Browsing by Subject "CARCINOGENESIS"

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  • Pussila, Marjaana; Sarantaus, Laura; Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi Mari-Anna; Peltomäki, Päivi T; Mutanen, Marja; Nyström, Minna (2013)
  • Siltanen, Sanna; Wahlfors, Tiina; Schindler, Martin; Saramaki, Outi R.; Mpindi, John Patrick; Latonen, Leena; Vessella, Robert L.; Tammela, Teuvo L. J.; Kallioniemi, Olli; Visakorpi, Tapio; Schleutker, Johanna (2011)
  • Kylmä, Anna Kaisa; Jouhi, Lauri; Mohamed, Hesham; Randen-Brady, Reija; Mäkitie, Antti; Atula, Timo; Haglund, Caj; Sorsa, Timo; Hagström, Jaana (2020)
    Objectives: In oropharyngeal squamous cell carcinoma (OPSCC), toll-like receptors (TLR) 5 and 7 associate with the tumor's human papilloma virus (HPV) status (Jouhi et al., 2017). TLR 2, on the other hand, has been linked to head and neck squamous cell carcinoma (HNSCC), and to oral carcinogenesis (Farnebo et al., 2015; Binder Gallimidi et al., 2015). Here we investigated the presence of TLR 2 and 4 in HPV-positive and HPV-negative OPSCC, and their relationship to opportunistic oral pathogen Treponema denticola chymotrypsin-like protease (Td-CTLP) immunoexpression, clinical parameters, and patient outcome. Materials and methods: Clinicopathological data of 198 unselected consecutive OPSCC patients came from hospital registries. Immunoexpression of TLRs 2 and 4 we evaluated by immunohistochemistry, and earlier in this patient series we studied immunoexpression of Td-CTLP and HPV DNA, HPV mRNA, and p16 status. Results: Immunoexpression of both TLRs 2 and 4 showed a significant association with HPV-status. Strong expression was associated with HPV-positivity and mild expression with HPV-negativity. Patients with strong TLR 2 immunoexpression in the HPV negative subgroup had significantly poorer 5-year DSS (58%) than did patients with mild TLR 2 expression (77%), and strong TLR 2 immunoexpression remained as an independent factor linked to increased disease mortality in the multivariable setting (P = 0.019). No association existed between TLR 2 or 4 and Td-CTLP expression. Conclusion: Our results support the role of TLR 2 receptor as a possible target for development of therapeutics as earlier proposed (Farnebo et al., 2015). The involvement of Td and other oral pathogens in carcinogenesis of OPSCC, remains open and calls for further study.
  • Kauppi, Juha; Räsänen, Jari; Sihvo, Eero; Nieminen, Urpo; Arkkila, Perttu; Ahotupa, Markku; Salo, Jarmo (2016)
    OBJECTIVES: Oxidative stress (OS) is an essential element in the pathogenesis of Barrett's esophagus (BE) and its transformation to adenocarcinoma (EAC). The state of OS in the proximal stomach of patients with BE and EAC is unknown. Isoprostanes are a specific marker of OS not previously used to determine OS from BE/EAC tissue samples. PATIENTS AND METHODS: OS was measured in 42 patients with BE (n = 9), EAC (n = 9), or both (n = 24) and 15 control patients. A STAT-8-Isoprostane EIA Kit served to identify 8-Isoprostanes (8-IP), and a Glutathione Assay Kit was used to measure glutathione reduced form(GSH) and glutathione oxidized form. An OxiSelect Oxidative DNA Damage ELISA Kit (8-OHdG) served to measure 8-OH-deoxyguanosine. RESULTS: The 8-IP (P = .039) and 8-OHdG (P = .008) levels were higher, and the GSH level lower (P = .031), in the proximal stomach of the study group than in that of the controls. Helicobacter pylori infection was present in 8% of the study patients. CONCLUSIONS: In the proximal stomach of BE and EAC patients, OS was elevated and antioxidative capacity was reduced. This finding suggests that the gastroesophageal reflux causing BE also induces oxidative stress in the proximal stomach and may contribute to the development of cancer in the proximal stomach and gastric cardia.
