Cristin-prosjekt-ID: 529322
Sist endret: 22. juni 2017 13:43
Cristin-prosjekt-ID: 529322
Sist endret: 22. juni 2017 13:43
Prosjekt

Retinoids in bladder cancer: Prognostic and therapeutic implications

prosjektleder

Rolf Wahlqvist
ved Oslo universitetssykehus HF

prosjekteier / koordinerende forskningsansvarlig enhet

  • Sykehuset Telemark HF

Finansiering

  • TotalbudsjettNOK 2.567
  • Sykehuset Telemark

    • Prosjektkode: 8397.04

Klassifisering

Vitenskapsdisipliner

Klinisk medisinske fag

Emneord

Klinisk kreftforskning

HRCS-helsekategori

  • Kreft
  • Nyrer, urinveier og kjønnsorgan

HRCS-forskningsaktivitet

  • 2.1 Biologiske og indre faktorer
  • 4.2 Evaluering av markører og teknologier
  • 5.1 Legemidler
  • 6.4 Kirurgi

Kategorier

Prosjektkategori

  • Doktorgradsprosjekt

Kontaktinformasjon

Telefon
47654101
Sted
Isfoss, Björn Logi

Tidsramme

Aktivt
Start: 1. februar 2016 Slutt: 31. desember 2021

Beskrivelse Beskrivelse

Tittel

Retinoids in bladder cancer: Prognostic and therapeutic implications

Populærvitenskapelig sammendrag

Blærekreft er den 5. mest vanlig forekommende kreftsykdommen, og den dyreste å behandle. Vår forskergruppe har vist at visse bindevevsceller mangler i mange pasienter med blærekreft. Vi vil studere hvorvidt slik mangel i selve svulstvevet gir dårlig prognose, og om kreftcellene har karakteristika som forutser følsomhet for dette. Resultatene vil kunne anvendes for prognostisering, og kan underbygge anvendelse av et eksisterende medikament på en helt ny måte, mot kreft.

Vitenskapelig sammendrag

There are no good molecular markers for prognostication or targeted therapy in bladder cancer. Most marker studies have focused on carcinoma cells, overlooking stroma. Stromal cells are known to cooperate with tumor cells to prepare invasion, but their roles are poorly understood. We reported that stellate cells (vitamin A storing cells) are often absent in bladder stroma in cancer patients. Stellate cells produce retinoic acid which is important for epithelial cell differentiation. Retinoic acid has anti-cancer effect. We propose that bladder cancer may be treated by topical use of retinoic acid, which has never been investigated.

AIMS 1) Determine the distribution of stellate cells in bladder cancer stroma, and correlate with patient outcome. 2) Determine the distribution of retinoic acid receptors in urothelial carcinoma cells, and correlate with patient outcome. 3) Determine the distribution of stellate cells and retinoic acid receptors in rat bladder cancer. 4) Identify the maximum tolerable concentration of retinoic acid in bladder instillations for rat.

HYPOTHESES 1) Low numbers of stellate cells in bladder cancer stroma predict bad patient outcome i.e. tumor recurrence, tumor progress and early death. 2) Low presence of retinoic acid receptors in urothelial carcinoma cells predicts bad outcome. 3) Some bladders in rat lack stellate cells but contain retinoic acid receptors. 4) Rats tolerate retinoic acid intravesically.

 

Metode

The 1st hypothesis will be tested using an existing tissue microarray of archival bladder tumor tissue from 300 patients with clinicopathological data and long-term follow-up including recurrence, tumor progress, and survival (overall and disease-specific). We will apply immunohistochemistry reactions for chromogenic visualization of labelled cells, using 3 antibodies that label stellate cells: ALDH1, and CRBP1 and vinculin. Computerized image analysis will be used for standardized quantitation of positive cells per cut-section area, with manual supervision. The assessement for Hypothesis II will be done on the same patient material. This work is immunohistological, using 3 antibodies against retinoic acid receptors. Retinoid acid receptor positive cells will be quantified by image analysis. For Hypothesis III we will investigate the histology and cellular reactivity for ALDH1, CRBP1 or vinculin, and retinoic acid receptor antibodies in archival tumor tissue from two rat bladder tumor models that one of the participants (CJA) has studied: an AY-27 orthotopic model in which cancer cells were instilled into the bladders, and a BBN-model in which cancer was inititated using N-butyl-N-(4-hydroxybutyl) nitrosamine in drinking water. We will investigate a limited number of specimens (n=40) but in great detail. For Hypothesis IV, in an optional pilot study we will instill retinoic acid into the bladders of 9 normal rats under general anaesthesia using 3 different concentrations of retinoic acid in order to observe the tolerance for the drug, and 3 rats will receive instillations of isotonic saline with no drug. This will result in a rough estimate of the maximum concentration of retinoic acid that is tolerated without debilitating side effects. Animals will be observed for signs of toxicity, and sacrificed at the end of the experiment so that the bladder and vital organs of treated rats can be examined microscopically and compared with the control group of non-medication treated rats.

Utstyr

The equipment used in this study includes standard histological laboratory equpipment including immunohistochemistry apparatus. Tissue microarray has been prepared by forehand for this study, by one of the participants. Image analysis will be done using whole slide imaging (slide scanner) and a computer with free software that will customized for this project by a participant. Additionally there is need for a portable computer and a portable projector for demonstration of images and data at meetings (the participants are located in 7 different cities in Scandinavia). 

prosjektdeltakere

prosjektleder

Rolf Wahlqvist

  • Tilknyttet:
    Prosjektleder
    ved Oslo universitetssykehus HF

Helena Hermelin

  • Tilknyttet:
    Prosjektdeltaker
    ved Sverige

Bo Holmqvist

  • Tilknyttet:
    Prosjektdeltaker
    ved Lunds universitet

Lars Dyrskjøt

  • Tilknyttet:
    Prosjektdeltaker
    ved Aarhus Universitet

Christer Busch

  • Tilknyttet:
    Prosjektdeltaker
    ved Uppsala universitet
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Resultater Resultater

Histologic characterization of stem cells in mammary epithelium and stroma.

Isfoss, Björn Logi. 2017, TELEMARKDoktorgradsavhandling

Survival and inflammatory response in adipose-derived mesenchymal stem cell-enriched mouse fat grafts.

Begic, Anadi; Isfoss, Björn Logi; Lønnerød, Linn Kristine Rygh; Vigen, Alexander; Moskaug, Jan Øivind. 2016, Plastic and reconstructive surgery. Global open. TELEMARK, VESTFOLD, HAUKELAND, UIOVitenskapelig artikkel

The absence of aldehyde dehydrogenase I AI-positive cells in benign mammary stroma is associated with risk factors for breast cancer.

Isfoss, Björn Logi; Holmqvist, Bo; Jernstrøm, Helena; Alm, Per; Olsson, Håkan. 2016, Breast Cancer: Targets and Therapy. SUS, TELEMARK, Lu, SVERIGEVitenskapelig artikkel
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