Year report 2003 Work Package 5.3 – National Tissue Microarray Center
page
• Research groups using the facility and staff
• SCIENTIFIC GOALS AND RESULTS
1. Perform a pilot demonstration project regarding the efficient and accurate assembly of tissue arrays using computerized, robotic array systems.
• Robot installed August 2003. Now fully functional and in use for all studies described
below. Continuous evaluation together with the advisory board and in particular,
2. Pilot tissue array study of an extremely well characterized tumor material regarding clinical
data and environmental exposures (all prospectively occurring cancers in the Malmö Diet
and Cancer cohort). Specifications below
1) histopathological rereview - completed,
2) document the specimens for arraying on digital medium – included in the
robot arrayer. Will be performed within the Scanscope project (se 3) test the suitability of the arrays for protein, RNA and DNA analyses – protein (ref 1-8), DNA (ref 1, 8) and RNA done (ref 5)
4) Collect clinical data - completed
5) build a tissue array database - completed
6) Arraying, storing and providing the arrays for research should be quality-
assured – ongoing together WP1
• 406 breast cancer samples. The array completed and all clinical information available.
Pathology re-reviewed and graded. ER, Ki-67, cyclin D1, cyclin E, p27, p16 evaluated.
Promising results showing strong links between diet behaviours, environmental
exposures and tumor biology. Manuscript under preparation. Will be submitted to
Will be arrayed with the robot during 2004
• A reference Tissue Array for breast cancer, representing cancers with different prognosis
and/or specifically containing patients that have been included in randomized treatment
2.1) Randomized treatment trial – tamoxifen/no treatment.
a) Pre-menopausal (SB II:2) 1985-1991, 565 patients
All arrays completed. Clinical information and data base completed.
VEGF, VEGFR2, cyclin D1 analyzed. Three manuscripts under preparation
(submitted during 2004). Six other projects initiated (four different research groups in
1) ER alpha and beta, PR (Bo Nordenskjöld, Linköping)
2) proliferation, grade and tumor type in relation to tamoxifen response
3) c-erbB2 overexpression and tamoxifen response (Sten Torstensson,
4) Akt and p21 in relation to tamoxifen response (Olle Ståhl,
5) cyclin E in relation to tamoxifen response (Landberg, Lund)
6) ERK activity and tamoxifen response (Landberg, Lund)
b) Post-menopausal (northern Sweden) 1980-1987, 168 patients
Array, clinical data and data base completed.
2.2 Well characterized multi tissue array consisting of 120 breast cancer samples
Several projects running. Collaboration with Dublin, Toronto and Umeå.
2.3 Consecutive series of breast cancer samples from Malmö University Hospital (650 cases)
Array completed. Several analyses performed. Clinical data will be gathered during
3. Perform a feasibility study regarding the practicability to array specimens from the Malmö
population-based autopsy bank, e.g. for studies of diabetes or cardiovascular diseases.
• 75 heart samples, different diseases. Completed.
Conclusion: Feasible but need responsible PI.
SUMMARY OF ACHIEVEMENTS 2003:
• Large breast cancer array (2000 patients) with clinical data completed
o Unique pre-menopausal randomized treatment trial (Tamoxifen) in use
• Breast cancer Malmö diet and cancer completed and in use.
• Around 15 publications with associations to the center
• Several manuscripts under preparation
• A powerful international advisory board
• Several other arrays completed: prostate cancer, heart, colorectal cancer, AML, ALL
• Pre-cancerous “arrays” and progression, DCIS-120 patients
• Start the application process and distribution of parts of the arrays including anonymous
• Robot installed and fully functional
• protein, RNA and DNA analyses on tissue array evaluated
• Center open for array constructions of external materials
• Purchase of a digital scanner of arrays – Scanscope (se below).
• More then 20 research projects using arrays from the center
Future plans
• All arrays that are under construction should be available for researchers (see below).
• All cancers within the Malmö Diet cancer cohort should be completed and available
• Breast cancer progression array completed
• Arraying of other diseases initiated and running.
• Large randomized treatment trials – cytostatic drug combinations – collaboration
Stockholm, predictive information
• 1200 - DCIS with breast preserving surgery randomized to radiotherapy/0
• Arrays including normal stroma and stroma next to invasive breast cancer and DCIS.
Changes ins stromal cells and potential importance for malignant behaviors.
• Cervix cancer, 1200 patients (Adami and Dillner)
Special considerations
The center will function as the tissue array center for Jonas Berghs cDNA and breast cancer project (KI, Stockholm). William Gallagher (Dublin, Ireland) will use arrays from the center for testing of candidate genes selected in large cDNA array screens. The application process for obtaining arrays has been outlined and will be detailed on the homepage. Tissue Array Workshop 18-19 May 2004 in Malmö together with advisory board (Stephen Hewitt
Digital scanning of microscope slides.
With the purchase of a Scanscope from Dakopats (financed in part from Swegene) we will be able to scan all stained arrays and instead of sending slides to researchers a large computer file will be sent containing all information. This technology is state of the art in modern pathology and will be extremely useful when arrays are analyzed. More information will be presented at the meeting in Stockholm in January 2004 and later this year when the scanner has been installed. Research groups currently using the array center.
