| 1. |
- Emterling, A, et al.
(författare)
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Clinicopathological significance of microsatellite instability and mutated RIZ in colorectal cancer
- 2004
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 15:2, s. 242-246
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies have shown that microsatellite instability (MSI) is related to favourable survival in colorectal cancer patients but there are controversial results. Tumour suppressor gene RIZ is a susceptible mutational target of MSI. However, its clinicopathological significance has not been investigated. We investigated the prognostic significance of MSI in Swedish colorectal cancer patients and the clinicopathological significance of RIZ mutations. Patients and methods: We analysed 438 colorectal adenocarcinomas for MSI by microsatellite analysis. Among them, 29 MSI and 28 microsatellite stable (MSS) tumours were examined for RIZ mutations by DNA sequencing. Results: MSI (13% of 438 cases) was not associated with survival (rate ratio=0.97, 95% confidence interval =0.57-1.64, P=0.90), although it was related to proximal tumour (P <0.001), poor differentiation and mucinous carcinomas (P <0.001), multiple tumours (P=0.01) and negative/weak expression of hMLH1 (P=0.03). RIZ mutations were detected in 31% of 29 MSI tumours but in none of the 28 MSS tumours. The mutations were related to female (P=0.01), proximal tumour (P=0.01), stage B (P=0.01) and poor differentiation (P=0.047). Conclusions: MSI was not a prognostic factor in the Swedish patients included in this study. Clinicopathological variables associated with RIZ mutations might be a consequence of the MSI characteristics.
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| 2. |
- Evertsson, Sofia, 1972-, et al.
(författare)
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Microsatellite instability and MBD4 mutation in unselected colorectal cancer
- 2003
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 23:4, s. 3569-3574
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We investigated the prognostic significance of microsatellite instability (MSI) and the association with clinicopathological factors in colorectal cancer, and further identified MBD4 mutations and their clinicopathological significance.PATIENTS AND METHODS: MSI was analyzed in 201 colorectal cancers. Sequencing analysis of MBD4 was performed in 26 MSI and 28 microsatellite stable (MSS) tumors.RESULTS: Twenty-seven tumors (13.4%) were MSI but did not correlate with improved survival. MSI was significantly correlated with proximal colon tumors (p < 0.001), poor differentiation or mucinous type (p = 0.005) and multiple tumors (p = 0.04). MBD4 mutations were found in 15% MSI but not in MSS tumors. The mutated cases showed female overrepresentation, proximal site and poorly-differentiated/mucinous type.CONCLUSION: MSI was not correlated with survival, but shared other features associated with MSI in colorectal cancer as demonstrated by others. The clinicopathological variables associated with the MBD4 mutations were probably the reflection of MSI features.
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| 3. |
- Moparhti, Satish Babu, et al.
(författare)
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Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers
- 2007
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Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 30:1, s. 91-95
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Tidskriftsartikel (refereegranskat)abstract
- MAC30 is highly expressed in several types of tumors including colorectal cancers, however, its clinicopathological and biological significance in colorectal cancers is currently not known. The aim of our study was to investigate MAC30 expression in distant normal mucosa, adjacent normal mucosa, primary tumors and metastases of colorectal cancer, and to determine the relationship between MAC30 expression and clinicopathological and biological variables. MAC30 expression was immunohistochemically examined in distant normal mucosa (n = 54), adjacent normal mucosa (n = 123), primary tumors (n = 217) and lymph node metastases (n = 56) from colorectal cancer patients. MAC30 cytoplasmic expression was increased from distant normal mucosa to primary tumor and to metastasis (p < 0.0001-0.04). Furthermore, 40% primary and 37% metastatic tumors showed stronger cytoplasmic expression of MAC30 at the tumor invasive margins compared to inner tumor areas. Strong cytoplasmic expression of MAC30 in the metastasis was related to a poor prognosis (p = 0.04). MAC30 cytoplasmic expression was positively related to expression of proliferating cell nuclear antigen (p = 0.04), p53 (p = 0.04), nucleoporin 88 (p = 0.001), legumain (p = 0.004) and particularly interesting new cysteine-histidine rich protein (p = 0.004). However, MAC30 expression in the nucleus and stroma did not have any clinicopathological and biological significance (p > 0.05). In conclusion, MAC30 protein may play a role in development of colorectal cancer, and can be considered as a prognostic factor.
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| 4. |
- Permert, Johan, et al.
(författare)
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Life Science på östgötska : förslag till Life science-satsning i Östergötland.
