CIP2An rooli syövän synnyssä

Worldwide and notably in the developed countries, cancer is an increasing cause of morbidity and mortality, being the second most common cause of death after ischemic heart disease. Now and in the future new cancer cases need to be diagnosed earlier. Prognostic factors may be helpful in recognizing and handling those patients who need more aggressive therapy, and it is also desirable to predict treatment response accurately. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein predominantly expressed in malignant tissues and inhibiting protein phosphatase 2A (PP2A) activity; it is a promising target for cancer therapy. The aim of this thesis was to evaluate the prognostic role of CIP2A in solid cancers, and for this purpose to explore expression of CIP2A, and investigating regulation of CIP2A in order to gain insight into signalling pathways leading to alteration in prognosis. Patients diagnosed with gastric, serous ovarian, tongue, or colorectal cancer at Helsinki University Central Hospital were included. Tumour tissue microarrays assembled from specimens from these patients were prepared and stained immunohistochemically for CIP2A protein expression. Associations with clinicopathologic parameters and other biomarkers were explored, and survival analyses were done according to the Kaplan-Meier method. Study of the role of CIP2A in intracellular signalling in vitro involved gastric, ovarian, and tongue cancer cell lines. We found CIP2A to be highly expressed in gastric, ovarian, tongue, and colorectal cancer specimens. CIP2A was associated with clinicopathologic parameters characterizing an aggressive disease, namely advanced stage, high grade, p53 immunopositivity, and high proliferation index. CIP2A led to recognition of gastric, ovarian, and tongue cancer patients with poor prognosis, however, with a cancer type-specific cut-off level for prognostic significance. In tongue cancer, it served as an independent prognostic marker. In contrast, in colorectal cancer, CIP2A provided no prognostic value. In cancer cell lines, CIP2A was highly expressed at both protein and mRNA levels, and promoted cell proliferation and anchorage-independent growth. In gastric cancer, we demonstrated with a MYCER construct in mouse embryo fibroblasts that activation of MYC led to increased CIP2A mRNA expression, and hence we suggested that a positive feedback mechanism between CIP2A and MYC may potentiate and prolong the oncogenic activity of these proteins. We demonstrated in ovarian cancer an association between CIP2A and EGFR protein overexpression and EGFR gene amplification. In ovarian and tongue cancer cells we showed that depletion of EGFR downregulates CIP2A expression. In conclusion, high CIP2A expression occurred frequently among patients with aggressive disease. CIP2A may serve as a prognostic marker in gastric, ovarian, and tongue cancer and thus may help in tailoring therapy for cancer patients. The positive feedback mechanism between CIP2A and MYC, as well as the positive regulation of CIP2A by EGFR, are a few signalling pathways regulating and regulated by CIP2A. These and other mechanisms need to be studied further, however. CIP2A is a potential target for therapy, and its potential role as predictive marker and as a tumour marker in serum requires exploration.Högt uttryck av onkoproteinet cancerous inhibitor of protein phosphatase 2A (CIP2A) i tumörvävnad ses ofta hos cancerpatienter som har en aggressiv form av cancer. CIP2A kan förutspå en sämre prognos i magcancer, tungcancer och äggstockscancer och det kan därför möjligtvis vara till nytta för att skräddarsy behandlingen för dessa patienter. I undersökningen identifierades en positiv feedback-mekanism mellan CIP2A och onkoproteinet MYC som är känt för att stimulera celldelning. Denna och andra regleringsmekanismer