Merima Herac

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Expression of somatostatin receptor 2A in medullary thyroid carcinoma is associated with lymph node metastasis.

Medullary carcinoma (MTC) is an aggressive tumour that derives from the thyroid parafollicular calcitonin‐secreting cells (C cells). Lymph node metastasis may occur early in disease pathogenesis and is one of the most important negative prognostic parameters. Surgery is the only curative therapy while chemotherapeutic options are limited. Neuroendocrine differentiated C cells may express somatostatin receptors (SSTR), which have a wide range of biological actions including inhibitory effects on cell survival and angiogenesis and antiproliferative effects on cancer cell lines. Moreover, they are a potential target for various somatostatin analogues. Aim of this study was to analyse the protein expression of SSTR2A and 5 in MTCs with or without the presence of lymph node metastases in correlation with various clinicopathological parameters. This retrospective immunohistochemical analysis included 97 patients with medullary thyroid carcinomas. Protein expression was detected by immunohistochemistry for somatostatin receptors 2A and 5. Various clinicopathological parameters, such as Ki‐67 proliferation index or presence of desmoplasia, were included for statistical analysis. SSTR2A protein expression significantly correlated with the presence of lymph node metastases (p = 0.009), locally advanced MTCs staged according to the TNM (p < 0.001) and degree of desmoplasia (p = 0.029). Although SSTR5 protein expression significantly correlated with advanced stages of MTCs (p = 0.023) and degree of desmoplasia (p = 0.020), no correlation was found with the presence of lymph node metastases. Our results provide additional information concerning the aggressiveness of MTCs and reveal that a high SSTR2A and SSTR5 expression might be a poor prognostic feature.

AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M

Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with hepatic steatosis and its progression to steatohepatitis (NASH), fibrosis and cancer. We aimed to explore the role of AQP3 for HSC activation and unveil its potential interactions with PNPLA3. HSC were isolated from human liver, experiments were performed in primary HSC and human HSC line LX2. AQP3 was the only aquaglyceroporin present in HSC and its expression decreased during activation. The PPARγ agonist, rosiglitazone, recovered AQP3 expression also in PNPLA3 I148M carrying HSC. When PNPLA3 was silenced, AQP3 expression increased. In liver sections from patients with NASH, the decreased amount of AQP3 was proportional to the severity of fibrosis and presence of the PNPLA3 I148M variant. In PNPLA3 I148M cells, the blockade of JNK pathway upregulated AQP3 in synergism with PPARγ. In conclusion, we demonstrated profound reduction of AQP3 in HSC carrying the PNPLA3 I148M variant in parallel to decreased PPARγ activation, which could be rescued by rosiglitazone and blockade of JNK.

Erratum: STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Nature Communications 6: Article number:7736 (2015); Published: 22 July 2015; Updated: 26 October 2015 The affiliation details for Jan Pencik are incorrect in this Article. The correct affiliation details for this author are given below: Ludwig Boltzmann Institute for Cancer Research, Waehringerstrasse 13A, 1090 Vienna, Austria.

Biochemical and genetic predictors of overall survival in patients with metastatic pancreatic cancer treated with capecitabine and nab-paclitaxel.

Pancreatic cancer is a dismal disease with a mortality rate almost similar to its incidence rate. To date, there are neither validated predictive nor prognostic biomarkers for this lethal disease. Thus, the aim of the present study was to retrospectively investigate the capability of biochemical parameters and molecular profiles to predict survival of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who participated in a phase II clinical trial to test the safety and efficacy of the combination treatment of capecitabine plus nab-paclitaxel. Herein, we investigated the association of 18 biochemical parameters obtained from routine diagnosis and the clinical outcome of the 30 patients enrolled in the clinical trial. Furthermore, we analysed formalin-fixed paraffin-embedded (FFPE) tumour tissue to identify molecular biomarkers via RNA seq and the Illumina TruSeq Amplicon Cancer panel which covers 48 hotspot genes. Our analysis identified SERPINB7 as a novel transcript and a DNA mutation signature that might predict a poor outcome of disease. Moreover, we identified the bilirubin basal level as an independent predictive factor for overall survival in our study cohort.

Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma

Tumor-infiltrating immune cells are highly relevant for prognosis and identification of immunotherapy targets in hepatocellular carcinoma (HCC). The recently developed CIBERSORT method allows immune cell profiling by deconvolution of gene expression microarray data. By applying CIBERSORT, we assessed the relative proportions of immune cells in 41 healthy human livers, 305 HCC samples and 82 HCC adjacent tissues. The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. Mast cells were evaluated by immunohistochemistry in ten HCC patients. Activated mast cells, monocytes and plasma cells were decreased in HCC, while resting mast cells, total and naïve B cells, CD4+ memory resting and CD8+ T cells were increased when compared to healthy livers. Previously described S1, S2 and S3 molecular HCC subclasses demonstrated increased M1-polarized macrophages in the S3 subclass with good prognosis. Strong total immune cell infiltration into HCC correlated with total B cells, memory B cells, T follicular helper cells and M1 macrophages, whereas weak infiltration was linked to resting NK cells, neutrophils and resting mast cells. Immunohistochemical analysis of patient samples confirmed the reduced frequency of mast cells in human HCC tumor tissue as compared to tumor adjacent tissue. Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition of HCC patients.

