Glykoproteiinit ja kasvaimen glykosylaatio biomarkkereina paksu- ja peräsuolen syövässä

Background and aims Colorectal cancer (CRC) is one of the world s three most common cancers, and its incidence is rising. Novel biomarkers are essential for diagnostic and prognostic tools and to identify patients for targeted and individualized therapy. Covering all human cells, the carbohydrate units of glycoproteins, glycolipids, and proteoglycans are glycans. Carcinoma-related glycan structures are potential cancer biomarkers, since glycosylation evolves during carcinogenesis. Suggested to play a role in carcinogenesis are glycoproteins podocalyxin (PODXL) and regenerating islet-derived gene (REG) 4. PODXL s aberrant expression or allelic variation or both associate in different cancers with poor prognosis and unfavourable clinicopathological characteristics. Up-regulated REG4 expression occurs in inflammatory bowel diseases and also in gastrointestinal cancers. Reports on the association of REG4 expression with CRC prognosis have been mixed, however. Material and Methods Comparison of the N-glycan profiles of 5 rectal adenomas and 18 rectal carcinomas of different stages was by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry. Tumour expression of REG4 and PODXL was evaluated by immunohistochemistry in 840 consecutive CRC patients surgically treated between 1983 and 2001. In addition we evaluated in a subgroup of 220 consecutively surgically treated CRC patients the tumour expression of MUC1, MUC2, MUC5AC, synapthophysin, chromogranin, sialyl Lewis a (sLea), and pauci-mannose. All patients were treated at Helsinki University Hospital (HUH). Results Rectal adenomas and carcinomas can be distinguished from one another based on their N-glycosylation profile. Differences in N-glycosylation existed also between carcinomas of different stages. Based on these results pauci-mannose and sLea were chosen for immunohistochemical analysis: in CRC sLea correlated with poor prognosis, and in advanced CRC, pauci-mannose expression correlated with poor prognosis. PODXL was an independent marker of poor prognosis in CRC. The two antibodies showed similar prognostic profiles, but their staining patterns differed, and they recognized different groups of patients with a poor prognosis. Combination of the two PODXL antibodies identified a group of patients with even worse prognosis. REG4 expression associated with MUC1, MUC2, and MUC5AC expression in CRC and was a marker of favourable prognosis in non-mucinous CRC. Conclusion Mass spectrometry identified several carcinoma-related glycans and a method of transforming these results into immunohistochemistry was demonstrated. PODXL was a marker of poor prognosis in CRC, whereas REG4 expression predicted a favourable prognosis in non-mucinous CRC.Paksu- ja peräsuolensyöpä on yksi maailman kolmesta yleisimmästä syövästä ja sen esiintyvyys on kasvussa. Hoitojen yksilöimiseksi ja paremmaksi kohdentamiseksi tarvitaan uusia biomarkkereita. Väitöskirjassa tutkittiin kahden eri glykoproteiinin, podokalyksiinin ja REG4, vaikutusta paksu- ja peräsuolen syövän käyttäytymiseen. Fysiologisesti podokalyksiini osallistuu solujen liikkeen ja muodon säätelyyn ja lisääntyneen esiintymisen tiedetään liittyvän monissa syövissä aggressiiviseen kasvaintyyppiin ja huonompaan ennusteeseen. REG4 osallistuu normaalisti solujen lisääntymiseen ja uudistumiseen, mutta sen vaikutukset syöpäsolujen käyttäytymiseen on epäselvää. Lisäksi tutkittiin peräsuolisyövässä tapahtuvia muutoksia glykaaneissa, jotka ovat glykoproteiininen, glykolipidien ja proteoglykaanien hiilihydraattiyksiköitä. Suurin osa glykaaneista sijaitsee solujen pinnalla ja osallistuvat solun toiminnan ja selviytymisen kannalta oleellisiin toimintoihin. Glykaanien määrät ja rakenteet muuttuvat karsinogeneesin aikana, minkä takia syöpään liittyvät glykaanirakenteet ovat potentiaalisia biomarkkereita. Glykaanien massapektometrianalyyseja varten valitsimme viisi peräsuolen adenooma- ja kahdeksantoista syöpäpotilasta. Glykoproteiinien immunohistokemialliset analyysit suoritettiin HUS Kirurgian klinikassa vuosina 1983-2001 leikatuilla potilailla (N=840). Kudosnäytteet saatiin Helsingin Yliopiston Patologian laitoksen ja HUSLAB:n arkistosta. Tutkimus osoitti, että peräsuolen syövissä on suurentuneita määriä yleisesti syöville ominaisia glykaanirakenteita, kun taas suolen limakalvon soluille tyypilliset glykaanirakenteet ovat hävinneet. Tutkimus osoitti, että peräsuolen adenoomat ja syövät voidaan erottaa glykaanirakenteidensa perusteella toisistaan, lisäksi eroja havaittiin eri levinneisyysluokkien syöpien välillä. Immunohistokemialliset tutkimukset osoittivat, että podokalyksiinin lisääntynyt ekspressio ennustaa huonompaa selviytymistä. Immunohistokemiallisten analyysien perusteella lisääntynyt REG4 ekspressio liittyi parempaan ennusteeseen. Paksu- ja peräsuolisyövässä lisääntynyt podokalyksiinin esiintyminen liittyi huonompaan ennusteeseen kun taas lisääntynyt REG4 ekspressio liittyi parempaan ennusteeseen. Peräsuolen adenoomat pystytään erottamaan syövistä glykaanirakenteidensa perusteella. Saadut tulokset voivat jatkossa johtaa siihen, että leikkauksen jälkeisiä syöpähoitoja pystytään paremmin kohdentamaan niille potilaille, jotka niistä eniten hyötyvät