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Östergötland är inte någon traditionell Life Science-nod i Sverige, men beslutade våren 2017 att undersöka möjligheterna att finna en position baserat på erkänd kunskapsbas kring mötet människa – teknik. En förstudie initierades med Region Direktören som beställare och uppdraget innebar att kartlägga, analysera och ge förslag till hur en Life Science-satsning skulle kunna vara genomförbar i Östergötland. Triple Helix-modellen, det vill säga samhandling mellan offentlig sektor, universitet och näringsliv är den anmodade modellen för Life Science-satsningar i Sverige. Den tidigare Life Science-satsningen i Östergötland hade fallit på grund av obalans i styrka hos Triple Helixens ingående parter.Ett lyckat Triple Helix-initiativ i Östergötland, som även fått internationell genomslagskraft är CMIV, där radiologin är världskänt genom samarbetet mellan RÖ, LiU och Sectra. Detta initiativ är ett exempel på Triple Helix-samhandling som gett resultat för alla ingående parter. Runt CMIV kan såväl samhällsnytta som patientnytta och tillväxt tydligt identifieras. Ytterligare ett exempel som lyftes fram i direktivet är utveckling av kliniska beslutsstöd för användning i klinisk verksamhet och vidare forskning på kliniska data.För att få en rik bild av CMIV, och andra initiativ kring Life Science i Östergötland, har arbetsgruppen använt sig av berättarteknik och på djupet studerat fem fall inom Life Science-området. Analys av dessa fall har sedan jämförts med erfarenheter av Life Science från andra regioner och ett förslag till lösning har successivt växt fram i diskussioner med arbetsgruppen och den taktiska styrgruppen. Triple Helix-samhandling är tämligen utmanande i praktiken då de olika aktörerna i vård, forskning- och näringsliv måste samhandla för att uppnå ett gemensamt mål. Berättelserna vittnar om att det krävs vilja, mod och förmåga att korsa såväl ämnes- som organisatoriska gränser. Slutsatsen är därför att det finns behov av att träna denna förmåga, men också att skapa en ”en väg in” där möten kan uppstå för att identifiera, matcha och förfina initiativ som kan lösas med hjälp av Triple Helix-samhandling.Förstudien visar att det finns goda förutsättningar att genomföra en Life Science-satsning i Östergötland. Ett flerfakultetsuniversitet samt ett komplett sjukvårdssystem ger den mylla av kunskap, problem/behov samt kritiska massa som visat sig krävas för den här typen av satsningar. Att begränsa den möjligheten till enbart vidareutveckling av CMIV och byggandet av kliniska beslutsstöd vore dock inte att göra möjligheterna rättvisa. Istället föreslås två interrelaterade verksamheter vars huvuduppdrag är att facilitera och stödja innovation och utveckling inom Life Science-sektorn i Östergötland; Triple Helix-Labb och Triple Helix-Akademi. I Triple Helix-Labbet kan problem/behov och lösningar mötas, matchas och förfinas i en vägledningsprocess som kan leda till såväl ökad patientnytta som ökad tillväxt i Östergötland. I Triple Helix-Akademin stärks förmågan till samhandling i Triple Helix för att överbyggakunskap, förståelse och respekt för de värdesystem som korsas. Genom dessa interorganisatoriska strukturer finns förutsättningar att adressera vårdens problem, samtidigt som dessa kan agera tillväxtmotor i Östergötland. I förstudien identifieras fyra olika växtvägar som kan stimuleras via ovan nämna strukturer.För att få utväxling av ovanstående förslag behöver strukturer med närliggande och överlappande uppdrag ses över och ersättas/integreras i Triple Helix-Labbet. Detta arbete är påbörjat i förstudien, men behöver förfinas i det etableringsuppdrag som är nästa steg för att kraftsamla kring Life Science i Östergötland. En Life Science-satsning är en långsiktig handling och kräver en politisk överenskommelse för att bli hållbar över tid. Därför ses detta som en förutsättning för att starta det etableringsprojekt som föreslås i föreliggande rapport.Den här förstudien handlar om Östergötland. Redan idag finns dock etablerade samarbeten med Sydöstra sjukvårdsregionen men även nationellt och internationellt. Östergötland är därmed en nod i flera större nav, beroende på vilket perspektiv som antas. Nodtänkandet är en av förstudiens viktigaste grundpelare, men samtidigt måste förändringsarbetet starta hos var och en av de ingående parterna i en Life Science-satsning och därmed adresserar förstudien främst samhandling mellan de parter som utgör själva hjärtat i satsningen; RÖ och LiU.Den största risken för att en Life Science-satsning ska fallera även denna gång är att den politiska överenskommelsen uteblir, eller att RÖ och LiU stannar i sina invanda samverkanspositioner, och därmed inte antar samhällsutmaningen om ökad patientnytta och ökad tillväxt.Förstudien beslutades av Regionstyrelsen 2018-11-08.