av CIP2A kan användas för att i framtiden rikta in specifik terapi mot tumörer som påvisar CIP2A-proteinet. Därtill gav avhandlingsarbetet skäl till att i fortsättningen utreda huruvida CIP2A kunde fungera som en tumörmarkör för att upptäcka cancer. Cancer är en av de vanligaste sjukdomsgrupperna i västvärlden och den näst vanligaste dödsorsaken efter iskemisk hjärtsjukdom. För att förbättra prognosen blir det allt viktigare att tidigare diagnosticera cancerfall och skräddarsy behandlingen. Prognostiska faktorer kan vara gynnsamma för att identifiera de patienter som behöver mer aggressiv behandling. CIP2A förekommer främst i cancervävnader och fungerar genom att inhibera protein fosfatas 2A (PP2A) och därmed stabilisera onkoproteinet MYC. Målsättningen med avhandlingen var att utreda CIP2As prognostiska roll hos cancerpatienter samt att studera hur regleringen av CIP2A-proteinet eventuellt kunde påverka en avvikande prognos. Vävnadsprover från patienter med magcancer, äggstockscancer, tungcancer och tjock- och ändtarmscancer samlades och färgades immunhistokemiskt för CIP2A proteinexpression. Associationer med vanliga kliniskpatologiska faktorer och andra biomarkörer studerades och därtill gjordes överlevnadsanalyser. CIP2As roll i intracellulär signallering studerades även i mag-, ovarie- och tungcancercellinjer. I magcancer-, äggstockscancer- och tungcancerpatienter fungerade högt uttryck av CIP2A-proteinet som prognostisk faktor, men däremot inte i tjock- och ändtarmscancerpatienter. Styrkan av uttrycket varierade i de olika cancerformerna och därför bör gränsvärdet för CIP2A-positivitet i tumörvävnad vid bedömning av prognos slås fast specifikt för varje enskild cancerform.Syöpäproteiini cancerous inhibitor of protein phosphatase 2A :n (CIP2A) vahva ilmentyminen kasvainkudoksessa voi kuvata huonoa ennustetta mahasyöpä-, kielisyöpä- ja munasarjasyöpäpotilailla ja voi siten mahdollisesti olla hyödyksi hoidon räätälöimisessä näille potilaille. Tässä väitöstutkimuksessa löydettiin positiivinen yhteys CIP2An ja syöpäsolujen kasvun säätelyssä tärkeän MYC-onkoproteiinin välillä, joka voisi siten olla lupaava syöpähoitojen kohde CIP2A-positiivisissa kasvaimissa. Lisäksi löydettiin viitteitä siitä, että olisi hyödyllistä tutkia CIP2An ilmentymää myös kasvainmerkkiaineena syövän löytämisessä ja toteamisessa. Syöpätaudit aiheuttavat suuren osan sairastavuudesta ja ovat toiseksi yleisin kuolinsyy länsimaissa iskeemisen sydänsairauden jälkeen. Potilaan ennusteen parantamiseksi on tärkeää todeta syöpä sekä löytää ennusteellisia tekijöitä jotka voivat olla hyödyksi tehokkaampaa hoitoa vaativien potilaiden tunnistamisessa. CIP2A-proteiini ilmentyy lähinnä syöpäkudoksissa ja estää proteiinifosfataasi 2An (PP2A) toimintaa stabiloiden siten MYC-onkoproteiinia. Tämän väitöstutkimuksen tavoitteena oli selvittää miten CIP2A toimii ennusteellisena tekijänä syöpäpotilailla ja tutkia miten CIP2A-proteiinin säätely mahdollisesti vaikuttaa ennusteeseen. Mahasyöpä-, munasarjasyöpä-, kielisyöpä- ja paksu- ja peräsuolisyöpäpotilailta kerättiin kudosnäytteitä, jotka värjättiin immunohistokemiallisesti CIP2An ilmentymisen osoittamiseksi. CIP2An yhteyttä kliinispatologisiin tekijöihin ja muihin biomarkkereihin tutkittiin ja lisäksi analysoitiin CIP2A-ilmentymisen yhteyttä eloonjäämiseen. CIP2An merkitystä solunsisäisessä signaloinnissa tutkittiin maha-, munasarja- ja kielisyöpäsolulinjoissa. CIP2A-proteiinin vahva ilmentyminen kuvasi huonoa ennustetta mahasyöpä-, munasarjasyöpä- ja kielisyöpäpotilailla, ei kuitenkaan paksu- ja peräsuolisyöpäpotilailla. Ennusteellisen merkityksen saavuttamiseksi tarvittiin jokaiselle syöpäkudokselle oma raja-arvo CIP2An ilmentymisen suhteen. Tuloksien yleistäminen muihin syöpätauteihin on siten haastavaa ja tulevaisuudessa tuleekin arvioida CIP2An ennusteellista arvoa syöpäkohtaisesti

