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Cell adhesion proteins in different invasive patterns of colon carcinomas: a morphometric and molecular genetic study
Örebro University, School of Health and Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal carcinoma is the second most common type of cancer in both men and women in Sweden. Cancer of the colon and rectum are often considered together and their ten year survival rate is approximately 50 – 60 % depending on sex and location. Different histopathological characteristics of such cancers, including the complexity of growth, are of importance for prognosis.

This thesis has compared different morphometric methods in order to achieve a quantitative and objective measurement of the invasive front of colon carcinoma. Since the growth pattern is dependent on the cell adhesiveness of different proteins we studied the distribution and localization of E-cadherin, Beta-catenin, Claudin 1,2,7 and Occludin as well as screened the genes for mutations.

We found a perturbed protein expression of E-cadherin, Beta-catenin, Claudin 1,2,7 and Occludin in tumor sections compared to normal mucosa, but no relation to tumor volume or growth pattern could be seen. The tumor volume was found to be correlated to the growth pattern but not responsible to the perturbed protein expression. In the mutation screening we found a SNP in exon 13 the E-cadherin gene in the tumor, as well as in exon 2 of Claudin 1 and exon 4 of Claudin 7 in both tumor and normal mucosa. No correlation between mutations and growth pattern or tumor volume was found.

In conclusion, this thesis shows that the computer image analysis with estimation of fractal dimension and number of free tumor cell clusters is superior to the semi quantitative visual grading of tumor invasive complexity. The aberrant expression of cell adhesion proteins in the tumor compared to normal mucosa as well as polymorphisms in the cell adhesion genes CLDN1 and CLDN7 in both tumor and normal mucosa can suggest that these aberrations are important in the tumorigenesis of colon carcinoma.

 

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2008. , 61 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 24
Keyword [en]
colon carcinoma, growth pattern, tight junction, Complexity Index, cell adhesion, E-cadherin, Beta-catenin, Occludin, Claudin.
National Category
Clinical Science
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-2603ISBN: 978-91-7668-640-9 (print)OAI: oai:DiVA.org:oru-2603DiVA: diva2:136463
Public defence
2008-11-28, Wilandersalen, USÖ, Universitetsjukhuset, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2011-05-17Bibliographically approved
List of papers
1. Characterization of colon carcinoma growth pattern by computerized morphometry: definition of a complexity index
Open this publication in new window or tab >>Characterization of colon carcinoma growth pattern by computerized morphometry: definition of a complexity index
2008 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 22, no 4, 465-472 p.Article in journal (Refereed) Published
Abstract [en]

The invasive front of carcinomas may vary in complexity from smooth to highly complex when the front splits up into small cell clusters or even single cancer cells. The degree of complexity is usually estimated visually and semiquantitatively by a pathologist, although more objective methods based on computer-assisted image analysis are available. In this study, we compared the visual estimation of the irregularity of the tumour invasion front of colon carcinomas to different quantitative image analytical techniques and defined a complexity index for the invasive margin. Sections from 29 archived colon carcinomas were stained immunohistochemically for cytokeratin 8. Images of the tumour invasion front were read into a computer and thresholded so that the tumour tissue became black and the background white or so that the tumour front was outlined by a single pixel line. The invasive front was visually classified into four degrees of irregularity by a pathologist. The complexity of the front was then assessed using four different image analysis techniques, i.e. the estimation of fractal dimension, tumour front length, number of tumour cell clusters and lacunarity. Fractal dimension and tumour cell clusters together gave the best correlation to visual grading using a discriminant analysis. A cluster analysis and a tree diagram analysis were then performed and were found to be superior to visual estimation. The clusters represent different degrees of complexity and the result of the tree diagram analysis can be used to assign complexity indices to colon tumours. The fractal dimension separated tumours up to a certain level (1.5-1.6) of complexity. When the tumour front split up into small cell clusters, the counting of tumour cell clusters separated the cells over and above the fractal dimension. This new technique can be used to objectively and quantitatively describe the complexity of the invasive front of tumours.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-3031 (URN)10.3892/ijmm_00000044 (DOI)18813853 (PubMedID)
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2016-12-06Bibliographically approved
2. Disturbed expression of E-cadherin, beta-catenin and tight junction proteins in colon carcinoma is unrelated to growth pattern and genetic polymorphisms
Open this publication in new window or tab >>Disturbed expression of E-cadherin, beta-catenin and tight junction proteins in colon carcinoma is unrelated to growth pattern and genetic polymorphisms
2008 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 4, 253-262 p.Article in journal (Refereed) Published
Abstract [en]

