The association of Wnt-signalling and EMT markers with clinical characteristics in women with endometrial cancer.

Endometrial cancer is the most common gynecologic malignancy in the developed world. Risk stratification and treatment approaches are changing due to better understanding of tumor biology. Upregulated Wnt signaling plays an important role in cancer initiation and progression with promising potential for development of specific Wnt inhibitor therapy. One of the ways in which Wnt signaling contributes to progression of cancer, is by activating epithelial-to-mesenchymal transition (EMT) in tumor cells, causing the expression of mesenchymal markers, and enabling tumor cells to dissociate and migrate. This study analyzed the expression of Wnt signaling and EMT markers in endometrial cancer. Wnt signaling and EMT markers were significantly correlated with hormone receptors status in EC, but not with other clinico-pathological characteristics. Expression of Wnt antagonist, Dkk1 was significantly different between the ESGO-ESTRO-ESP patient risk assessment categories using integrated molecular risk assessment.

The Co-Expression of Estrogen Receptors ERα, ERß, and GPER in Endometrial Cancer.

Estrogens have important roles in endometrial cancer (EC) and exert biological effects through the classical estrogen receptors (ERs) ERα and ERß, and the G-protein-coupled ER, GPER. So far, the co-expression of these three types of ERs has not been studied in EC. We investigated ERα, ERß, GPER mRNA and protein levels, and their intracellular protein distributions in EC tissue and in adjacent control endometrial tissue. Compared to control endometrial tissue, immunoreactivity for ERα in EC tissue was weaker for nuclei with minor, but unchanged, cytoplasmic staining; mRNA and protein levels showed decreased patterns for ERα in EC tissue. For ERß, across both tissue types, the immunoreactivity was unchanged for nuclei and cytoplasm, although EC tissues again showed lower mRNA and protein levels compared to adjacent control endometrial tissue. The immunoreactivity of GPER as well as mRNA levels of GPER were unchanged across cancer and control endometrial tissues, while protein levels were lower in EC tissue. Statistically significant correlations of estrogen receptor α (ESR1) versus estrogen receptor ß (ESR2) and GPER variant 3,4 versus ESR1 and ESR2 was seen at the mRNA level. At the protein level studied with Western blotting, there was significant correlation of ERα versus GPER, and ERß versus GPER. While in clinical practice the expression of ERα is routinely tested in EC tissue, ERß and GPER need to be further studied to examine their potential as prognostic markers, provided that specific and validated antibodies are available.

Tissue Integration of Calcium Phosphate Compound after Subchondroplasty: 4-Year Follow-Up in a 76-Year-Old Female Patient.

Subchondroplasty is a new minimally invasive surgical technique developed to treat bone marrow lesions (BML) and early osteoarthritis (OA). During the procedure, engineered calcium phosphate compound (CPC) is injected. It is claimed by the manufacturer that during the healing process, the CPC is replaced with new bone. The purpose of this study was to verify the replacement of CPC with new bone after subchondroplasty for the first time in humans. A 76-year old woman was referred for resistant medial knee pain. Standing radiographs showed varus knee OA and magnetic resonance imaging (MRI) revealed BML. She was treated with subchondroplasty of medial femoral condyle. Excellent relief of pain was achieved after procedure. Afterwards, the pain worsened, the radiographs confirmed the OA progression and the patient was treated with a total knee arthroplasty (TKA) 4 years after primary procedure. The resected bone was examined histologically and with micro-computed tomography (CT). Histologically, bone trabeculae of subcortical bone were embedded in the amorphous mass. However, no signs of CPC resorption and/or bone replacement have been found with micro-CT. In short term, excellent pain relief could be expected after the subchondroplasty procedure. However, there was no replacement of CPC with bone and the technique probably did not influence the natural process of knee OA.

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer.