Mucin 16 and kallikrein 13 as potential prognostic factors in colon cancer: Results of an oncological 92-multiplex immunoassay

Colon cancer represents one of the most common cancers in the world. Despite improved treatment, mortality remains high. In order to improve the assessment of prognosis for colon cancer patients, identifying new prognostic markers remains necessary. We analyzed preoperative serum samples from 148 colon cancer patients surgically treated at Helsinki University Hospital from 1998 through 2002 using a multiplex proximity extension assay (Oncology II panel, Olink Bioscience, Uppsala, Sweden), a panel constituting 92 immunological and oncological markers. We performed univariate and multivariate analyses on these patients and calculated the disease-specific survival among patients using the log-rank test for Kaplan?Meier estimates. In the univariate survival analysis of 92 biomarkers, 26 resulted in p?Peer reviewe

Long-term survival among colorectal cancer patients in Finland, 1991-2015 : a nationwide population-based registry study

Background Colorectal cancer (CRC) incidence in Finland has risen steadily. Given development in cancer treatments in recent decades, disease-specific data on the long-term prognosis of patients may be obsolete. Thus, this study aimed to report 5-year disease-specific survival (DSS) and relative survival based on tumour spread and site among CRC patients diagnosed between 1991 and 2015 in Finland. Material and methods We conducted a population-based registry study among 59 465 CRC patients identified from the Finnish Cancer Registry. Results The 5-year DSS for all CRC patients was 56.7% [95% confidence interval (CI) 56.3-57.1%] for 1991 through 2015. Tumour site-specific survival has improved for the period 2006-2015 versus 1991-2005 for right-sided colon cancer from 54.8% (95% CI 53.8-55.8%) to 59.9% (95% CI 58.7-61.1%), for left-sided colon cancer from 54.1% (95% CI 52.9-55.3%) to 61.0% (95% CI 59.8-62.2%) and for rectal cancer from 53.6% (95% CI 52.2-55.0%) to 62.3% (95% CI 61.3-63.3%). The 5-year relative survival for the period 2006 through 2015 was 93.6% for localised disease (stage I); 84.2% for locally advanced tumour invading adjacent structures (stage II); 68.2% for regional disease with regional lymph node metastases (stage III); and 14.0% for metastatic disease (stage IV). Conclusions This study confirms that survival for CRC has improved in recent decades in Finland, mirroring observations from other Western countries. However, the classification of tumour spread within the Finnish Cancer Registry differs slightly from the TNM classification, thereby limiting the generalisability of these results.Peer reviewe

High TKTL1 expression as a sign of poor prognosis in colorectal cancer with synchronous rather than metachronous liver metastases : Cancer Biology & Therapy

ABSTRACT Colorectal cancer (CRC) is the third most common cancer in the world. More than half of all affected patients develop liver metastases during the course of the disease, and over half experience recurrence despite radical primary surgery. Transketolase-like protein 1 (TKTL1) is a key enzyme in the glucose metabolism of cancer cells, and its expression in tumor tissue was previously shown to indicate a poor prognosis in colorectal cancer. In this study, we investigated the prognostic significance of TKTL1 in 111 patients with surgically resected colorectal liver metastases, with a minimum follow-up time of 10.3 years. TKTL1 expression was examined in tissue samples of both primary tumors and liver metastases, and compared to clinicopathological parameters, disease-free survival, and overall survival. We show that a high expression of TKTL1 in primary tumor tissue associated with poor disease-free survival in patients with synchronous liver metastases (P = .026, Kaplan-Meier log-rank test), but with better disease-free survival in patients with metachronous metastases, although not statistically significantly (P = .073). We found similar tendencies for TKTL1 expression in liver metastases. Thus, TKTL1 could serve as a candidate marker to identify patients who benefit from liver resection or who need more aggressive perioperative chemotherapy.Peer reviewe

Tumor-associated trypsin inhibitor (TATI) and tumor-associated trypsin-2 (TAT-2) predict outcomes in gastric cancer

Introduction: Tumor-associated trypsin inhibitor (TATI) limits serine proteases, promotes carcinogenesis in several cancers and functions as an acute-phase reactant. Tumor-associated trypsin-2 (TAT-2), a proteolytic target enzyme for TATI, can enhance invasion by promoting extracellular matrix degradation. Here, we aimed to study serum TATI and TAT-2 levels, including the TAT-2/TATI ratio, as prognostic and diagnostic biomarkers in gastric cancer. We compared the results with the plasma level of C-reactive protein (CRP). Material and Methods: We selected 240 individuals operated on for gastric adenocarcinoma at the Helsinki University Hospital, Finland, between 2000 and 2009. We determined the preoperative serum TAT-2, TATI and plasma CRP levels using time-resolved immunofluorometric assays using monoclonal antibodies. Results: The medium serum TAT-2 level was higher among gastric cancer patients [8.68 ng/ml; interquartile range (IQR) 5.93-13.2] than among benign controls (median 5.41 ng/ml; IQR 4.12-11.8; p = .005). Five-year survival among patients with a high serum TAT-2 was 22.9% [95% confidence interval (CI) 11.7-34.1], compared to 52.2% (95% CI 44.6-59.8; p <.001) among those with a low level. The five-year survival among patients with a high serum TATI was 30.6% (95% CI 20.4-40.8), compared to 52.9% (95% CI 44.7-61.1; p <.001) among those with a low level. The serum TATI level remained significant in the multivariable survival analysis (hazard ratio 2.01; 95% CI 1.32-3.07). An elevated plasma CRP level associated with a high serum TATI level (p = .037). Conclusions: This study shows for the first time that a high serum TAT-2 may function as a prognostic biomarker in gastric cancer and that TAT-2 levels may be elevated compared to controls. Additionally, we show that the prognosis is worse among gastric cancer patients with a high serum TATI. These biomarkers serve as prognostic factors particularly among patients with a metastatic or a locally advanced disease.Peer reviewe