SERPINB7 Expression Predicts Poor Pancreatic Cancer Survival Upon Gemcitabine Treatment

Stratification of patients with pancreatic ductal adenocarcinoma (PDAC) remains a key challenge in the field of clinical oncology. No predictive biomarkers have yet been found for any available treatment options. Previously, we identified SERPINB7 as a putative biomarker for PDAC and thus, herein, we aimed to validate our previous findings and assessed the predictive value of SERPINB7. Patients who underwent surgery and received gemcitabine (gem) or gemcitabine plus nab-paclitaxel (gem/nab) as adjuvant therapy, between 2011 and 2017, were included in this study (n = 57). Expression level of SERPINB7 was assessed in tumor tissue by immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH). Its association with disease-free survival (DFS) and overall survival (OS) was investigated. While IHC did not show any correlation between survival and the protein level of SERPINB7, RNA ISH revealed that expression of SERPINB7 was associated with a poor DFS (P = .01) and OS (P = .002) in the gem group but not in the gem/nab. Adjusted Cox-regression analysis confirmed the independent predictive value of SERPINB7 on OS (P = .006, HR: 3.47; 95% CI: 1.49–8.09) in the gem group. In conclusion, SERPINB7 was identified as the first predictive RNA biomarker for PDAC. This study suggests that patients who expressed SERPINB7 might receive another treatment than gem alone.

FISH Technique as Additional Diagnostic Tool in Differentiating Testicular Pulmonary Metastasis from Pulmonary Congenital Cystic Adenomatoid Malformation.

To the Editor: Testicular cancers are rare, making up a small percentage (1.1%) of all malignant tumors in men with an overall mortality rate of 0.4 per 100,000 (http:// eu-cancer.iarc.fr/EUCAN/CancerOne. aspx?Cancer=30&Gender=1). Germ cell tumors comprise >95% of all testicular malignancies. They are the most common malignancies and, are one of the most common causes of cancer-related death in males between 15 and 35 years. Typical sites of metastases include retroperitoneal, mediastinal, and supraclavicular lymph nodes. Pulmonary metastases are the most common site of visceral organ metastases. Liver, brain and bone metastases are less common.1 Although testicular mixed germ cell tumors are malignant, they are curable. Important factors for clinical outcome are serum tumor marker levels, tumor stage, presence/absence of vascular invasion, and correct histologic interpretation of tumor components.2–4 All these parameters should be taken into account for selecting the therapeutic management of a testicular germ cell tumor. A 44-year-old patient presented with a painless gradual enlargement of the right testis during a period of several months. Physical examination was normal except for a palpable mass in the right testis. Serum a-fetoprotein was 65.41 ng/mL (normal, 0 to 15 ng/mL), b-human chorionic gonadotropin was 8.97 ng/mL (normal, 0 ng/mL). Ultrasonography of the scrotum revealed a nonhomogeneous mass in the right testis with varying echogenicity. Subsequent radical inguinal orchiectomy was performed. Histopathology showed a mixed germ cell tumor composed of mature teratoma and embryonal carcinoma. A diagnosis of a pT2 mixed germ cell tumor of the testis with vascular invasion was made. The patient underwent 4 cycles of chemotherapy with Etoposide and Cisplatin within a period of 4 months. A follow-up computed tomography scan of the chest, 6 weeks after surgery, revealed a middle lobe nodular-cystic density of the right lung. Histopathology of this lesion suggested a diagnosis of a pulmonary congenital cystic adenomatoid malformation (CCAM), although a fully differentiated metastasis of germ cell origin could not be ruled out by histopathology alone. Primitive forms of testicular germ cell tumors such as seminoma and embryonal carcinoma respond well to chemotherapy, whereas mature teratoma is not chemosensitive.5 Lung metastases of mixed germ cell tumors often show a pattern of mature teratoma, especially after chemotherapy. Typical components of teratomatous metastases are cysts lined by gastrointestinal or squamous epithelium, foci of smooth muscles, lymphoid tissue, cartilage, and striated muscles. Some metastases can be mistaken for CCAM. By applying fluorescence in situ hybridization with TelVysion 12p Spectrum Green and CEP 12 Spectrum Orange (Vysis) on tissues taken from the lung lesion and the testicular tumor, we demonstrated the presence of polysomy 12, amplification of 12p, and isochromosome 12p in both the lesions. These are characteristic chromosomal aberrations found in testicular neoplasms.6

Abstract 3138: IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence

IL-6/Stat3 signaling plays a role as a proto-oncogene in various tumors including prostate cancer, where IL-6 has been explored as therapeutic target. Deficiency of Pten, one of the most commonly mutated genes in cancer, directly triggers a senescence program critically depending on the p19Arf-p53 fail-safe pathway. We identified a novel and unexpected tumor suppressive role of IL-6/Stat3 signaling in a Pten-deficient murine prostate cancer model. Our data provide evidence that activation of IL-6/Stat3 signaling axis is implicated in oncogene-induced senescence (OIS). Strikingly, genetic ablation of IL-6 strongly promoted prostate cancer initiation, progression and metastasis in Pten-deficient mice. Mechanistically, IL6/Stat3 signaling regulates p19Arf-p53-induced senescence by modulating expression of the ubiquitin ligase MDM2 in pre-neoplastic cells. Critically, in prostate cancer patients low expression of Stat3 or p14Arf, the human homologue of p19Arf, correlates with poor survival. Therefore, the IL-6/Stat3 signaling axis may represent a novel molecular target for senescence-based cancer therapies. Citation Format: Jan Pencik, Michaela Schlederer, Melanie Hassler, Wolfgang Gruber, Fritz Aberger, Richard Kennedy, Stephen Walker, Stephan Rose-John, Valeria Poli, Robert Eferl, Harald Esterbauer, Osman Aksoy, Merima Herac, Peter Mazal, Andrea Haitel, Martin Susani, Richard Moriggl, Zoran Culig, Lukas Kenner. IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2014-3138