• Bo Nordenskjöld, Linköping • Sten Torstensson, Kalmar
• Mef Nilbert, Lund • Göran Roos, Umeå
• Göran Stenman, Göteborg • Pierre Åman, Göteborg
• Håkan Axelson, Malmö • Tommy Anderson, Malmö
• Per Ebbe Jönsson, Helsingborg • Björn Dahlbäck, Malmö
• Anders Zetterberg, Stockholm • John Öhd, Stockholm
• Kristian Helin, Milano • Arun Seth, Toronto
Collaboration with tissue array technologies
• Fredrik Pontén, Uppsala • Stephen Hewitt, Washington (NCI/NIH)
Staff at the tissue array center
Advisory board
Olli Kallioniemi National Institutes of Health, Bethesda, MD, USA Stephen Hewitt Director Tissue Array Research Program (TARP) - NCI National Institutes of Health, Bethesda, MD, USA. Steering Committee Professor Göran Landberg Division of Pathology Department of Laboratory Medicine Lund University Malmö University Hospital S-205 02 Malmö Sweden Professor Jonas Bergh Oncology Karolinska Institute Sweden Professor Göran Berglund Department of Medicine Lund University Malmö University Hospital Sweden Associate Professor Mårten Fernö Department of Oncology Lund University Lund University Hospital Sweden Professor Bo Nordenskjöld Department of Oncology Linköping University Sweden PUBLICATIONS WITHIN THE CENTER
1. Lodén M, Stighall M, Nielsen NH, Östlund H, Roos G, Emdin SO, Landberg G. The cyclin
D1 high and cyclin E high subgroups of primary breast cancer. Separate pathways in tumourogenesis based on pattern of genetic abnormalities. Oncogene 21: 4680-4690, 2002.
2. Landberg G. Multiparameter analyses of cell cycle regulatory proteins in human breast
cancer: a key to definition of separate pathways in tumorigenesis. Adv Cancer Res: 84:35-56, 2002.
3. Cao Y, Lundwall Å, Gadaleanu V, Lilja H, Bjartell A. Anti-trombin is expressed in the
benign prostatic epithelium and in prostate cancer and is capable of forming complexes with prostate-specific antigen and human glandular kallikrein 2. Am J Pathol 161: 2053-2063, 2002.
4. Hedberg Y, Ljungberg B, Roos G, Landberg G. Aberrant cyclin E and p27 protein content
in human renal cell carcinoma. Internation J Cancer 102: 601-607, 2002.
5. Öhd J, Kamp JF, Nielsen C, Campbell J, Landberg G, Löfberg H, Sjölander A. Expression
of the leukotriene D4 receptor cycLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas. Gastroenterology 1: 57-70, 2003.
6. Hedberg Y, Ljungberg B, Roos G, Landberg G. Expression of cyclin D1, D3 E and p27 in
human renal cell carcinoma analysed by tissue micro array. British J Cancer 89: 1920-1926, 2003.
7. Jirström K, Ringberg A, Fernö M, Anagnostaki L, Landberg G. Tissue microarray analyses
of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that cyclin D1 is a predictive factor for local recurrence. Br J Cancer 17: 1920-1926, 2003
8. Rydén L, Linderholm B, Nielsen NH, Emdin S, Jönsson P, Landberg G. Tumor specific
VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer. Breast Cancer Res 82: 147-154, 2003.
9. Lodén M, Perris F, Nielsen NH, Emdin S, Landberg G. C-erbB2, p27 and G1/S aberrations
in human primary breast cancer. AntiCancer Res 23: 1053-1062, 2003.
10. Burger AM, Grugel R, Landberg G, Kitching R, Seth A. The breast cancer-associated gene
Di12 has oncogenic activity. Anticancer Res 23: 2027-2033, 2003.
11. Helczynska K, Kronblad Å, Jöghi A, Landberg G, Påhlman S. Hypoxia induces
dedifferentiation in ductal carcinoma in situ carcinoma of the breast. Cancer Research April 1; 63 (7): 1441-1444, 2003.
12. Hedberg Y, Ljungberg B, Roos G, Landberg G. Retinoblastoma protein in human renal cell
carcinoma in relation to alterations in G1/S regulatory proteins. In press, International J Cancer, 2004.
13. Stendahl M, Kronblad Å, Rydén L, Emdin S, Bengtsson NO, Landberg G. Cyclin D1
overexpression is a negative predictive factor for tamoxifen response in post-menopausal low risk breast cancer patients. Prel. accepted British J Cancer
14. Dejmek J, Leandersson K, Manjer J, Bjartell A, Emdin SO, Vogel WF, Landberg G.
Andersson T. Expression of Wnt-5a in invasive breast carcinomas correlates with disease-specific survival and the expression, but not the activation, of Syk. Submitted, 2003.
15. Bladh J, Landberg G, Persson J. Regulation of the cyclin A1 protein is associated with its
differential subcellular localization in hematopoietic and leukemic cells. Submitted, 2003.
Ekonomisk redovisning ”Biobanking – Tissue Arraying” 2003 Budgeterat belopp 2003: 1.050.000:- Rekvirerat belopp: Utgifter: Lönemedel: Övriga utgifter: Insänd rekvisition men ännu ej erhållet belopp 1.123.387:71 1.144.093:83 Ekonomisk redovisning ”Inköp av robotutrustning” 2003 Budgeterat belopp: 1.550.000:- Rekvirerat belopp: Utgifter: Insänd rekvisition men ännu ej erhållet belopp 1.574.685:71 1.574.685:80
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