  • Hyvärinen, I.; Hukkinen, M.; Kivisaari, R.; Parviainen, H.; Nordin, A.; Pakarinen, M. P. (2019)
    Aim: The incidence of pancreaticobiliary maljunction is thought to approximate 1:100,000 within Western populations. We aimed to study the significance of pancreaticobiliary maljunction in biliary tract malignancies. Methods: Medical records and magnetic resonance cholangiopancreatography images of 252 consecutive patients treated for biliary malignancies during 2005-2016 were reviewed. Patients with other known risk factors for biliary cancers (n = 27) were excluded. A common pancreaticobiliary channel measuring > 10 mm outside the duodenal wall was defined as pancreaticobiliary maljunction. Main Results: Of the 225 patients, a reliably interpretable preoperative magnetic resonance cholangiopancreatography was available for 73 (32%). Sex (47% vs 57% females) and age at diagnosis (67 vs 66 years) were similar among patients with or without an magnetic resonance cholangiopancreatography (p = ns for both). In magnetic resonance cholangiopancreatography, a pancreaticobiliary maljunction with a median length of 20 mm (range 10-23 mm) was identified in four patients (5.5%, 95% confidence interval 1.6-14), while none had evident accompanying biliary tree dilatation. Pancreaticobiliary maljunction patients were significantly more often females (100% vs 43%, p = 0.043), less likely to have intrahepatic bile duct cancer (0% vs 65%, p = 0.019) while more likely to have gallbladder cancer (75% vs 22%, p = 0.044) compared to the others. Age at diagnosis (66 vs 67 years, p = 0.898), extrahepatic bile duct cancer incidence (25% vs 13%, p = 0.453), and survival status at last follow-up (50% vs 42% alive, p = 1.000) were comparable between the subgroups. Conclusion: The prevalence of pancreaticobiliary maljunction is substantially higher in adults with biliary malignancies than one would expect based on its incidence, reinforcing the etiologic role of pancreaticobiliary maljunction especially in females with gallbladder cancer.
  • Soovares, Piret; Pasanen, Annukka; Butzow, Ralf; Lassus, Heini (2017)
    Objective. Our aim was to study the expression of L1CAM in endometrioid and clear cell ovarian carcinomas and to evaluate its correlation with clinical parameters and patient prognosis. Methods. Tissue microarray-based immunohistochemical analysis of L1CAM expression was performed in 249 endometrioid and 140 clear cell ovarian carcinomas. Concurrent endometrial carcinoma was found in 57 of these patients. Results. L1CAM expression was found in 15% of endometrioid and 23% of clear cell ovarian carcinomas. L1CAM expression was strongly associated with poor disease-specific overall survival and poor disease-free survival in endometrioid (p <0.0001, p = 0.0005), but not in clear cell ovarian carcinomas. Significant association of L1CAM expression with poor overall survival was observed in grade 1-2 carcinomas (p <0.0001), but not in grade 3 tumors. In endometrioid ovarian carcinomas, L1CAM expression was associated with aggressive tumor characteristics, such as higher grade and stage, and incomplete response to primary therapy. However, L1CAM expression was not an independent prognostic factor for overall or disease-free survival. Of the 57 patients with concurrent endometrial carcinoma L1CAM positivity was found in 4 cases both in the ovarian and endometrial tumors, and in 3 cases only in the endometrial tumor. All these seven patients with L1CAM positive tumors had poor outcome. Conclusions. L1CAM expression could serve as a biomarker for predicting clinical outcome and response to therapy in patients with endometrioid ovarian carcinoma, but not in clear cell carcinomas. L1CAM positivity also predicts poor outcome in patients with concurrent endometrioid ovarian and endometrial carcinomas. (C) 2017 Elsevier Inc. All rights reserved.
