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Stromal collagens in colorectal cancer and in colorectal liver metastases: tumour biological implications and a source for novel tumour markers
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality. About 50 % of patients with CRC will develop subsequent liver metastases (CLM). The survival for untreated CLM is only a few months and liver resection provides the only chance for a lasting cure. It is therefore essential to detect CLM early, enabling successful surgical resection and achieving a long-term cure. There are no optimal tumour markers for CRC or CLM. The best marker available is Carcinoembryonic Antigen (CEA), a marker found elevated in about 50-60% of patients with CLM, but also in many other conditions. The main focus of cancer research has been on the malignant cancer cell. However, a tumour consists of more than cancer cells. A major part of all solid tumours is made up by the stroma. The tumour stroma is defined as the non-malignant cells of a tumour such as fibroblasts, the cells of the vascular and immune systems as well as the extracellular matrix (ECM). The basement membrane (BM) is a specialized form of the ECM in which type IV collagen is the major protein component. All epithelial cells need a contact to the BM and the definition of an invasive cancer is the degradation of the BM and the spread of cancer cells beyond this structure. Different metastatic growth patterns of CLM have previously been described, namely the desmoplastic, pushing and replacement type of CLM. These differ in their stromal reaction in the border, which separates the tumour from the normal liver. In this thesis the tumour stroma of CRC and CLM is studied with a special emphasis on stromal collagens. The aim is to investigate whether stromal collagens/ circulating type IV collagen can be used as tumour markers for CRC and CLM, and to compare this to the conventional marker CEA. The circulating type IV collagen level is also measured in liver metastases from other primary tumours than CRC. Furthermore, the differences between the stroma of a primary CRC that metastasizes to the liver when compared to a CRC that never spreads are analysed. Additionally, the metastatic growth pattern of CLM is studied in relation to the primary tumour, stromal components and survival. We also sought out to find whether CRC cell lines possess the trait to produce ECM proteins endogenously, and in response to a normal liver stroma in a novel organotypic model for CLM.

Methods: Expression patterns of type I, III and IV collagen were studied by immunofluorescence (IF), chemical staining and immunohistochemistry (IHC) in normal colorectal tissue, normal liver, CRC, CLM, benign liver lesions and in liver metastases of other origin than CRC. Circulating plasma levels of type IV collagen were analysed in healthy controls, patients with CRC (T stage I-III) and in patients with CLM. Samples were analysed at the time of diagnosis, during and after oncological and surgical treatment and at the time of relapsing or progressive disease. Additionally, circulating levels were analysed in patients with benign liver lesions and in liver metastases of other origin than CRC. The metastatic growth pattern of CLM was classified according to earlier descriptions. CRC cell lines were studied regarding their production of type IV collagen. The growth, invasiveness and stromal production in CRC cell lines were also investigated in a new organotypic model for CLM using human liver specimens.

Results: Circulating type IV collagen levels are increased in patients with CLM and other epithelial-derived liver metastases, and is found normal in patients with primary CRC (stage I-III), with liver metastases from tumours of non-epithelial origin, benign liver lesions and in healthy controls. The type IV collagen levels in patients with CLM reflect the tumour burden in the liver, decreases in response to therapy and is found increased in progressive or relapsing disease. The combination of circulating type IV collagen and CEA increased the sensitivity and specificity for detecting CLM. Livermetastatic CRC displayed an increased stromal production when compared to non-metastatic CRC, with an increased type IV collagen expression in the direct vicinity of the CRC cells. The earlier described growth patterns of CLM were verified, with the pushing type of CLM associated with a short survival and poor outcome. Furthermore, CRC cell lines possess the trait of endogenously producing type IV collagen. The novel organotypic liver model revealed that CRC cell lines grown in the context of normal liver stroma, devoid of other cells, does not elicit a desmoplastic reaction.

Conclusion: Circulating type IV collagen is a promising tumour marker for CLM, where the levels reflect the hepatic tumour burden and can detect disease relapse after liver surgery. The combination of the tumour markers CEA and type IV collagen is superior to CEA alone. The stromal composition of primary CRC predicts the risk of subsequent CLM and the metastatic growth pattern of CLM is related to survival.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 74 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1557
Keyword [en]
Colorectal cancer, colorectal liver metastases, tumour marker, stroma, type IV collagen, metastatic growth pattern
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-67860ISBN: 978-91-7459-581-9 (print)OAI: oai:DiVA.org:umu-67860DiVA: diva2:614502
Public defence
2013-04-19, Sal B, By 1 D, Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-08 Created: 2013-04-04 Last updated: 2013-04-08Bibliographically approved
List of papers
1. Type IV collagen as a tumour marker for colorectal liver metastases
Open this publication in new window or tab >>Type IV collagen as a tumour marker for colorectal liver metastases
2011 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 37, no 7, 611-617 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.

METHODS: The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.

RESULTS: In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.

CONCLUSIONS: Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Collagen, Basement membrane, Stroma, Biomarker, Cancer
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-48642 (URN)10.1016/j.ejso.2011.04.010 (DOI)21620632 (PubMedID)
Available from: 2012-07-10 Created: 2011-10-26 Last updated: 2017-12-07Bibliographically approved
2. Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour
Open this publication in new window or tab >>Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour
Show others...
2012 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 12, 5183-5191 p.Article in journal (Refereed) Published
Abstract [en]

Background: The tumour stroma is an important modulator of cancer cell behaviour. The aim of this study was to compare the stromal composition between primary colorectal cancer (CRC) and colorectal liver metastases (CLM).

Materials and Methods: The stromal composition in matched tissue sections of CRC and subsequent CLM was analysed, and related to clinical parameters.

Results: Differences in the expression pattern of type I collagen and type IV collagen in CRC was related to a higher risk of CLM. Two types of CLM the desmoplastic and pushing type were identified. The time between CRC and diagnosis of CLM was shorter (p=0.047) for desmoplastic CLM. The mortality rate was higher for pushing CLM due to frequent extrahepatic disseminated disease. A difference in the overall survival rate between patients with desmoplastic and those with pushing CLM was seen at follow-up of more than 60 months (p=0.046).

Conclusion: The liver-metastasizing potential is related to the stromal composition of primary CRC. There are distinct growth patterns in CLM with differences in stromal composition and clinical outcome.

Keyword
Extracellular matrix, surgery, tumour marker, colorectal cancer, liver metastasis, stromal composition
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:umu:diva-63762 (URN)000312040000006 ()
Available from: 2013-01-14 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
3. Improved tumor marker sensitivity by combined type IV collagen and CEA measurement in colorectal liver metastases
Open this publication in new window or tab >>Improved tumor marker sensitivity by combined type IV collagen and CEA measurement in colorectal liver metastases
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(English)Article in journal (Other academic) Submitted
Keyword
Surgery, Tumor marker, Colorectal cancer, Liver metastases, Stroma, Prognosis
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-67834 (URN)
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2013-07-08Bibliographically approved
4. Increased type IV collagen expression is a feature in liver metastases of epithelial origin and related to invasiveness of CRC cells in a novel organotypic liver metastatic model
Open this publication in new window or tab >>Increased type IV collagen expression is a feature in liver metastases of epithelial origin and related to invasiveness of CRC cells in a novel organotypic liver metastatic model
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(English)Article in journal (Other academic) Submitted
Keyword
Type IV collagen, Extracellular matrix, Surgery, Tumour marker, Colorectal cancer, Liver metastases, Stroma
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-67835 (URN)
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2013-07-08Bibliographically approved

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