mouse implantation sites . IL11 also regulates the migration and invasion of human trophoblast, a process that is highly regulated but nevertheless has many similarities with tumour cell invasion [21, 22]. Furthermore, IL11 and IL11Rα expression correlate with invasion and proliferation in human gastric and colorectal tumours [34, 35].
It remains to be determined whether IL11 similarly regulates tumour cell adhesion, migration and invasion in endometrial cancers. Angiogenesis is also a key determinant of tumour formation  and hence the localization of IL11 and IL11Rα to vascular smooth muscle and endothelial cells in the present study suggest a potential role in angiogenesis. In the stomach, IL11 increases angiogenesis accelerating ulcer healing in mice .
IL11Rα protein is a proposed candidate target for both human osteosarcoma and also bone metastasis . Furthermore IL11 alters the expression of proliferative and cytoprotective genes and promotes pre-tumorigenic cellular changes in mice in vivo suggesting that IL11 is involved early in tumourigenesis . pSTAT3 staining intensity tended to be higher in the tumour epithelial cells compared to endometrium from postmenopausal women although it did not reach significance likely due to the large variability in staining intensity within the control group of women. By contrast, pSTAT3 intensity was higher in Grade 1 and 2 tumours compared to endometrial glandular epithelium from proliferative phase tissue. This suggests that caution must be used when comparing endometrial cancer proteins with proliferative phase endometrium.
Overall, SOCS3 imunostaining intensity was low in epithelium from postmenopausal women and all tissues from the cancer patients. There was higher SOCS3 staining in endometrial glandular epithelium from proliferative phase endometrium compared to all other groups. This suggests that SOCS3 has different functions in cycling endometrium compared to endometrium from postmenopausal women and endometrial cancer.
IL11 increases pSTAT3 and SOCS3 protein in differentiating human endometrial stromal cells . STAT3 which is phosphorylated by numerous cytokines, growth factors and oncogenetic proteins, is constitutively phosphorylated in many human cancer tissues and cell lines . STAT3 target genes are implicated in multiple steps of tumour metastasis including cell invasion, survival, renewal and angiogenesis and thus pSTAT3 can be regarded as a pivotal regulator of tumour metastasis . It was of interest in the present study to investigate whether specifically IL11 regulated pSTAT3 and SOCS3 in cancer cells as both have been shown to be involved in numerous tumours. The intense staining identified for pSTAT3 in endometrial cancer associated epithelium and stroma, suggests a role in both stromal and epithelial compartments for pSTAT3 in endometrial tumour formation. IL11 is predominantly restricted to cancer epithelium and not cancer associated stromal fibroblasts, suggesting that in the cancer stroma, factors other than IL11 regulate pSTAT3. Whether IL11 alone activates STAT3 phosphorylation in endometrial cancer cells remains to be elucidated.
Several studies have shown that SOCS proteins including SOCS3 are expressed in tumours including head and neck cancer [39, 40], gastric carcinoma , chronic myeloid leukemia , melanoma  and prostate cancer [44, 45]. SOCS3 is upregulated in prostate cancer and inhibits the induction of apoptosis by cAMP .
In the present study SOCS3 staining intensity was absent or very minimal in tumour epithelial cells in the Grade 3 cancer specimens perhaps similarly indicating a reduced sensitivity to SOCS3 in endometrial cancers although this remains to be determined. 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 . Our in vitro studies identified that IL11 (from 1 ng/ml) stimulated SOCS3 protein abundance in non-carcinoma HES cells. By contrast IL11 weakly stimulated SOCS3 protein at 100 ng/ml in the carcinoma HEC-1A and Ishikawa cells possibly suggesting reduced sensitivity in endometrial cancer cells. The mechanisms by which this may occur are unknown. The consequences of this reduced sensitivity could be that IL11 signalling is unregulated in endometrial cancer cells. This however this remains to be determined and the functional significance remains to be elucidated.
Our study suggests that IL11 in uterine washings may be useful as an early marker of endometrial cancer. It is also the first study to demonstrate that IL11 protein is upregulated in Grade 1 endometrial cancers compared to postmenopausal endometrial epithelium and suggests that IL11 signalling is active in endometrial cancer cells. The present study suggests that IL11, along with its specific receptor and downstream signalling molecules pSTAT3 and SOCS3, are likely to play a complex role in the progression of endometrial carcinoma. Functional studies are required to elucidate the role of IL11 in tumourigenesis and determine its potential as a prognostic marker and therapeutic target for endometrial cancer. Large scale studies are required to determine whether IL11 in uterine washings may be useful as a diagnostic marker for endometrial cancer.
We thank Dr. Lorraine Robb for providing the IL11 and IL11Rα antibodies. Funding: JY, PKN, ED NHMRC# 550905, 550911; LAS NHMRC# 494802, 388901.
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