  • Abdel-Rahman, Wael Mohamed; Nieminen, Taina Tuulikki; Shoman, Soheir; Eissa, Saad; Peltomaki, Paivi (2014)
  • Hintsala, Hanna-Riikka; Jokinen, Elina; Haapasaari, Kirsi-Maria; Moza, Monica; Ristimaki, Ari; Soini, Ylermi; Koivunen, Jussi; Karihtala, Peeter (2016)
    Background/Aim: Increased expression and prognostic significance of major redox regulator nuclear factor erythroid-2-related factor (Nrf2) is recognized in many cancers. Our aim was to investigate the role of oxidative stress markers in melanoma. Materials and Methods: We characterized the immunohistochemical expression of Nrf2, kelch-like ECH-associated protein 1 (Keap1), BRAF(V600E), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine in 36 nevi, 14 lentigo maligna and 71 malignant melanomas. We measured Nrf2 expression in melanoma cell lines and conducted cytotoxicity assays combining BRAF/NRAS ablation and H2O2 treatment. Results: Nuclear Nrf2 expression in melanoma correlated with deeper Breslow (p
  • Nair, Vidhya A.; Valo, Satu; Peltomäki, Päivi; Bajbouj, Khuloud; Abdel-Rahman, Wael M. (2020)
    There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4-b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015-0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPK alpha 1, FAK, p53, GSK-3 alpha/beta, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis.
  • Bruserud, Oyvind; Costea, Danieta-Elena; Laakso, Saila; Garty, Ben-Zion; Mathisen, Eirik; Mäkitie, Antti; Mäkitie, Outi; Husebye, Eystein S. (2018)
    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Autoimmune polyendocrine syndrome type-1 (APS-1) (APECED, OMIM 240300) is a rare, childhood onset, monogenic disease caused by mutations in the Autoimmune Regulator (AIRE) gene. The overall mortality is increased compared to the general population and a major cause of death includes malignant diseases, especially oral and esophageal cancers. We here present a case series of four APS-1 patients with oral tongue cancers, an entity not described in detail previously. Scrutiny of history and clinical phenotypes indicate that chronic mucocutaneous candidiasis and smoking are significant risk factors. Preventive measures and early diagnosis are important to successfully manage this potentially fatal disease.
  • Acheva, Anna; Haghdoost, Siamak; Sollazzo, Alice; Launonen, Virpi; Kämäräinen, Meerit (2019)
    The aim of the study was to investigate the role of a microenvironment in the induction of epithelial-to-mesenchymal transition (EMT) as a sign of early stages of carcinogenesis in human lung epithelial cell lines after protracted low-dose rate gamma-radiation exposures. BEAS-2B and HBEC-3KT lung cell lines were irradiated with low-dose rate gamma-rays (Cs-137, 1.4 or 14 mGy/h) to 0.1 or 1 Gy with or without adding TGF-beta. TGF-beta-treated samples were applied as positive EMT controls and tested in parallel to find out if the radiation has a potentiating effect on the EMT induction. To evaluate the effect of the stromal component, the epithelial cells were irradiated in cocultures with stromal MRC-9 lung fibroblasts. On day 3 post treatment, the EMT markers: alpha-SMA, vimentin, fibronectin, and E-cadherin, were analyzed. The oxidative stress levels were evaluated by 8-oxo-dG analysis in both epithelial and fibroblast cells. The protracted exposure to low Linear Energy Transfer (LET) radiation at the total absorbed dose of 1 Gy was able to induce changes suggestive of EMT. The results show that the presence of the stromal component and its signaling (TGF-beta) in the cocultures enhances the EMT. Radiation had a minor cumulative effect on the TGF-beta-induced EMT with both doses. The oxidative stress levels were higher than the background in both epithelial and stromal cells post chronic irradiation (0.1 and 1 Gy); as for the BEAS-2B cell line, the increase was statistically significant. We suggest that the induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure and the presence of stromal component might enhance the effect through free radical production and accumulation.
  • Kylmä, Anna Kaisa; Jouhi, Lauri; Listyarifah, Dyah; Mohamed, Hesham; Mäkitie, Antti; Remes, Satu Maria; Haglund, Caj; Atula, Timo; Nieminen, Mikko T.; Sorsa, Timo; Hagström, Jaana (2018)
    BACKGROUND: An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome. METHODS: Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series. RESULTS: We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged. CONCLUSIONS: Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.