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

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

HLA-G expression correlates with histological grade but not with prognosis in colorectal carcinoma

cited By 0Trophoblast-specific expression of human leukocyte antigen-G (HLA-G) induces immune tolerance for the developing fetus. Pathological HLA-G expression later in life might contribute to immune escape of various cancers. We studied the still controversial role of HLA-G in colorectal carcinoma (CRC) using the MEM-G/1 antibody and a tissue microarray series of CRC tumors (n = 317). HLA-G expression appeared in 20% of the tumors and showed high intratumoral heterogeneity. HLA-G positivity was associated with better differentiation (p = 0.002) and non-mucinous histology (p = 0.008). However, HLA-G expression alone showed no prognostic value: 5-years disease-specific survival among patients with HLA-G expression was 68.9% (95% CI: 62.7%-75.0%) compared to 74.8% (95% CI: 63.2%-86.3%) among those without expression. These results support a modulatory role of HLA-G in CRC.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

A retrospective study of intraductal papillary neoplasia of the pancreas (IPMN) under surveillance

Background and objective: The growing number of identified intraductal papillary mucinous neoplasm (IPMN) patients places greater pressure on healthcare systems. Only a minority of patients have IPMN-related symptoms. Thus, more precise surveillance is required. Methods: In this retrospective single-center cross-sectional study, patients with an active diagnosis of branch duct IPMN (BD-IPMN) and >6 months of surveillance were classified as follows: presence/absence of worrisome features (WF) or high-risk stigmata (HRS), newly developed WF/HRS, under/over 15 mm cyst, growing/not growingPeer reviewe

Ornithine decarboxylase antizyme inhibitor 2 (AZIN2) is a signature of secretory phenotype and independent predictor of adverse prognosis in colorectal cancer

Ornithine decarboxylase (ODC) is the rate-limiting enzyme of polyamine synthesis. The two ODC antizyme inhibitors (AZIN1) and (AZIN2) are regulators of the catalytic activity of ODC. While AZIN1 is a regulator of cell proliferation, AZIN2 is involved in intracellular vesicle transport and secretion. There are no previous reports on the impact of AZIN2 expression in human cancer. We applied immunohistochemistry with antibodies to human AZIN2 on tissue micro- arrays of colorectal cancers (CRC) from 840 patients with a median follow-up of 5.1 years (range 0-25.8). The 5-year disease-specific survival rate was 58.9% (95% CI 55.0-62.8%). High AZIN2 expression was associated with mucinous histology (p = 0.002) and location in the right hemicolon (p = 0.021). We found no association with age, gender, stage, or histological tumor grade. High tumor expression of AZIN2 predicted an unfavorable prognosis (pPeer reviewe

N-glycomic profiling of colorectal cancer according to tumor stage and location

Alterations in glycosylation are seen in many types of cancer, including colorectal cancer (CRC). Glycans, the sugar moieties of glycoconjugates, are involved in many important functions relevant to cancer and can be of value as biomarkers. In this study, we have used mass spectrometry to analyze the N-glycan profiles of 35 CRC tissue samples and 10 healthy tissue samples from non-CRC patients who underwent operations for other reasons. The tumor samples were divided into groups depending on tumor location (right or left colon) and stage (II or III), while the healthy samples were divided into right or left colon. The levels of neutral and acidic N-glycan compositions and glycan classes were analyzed in a total of ten different groups. Surprisingly, there were no significant differences in glycan levels when all right- and left-sided CRC samples were compared, and few differences (such as in the abundance of the neutral N-glycan H3N5) were seen when the samples were divided according to both location and stage. Multiple significant differences were found in the levels of glycans and glycan classes when stage II and III samples were compared, and these glycans could be of value as candidates for new markers of cancer progression. In order to validate our findings, we analyzed healthy tissue samples from the right and left colon and found no significant differences in the levels of any of the glycans analyzed, confirming that our findings when comparing CRC samples from the right and left colon are not due to normal variations in the levels of glycans between the healthy right and left colon. Additionally, the levels of the acidic glycans H4N3F1P1, H5N4F1P1, and S1H5N4F1 were found to change in a cancer-specific but colon location-nonspecific manner, indicating that CRC affects glycan levels in similar ways regardless of tumor location.Peer reviewe

Elevated tumor expression of Astroprincin (FAM171A1) is an independent marker of poor prognosis in colon cancer

Background Colon cancer (CC) is one of the most commonly diagnosed malignancies worldwide. Several biomarkers have been suggested for improved prognostic evaluation, but few have been implemented in clinical practice. There is a need for biomarkers that predict the tumor behavior in CC and allow stratification of patients that would benefit from adjuvant therapy. We recently identified and functionally characterized a previously unknown protein that we called ASTROPRINCIN (APCN) due to its abundance in astrocytes. APCN, also annotated as FAM171A1, is found in trophoblasts of early placenta. We demonstrated that high expression levels of APCN in cancer cells induced motility and ability of invasive growth in semisolid medium. Methods We screened by immunohistochemistry a tissue microarray material from the tumors of 429 CC patients with clinical follow-up in a test series and 255 CC patients in a validation series. Results We showed that low or absent APCN expression correlates with a favorable prognosis while high APCN expression was a sign of an adverse outcome. Cox uni- and multivariable analysis revealed that elevated tumor expression of APCN constitutes a robust marker of poor prognosis independent of stage, grade, patient's age, or gender. Conclusion Our findings demonstrate that APCN is a novel independent prognostic marker in CC and could potentially select patients for more intense postoperative adjuvant treatment and follow-up.Peer reviewe

Association between local immune cell infiltration, mismatch repair status and systemic inflammatory response in colorectal cancer

Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.Peer reviewe