Although aldo-keto reductases (AKRs) have been widely studied in cancer, no study to date has examined the roles of AKR family 1 members B1 (AKR1B1) and B10 (AKR1B10) in a large group of ovarian cancer patients. AKR1B1 and AKR1B10 play a significant role in inflammation and the metabolism of different chemotherapeutics as well as cell differentiation, proliferation, and apoptosis. Due to these functions, we examined the potential of AKR1B1 and AKR1B10 as tissue biomarkers. We assessed the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 99 patients with high-grade serous ovarian cancer (HGSC) and compared these levels with clinicopathological characteristics, survival, and response to chemotherapy. A higher immunohistochemical AKR1B1 expression correlated with a better overall and disease-free survival of HGSC patients whereas AKR1B10 expression did not show any significant differences. A multivariant Cox analysis demonstrated that a high AKR1B1 expression was an important prognostic factor for both overall and disease-free survival. However, AKR1B1 and AKR1B10 were not associated with different responses to chemotherapy. Our data suggest that AKR1B1 is involved in the pathogenesis of HGSC and is a potential prognostic biomarker for this cancer.

AKR1B1 and AKR1B10 as Prognostic Biomarkers of Endometrioid Endometrial Carcinomas.

The roles of aldo-keto reductase family 1 member B1 (AKR1B1) and B10 (AKR1B10) in the pathogenesis of many cancers have been widely reported but only briefly studied in endometrial cancer. To clarify the potential of AKR1B1 and AKR1B10 as tissue biomarkers of endometrial cancer, we evaluated the immunohistochemical levels of AKR1B1 and AKR1B10 in tissue paraffin sections from 101 well-characterized patients with endometrioid endometrial cancer and 12 patients with serous endometrial cancer and compared them with the clinicopathological data. Significantly higher immunohistochemical levels of AKR1B1 and AKR1B10 were found in adjacent non-neoplastic endometrial tissue compared to endometrioid endometrial cancer. A trend for better survival was observed in patients with higher immunohistochemical AKR1B1 and AKR1B10 levels. However, no statistically significant differences in overall survival or disease-free survival were observed when AKR1B1 or AKR1B10 were examined individually in endometrioid endometrial cancer. However, analysis of AKR1B1 and AKR1B10 together revealed significantly better overall and disease-free survival in patients with both AKR1B1 and AKR1B10 staining above the median values compared to all other patients. Multivariant Cox analysis identified strong AKR1B1 and AKR1B10 staining as a statistically important survival prediction factor. Conversely, no significant differences were found in serous endometrial cancer. Our results suggest that AKR1B1 and AKR1B10 play protective roles in endometrioid endometrial cancer and show potential as prognostic biomarkers.

AKR1C3 Is Associated with Better Survival of Patients with Endometrial Carcinomas.

The aldo-keto reductase (AKR) superfamily is gaining attention in cancer research. AKRs are involved in important biochemical processes and have crucial roles in carcinogenesis and chemoresistance. The enzyme AKR1C3 has many functions, which include production of prostaglandins, androgens and estrogens, and metabolism of different chemotherapeutics; AKR1C3 is thus implicated in the pathophysiology of different cancers. Endometrial and ovarian cancers represent the majority of gynecological malignancies in developed countries. Personalized treatments for these cancers depend on identification of prognostic and predictive biomarkers that allow stratification of patients. In this study, we evaluated the immunohistochemical (IHC) staining of AKR1C3 in 123 paraffin-embedded samples of endometrial cancer and 99 samples of ovarian cancer, and examined possible correlations between expression of AKR1C3 and other clinicopathological data. The IHC expression of AKR1C3 was higher in endometrial cancer compared to ovarian cancer. In endometrioid endometrial carcinoma, high AKR1C3 IHC expression correlated with better overall survival (hazard ratio, 0.19; 95% confidence interval, 0.06-0.65, p = 0.008) and with disease-free survival (hazard ratio, 0.328; 95% confidence interval, 0.12-0.88, p = 0.027). In patients with ovarian cancer, there was no correlation between AKR1C3 IHC expression and overall and disease-free survival or response to chemotherapy. These results demonstrate that AKR1C3 is a potential prognostic biomarker for endometrioid endometrial cancer.

Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review).

The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments. On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target. The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately. Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2. Most of these influence cell proliferative activity. Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis. The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.

A synergistic interaction of 17-ß-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts.

The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-ß-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37°C, 5% CO2). In their 5th passage, HOB were exposed to different concentrations of i) 17-ß-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-ß-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-ß-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-ß-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-ß-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-ß-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.