High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients

Background: Colorectal cancer (CRC), the third most common cancer globally, caused 881,000 cancer deaths in 2018. Toll-like receptors (TLRs), the primary sensors of pathogen-associated molecular patterns and damage-associated molecular patterns, activate innate and adaptive immune systems and participate in the development of an inflammatory tumor microenvironment. We aimed to explore the prognostic value of TLR3, TLR5, TLR7, and TLR9 tissue expressions in CRC patients. Methods: Using immunohistochemistry, we analyzed tissue microarray samples from 825 CRC patients who underwent surgery between 1982 and 2002 at the Department of Surgery, Helsinki University Hospital, Finland. After analyzing a pilot series of 205 tissue samples, we included only TLR5 and TLR7 in the remainder of the patient series. We evaluated the associations between TLR5 and TLR7 tissue expressions, clinicopathologic variables, and survival. Using the Kaplan-Meier method, we generated survival curves, determining significance using the log-rank test. Univariate and multivariate survival analyses relied on the Cox proportional hazards model. Results: The 5-year disease-specific survival was 55.9% among TLR5-negative (95% confidence interval [CI] 50.6-61.2%) and 61.9% (95% CI 56.6-67.2%; p = 0.011, log-rank test) among TLR5-positive patients. In the Cox multivariate survival analysis adjusted for age, sex, stage, location, and grade, positive TLR5 immunoexpression (hazard ratio [HR] 0.74; 95% CI 0.59-0.92; p = 0.007) served as an independent positive prognostic factor. TLR7 immunoexpression exhibited no prognostic value in the survival analysis across the entire cohort (HR 0.97; 95% CI 0.78-1.20; p = 0.754) nor in subgroup analyses. Conclusions: We show for the first time that a high TLR5 tumor tissue expression associates with a better prognosis in CRC patients.Peer reviewe

The prognostic role of tissue TLR2 and TLR4 in colorectal cancer

Colorectal cancer (CRC), the second most common cancer globally, resulted in 881,000 deaths in 2018. Toll-like receptors (TLRs) are crucial to detecting pathogen invasion and inducing the host's immune response. This study aimed to explore the prognostic value of TLR2 and TLR4 tumor expressions in colorectal cancer patients. We studied the immunohistochemical expressions of TLR2 and TLR4 using tissue microarray specimens from 825 patients undergoing surgery in the Department of Surgery, Helsinki University Hospital, between 1982 and 2002. We assessed the relationships between TLR2 and TLR4 expressions and clinicopathological variables and patient survival. We generated survival curves using the Kaplan-Meier method, determining significance with the log-rank test. Among patients with lymph node-positive disease and no distant metastases (Dukes C), a strong TLR2 immunoactivity associated with a better prognosis (p <0.001). Among patients with local Dukes B disease, a strong TLR4 immunoactivity associated with a worse disease-specific survival (DSS; p = 0.017). In the multivariate survival analysis, moderate TLR4 immunoactivity compared with strong TLR4 immunoactivity (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89, p = 0.007) served as an independent prognostic factor. In the multivariate analysis for the Dukes subgroups, moderate TLR2 immunoactivity (HR 2.63, 95% CI 1.56-4.44, p <0.001) compared with strong TLR2 immunoactivity served as an independent negative prognostic factor in the Dukes C subgroup. TLR2 and TLR4 might be new prognostic factors to indicate which CRC patients require adjuvant therapy and which could spare from an unnecessary follow-up, but further investigations are needed.Peer reviewe

Tumor-associated CD3- and CD8-positive immune cells in colorectal cancer : The additional prognostic value of CD8+-to-CD3+ ratio remains debatable