Adhesion proteins are responsible for the structural integrity of epithelial tissue and in tumors this integrity is often lost, resulting in a disorganization of the tissue. In the present study the complexity of the invasive front of colon carcinomas was correlated with cell adhesion protein expression and with polymorphisms in their genes. A complexity index was constructed from 32 colon carcinomas using computer-assisted morphometry estimating fractal dimension and tumor cell clusters followed by tree analysis. Immunohistochemical staining of beta-catenin, E-cadherin, occludin and claudin 2 was used for assessment of protein expression. Genetic screening of tissue from the tumor invasion front with laser microdissection was performed using SSCP and DNA sequencing. Adhesion protein distribution was significantly disturbed in most carcinomas. A single mutation in the gene of beta-catenin was found but there was no correlation between protein expression and genetic polymorphism. Nor was there any correlation between the complexity of the invasive border and protein distribution or genetic alterations. The results indicate that the complexity of colon carcinoma invasion is not dependent on genetic derangements in the genes of adhesion proteins or the protein distribution. Rather, aberrations in the function of other proteins related to the adhesive proteins could be responsible.

Keyword
patology, molecular cell biology
National Category
Medical and Health Sciences Cell and Molecular Biology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-3032 (URN)10.1111/j.1600-0463.2008.00894.x (DOI)18397460 (PubMedID)
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2016-12-06Bibliographically approved
3. Tumor volume of colon carcinoma is related to the invasive pattern but not to the expression of cell adhesion proteins
Open this publication in new window or tab >>Tumor volume of colon carcinoma is related to the invasive pattern but not to the expression of cell adhesion proteins
2009 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 3, 205-211 p.Article in journal (Refereed) Published
Abstract [en]

Tumor volume increases during growth and due to tumor progression various mutations appear that may cause phenotypic changes. The invasive pattern may thus be affected resulting in a more disorganized growth. This phenomenon might be due to mutations in the genome of the adhesion proteins, which are responsible for the structural integrity of epithelial tissue. Tumor volume was assessed in whole mount sections of 33 colon carcinomas using Cavalieri's principle. Images from the entire invasive border were captured and used for calculating the irregularity of the border (Complexity Index). The expression of the adhesion proteins E-cadherin, beta-catenin, Claudin 2 and Occludin was assessed after immunohistochemical staining of two randomly selected areas of the invasive front of the tumor. Statistical significance for differences in volume was obtained for tumor Complexity Index, tumor stage (pT) and lymph node status (pN). Expression of adhesion proteins was significantly perturbed in the tumors compared with normal mucosa but only infrequently correlated to tumor differentiation or invasive pattern. The results show that when tumor volume increases the invasive pattern becomes more irregular which is compatible with tumor progression. A direct contribution of adhesion protein derangement to this process appears to be insignificant.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2009
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-3033 (URN)10.1111/j.1600-0463.2008.00011.x (DOI)000265487600006 ()19245593 (PubMedID)2-s2.0-61349175837 (Scopus ID)
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2017-03-13Bibliographically approved
4. Claudin 1 and Claudin 7 gene polymorphisms and protein derangement are unrelated to the growth pattern of colon carcinoma
Open this publication in new window or tab >>Claudin 1 and Claudin 7 gene polymorphisms and protein derangement are unrelated to the growth pattern of colon carcinoma
(English)Manuscript (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-3034 (URN)
Available from: 2008-11-10 Created: 2008-11-10 Last updated: 2016-12-06Bibliographically approved

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