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| 5. |
- Pfeifer, Daniella, et al.
(författare)
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Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
- 2009
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 135:11, s. 1583-1592
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Tidskriftsartikel (refereegranskat)abstract
- We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.
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| 6. |
- Sun, Xiao-Feng, 1959-, et al.
(författare)
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Polymorphisms in sulfotransferase 1A1 and glutathione S-transferase P1 genes in relation to colorectal cancer risk and patients' survival
- 2005
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Ingår i: World Journal of Gastroenterology. - 1007-9327 .- 2219-2840. ; 11:43, s. 6875-6879
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine whether polymorphisms in SULT1A1 and GSTP1 genes contribute to colorectal cancer development and whether they are associated with clinicopathological variables are not well identified. Methods: We examined the genotypes of 125 colorectal cancer patients and 666 healthy controls in a Swedish population by using PCR restriction fragment length polymorphism (RFLP). Results: SULT1A1 *2/*2 genotype (OR = 2.49, 95%CI = 1.48-4.19, P = 0.0002) and *2 allele (OR = 1.56, 95%CI = 1.16-2.10, P = 0.002) had an effect on colorectal cancer susceptibility, while GSTP1 genotype was without effect. However, GSTP1 G-type predicted a worse prognosis in the patients independently of gender, age, Dukes' stage, growth pattern, and differentiation (P = 0.03). Conclusion: Polymorphism in SULT1A1 may predispose to colorectal cancer and GSTP1 may be a biological indicator of prognosis in the patients. © 2005 The WJG Press and Elsevier Inc. All rights reserved.
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| 7. |
- Wallin, Åsa, 1976-, et al.
(författare)
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Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential
- 2008
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 19:6, s. 1493-1498
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Tidskriftsartikel (refereegranskat)abstract
- SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 h and then exposed to SN-38 (2.5 µg/ml) at 37°C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.
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| 8. |
- Wallin, Åsa, 1976-, et al.
(författare)
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Gene Expression Profile of Colon Cancer Cell Lines Treated with SN-38
- 2010
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Ingår i: Chemotherapy. - : S. Karger AG. - 0009-3157 .- 1421-9794. ; 56:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Colorectal cancer is the third most common form of cancer in the industrial countries. Due to advances regarding the treatments, primarily development of improved surgical methods and the ability to make the earlier diagnosis, the mortality has remained constant during the past decades even though the incidence in fact has increased. To improve chemotherapy and enable personalised treatment, the need of biomarkers is of great significance. In this study, we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38, the active metabolite of topoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis. Material and Methods: The study included 3 colon cancer cell lines: KM12C, KM12SM and KM12l4a. The 3 cell lines were treated with SN-38, and samples were obtained after 24 and 48 hour treatments. The gene expression analyses were performed using oligonucleotide microarrays comprising of similar to 27,000 spots where the untreated controls were compared to the SN-38-treated samples. Results: Unsupervised clustering clearly distinguished the treated cell lines from the untreated. Supervised analysis identified 3,974 significant genes (p = 0.05) differentiating the treated samples from the untreated, majority of which were down-regulated after treatment. The top-ranked down-regulated genes in the treated cell lines included those related to receptor and kinase activity, signal transduction, apoptosis, RNA processing, protein metabolism and transport, cell cycle and transcription. A smaller number of genes were up-regulated in the cell lines after treatment and included genes involved in apoptosis, transcription, development and differentiation. Conclusions: These results demonstrate that the expression of the genes involved in cell proliferation and apoptosis as well as RNA, DNA and protein metabolism were affected by SN-38. The impact of certain genes on colorectal cancer development needs to be further evaluated; however, these results could serve as a basis for further studies in order to find targets for irinotecan treatment. Copyright (C) 2010 S. Karger AG, Basel
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| 9. |
- Wallin, Åsa, 1976-
(författare)
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Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments.The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV).In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.
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| 10. |
- Wallin, Åsa R., 1976-, et al.
(författare)
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Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy
- 2006
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 65:2, s. 452-458
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients.Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT.Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01).Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT.
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