Funding Information: This study was financially supported by the Competitive State Research Financing of the Expert Responsibility of Helsinki University Hospital, Finland (CH), the Finnish Cancer Foundation (CH), Finska Läkaresällskapet (CH, CB, JK, IB-L), the Sigrid Jusélius Foundation (CH, JK), and the K Albin Johanssons Foundation (TK, IB-L). Funding Information: This study was financially supported by the Competitive State Research Financing of the Expert Responsibility of Helsinki University Hospital, Finland (CH), the Finnish Cancer Foundation (CH), Finska L?kares?llskapet (CH, CB, JK, IB-L), the Sigrid Jus?lius Foundation (CH, JK), and the K Albin Johanssons Foundation (TK, IB-L). Publisher Copyright: © 2022 - The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).BACKGROUND: A large number of infiltrating CD3- and CD8-positive inflammatory cells indicates an improved survival in colorectal cancer (CRC), similar to many other cancers. OBJECTIVE: We investigated the prognostic value of different combinations of CD3- and CD8-positive immune cells in CRC patients. METHODS: The densities of CD3- and CD8-positive cells in intratumoral and stromal tissues were evaluated from 539 patients, for which we calculated a CD3 tumor-stroma index, a CD8 tumor-stroma index, and a CD3-CD8 tumor-stroma index. RESULTS: High CD3 and CD8 tumor-stroma indices associated with stage I to II disease (p < 0.001 for both). The CD3 tumor-stroma index associated with a colonic tumor location (p = 0.006), while the CD8 tumor-stroma index associated with right-sided tumors (p < 0.001) and histological grade 3 tumors (p = 0.032). High intratumoral and stromal densities for CD3- and CD8-positive immune cells, the CD3 tumor-stroma index, the CD8 tumor-stroma index, and the CD3-CD8 tumor-stroma index all indicated a better DSS. CONCLUSIONS: The CD3 tumor-stroma index carries a strong prognostic value in CRC, and none of the CD3 and CD8 combinations we analyzed proved superior.Peer reviewe

TKTL1 as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma and Its Correlation with FDG-PET-CT

Introduction: Glucose metabolism in cancer cells differs from noncancerous cells. The expression of transketolase-like protein 1 (TKTL1), a key enzyme in the glucose metabolism of cancer cells, predicts poor prognosis in several cancer types. We studied TKTL1 as a prognostic tool and whether TKTL1 expression correlates with 18F-FDG-PET-CT among patients with pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study examined two PDAC patient cohorts: 168 patients operated on at Helsinki University Hospital between 2001 and 2011, and 20 patients with FDG-PET-CT results available from the Auria Biobank. We used immunohistochemistry for TKTL1 expression, combining results with clinicopathological data. Results: Five-year disease-specific survival (DSS) was slightly but not significantly better in patients with a high versus low TKTL1 expression, with DSS of 28.0 versus 17.3%, respectively (p = 0.123). TKTL1 served as a marker of a better prognosis in patients over 65 years old (p = 0.012) and among those with TNM class M1 (p = 0.018), stage IV disease (p = 0.027), or perivascular invasion (p = 0.008). Conclusions: Our study shows that TKTL1 cannot be used as a prognostic factor in PDAC with the exception of elderly patients and those with advanced disease. The correlation of TKTL1 with 18F-FDG-PET-CT requires further study in a larger patient cohort.Peer reviewe

CA125 : A superior prognostic biomarker for colorectal cancer compared to CEA, CA19-9 or CA242

OBJECTIVES: The tumor stage represents the single most important prognostic factor for colorectal cancer (CRC), although more accurate prognostics remain much needed. Previously, we identified CA125 as an independent significant prognostic factor, which we have further validated along with CEA, CA19-9, and CA242 in a large cohort of CRC patients. METHODS: Using enzyme-linked immunosorbent assays, we analyzed preoperative serum samples in 322 CRC patients operated on between 1998 and 2003. RESULTS: Using the Spearman's rho model, we calculated the correlation between our previous findings on MUC16 and CA125, for which the correlation coefficient was 0.808 (p 67, with stage I-II or III-IV, and both colon and rectal cancer exhibited poor prognoses. In the multivariate analysis, we used clinical pathological variables in the model, where age, gender, and stage served as the background characteristics. We dichotomized CA125 using the Youden maximal cutoff point, and the median values for CEA, CA19-9, and CA242. CA125 emerged as the only marker remaining significant and independent together with stage, location, and age (HR 1.91; 95% CI 1.24-2.95; p 0.003). CONCLUSIONS: CA125 represents a significant and independent prognostic factor in CRC patients, superior to CEA. Furthermore, CA242 served as a better prognostic marker than both CEA and CA19-9. We recommend including both CA125 and CA242 in prognostic clinical trials among CRC patients.Peer reviewe