liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carcinogenesis is a progressive process involving multiple genetic alterations in tumor cells and complex interactions in the tumor-host microenvironment. To better understand the contribution of molecular alterations in tumor cells and stromal variables to the development of colorectal cancer (CRC) and identify prognostic factors, in this study we examined the clinicopathological and biological significance of stromal variables, including particularly interesting new cysteine-histidine rich protein (PINCH), inflammatory infiltration, angiogenesis and lymphangiogenesis, as well as hRAD50/hMRE11/hNBS1 proteins and hRAD50 mutation in tumor cell in CRC.

PINCH protein expression in the stroma was increased from normal mucosa to primary tumors and further to lymph node metastases. In particular, PINCH expression was most intense at the tumor invasive margin, which was related to low inflammatory infiltration and independently related to an unfavorable prognosis. Low inflammatory infiltration at the tumor invasive margin was related to advanced tumor stage, worse differentiation and microsatellite instability (MSI). Further, it was independently related to an unfavorable prognosis. Increased blood and lymphatic vessel density was observed in the primary tumors compared with the corresponding normal mucosa. However, neither angiogenesis nor lymphangiogenesis was associated with tumor stage and patients’ survival. Moreover, PINCH was present in a proportion of endothelial cells of the tumor vasculature, and PINCH expression in tumor-associated stroma was positively related to blood vessel density.

In primary tumor cells of CRC, strong expression of hRAD50, hMRE11 or hNBS1 was related to microsatellite stability (MSS). A high percentage of hMRE11 expression was associated with less local recurrence and high apoptotic activity. Further, we observed that the expression of hRAD50, hMRE11 or hNBS1 among normal mucosa, primary tumors and metastases in MSS CRC differed from that in MSI CRC. In MSS CRC, the expression intensity of hRAD50, hMRE11 and hNBS1 was consistently increased with respect to normal mucosa, but there was no difference between the primary tumors and metastases. In the primary MSS tumors, the expression of individual or combination of hRAD50/hMRE11/hNBS1 was associated with a favorable prognosis in the same series of the CRCs. Moreover, strong/high hRAD50 in MSS primary tumors was related to earlier tumor stage, better differentiation and high inflammatory infiltration, whereas strong hNBS1 expression tended to be independently related to a favorable prognosis in MSS CRC with earlier tumor stage. However, in MSI CRC, there were neither differences in the expression of hRAD50/hMRE11/hNBS1 among normal mucosa, primary tumors and metastases, nor any association of the protein expressions with clinicopathological variables. On the other hand, frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRC.

Our study indicates that 1) PINCH is likely a regulator of angiogenesis, and PINCH expression at the tumor invasive margin is an independent prognostic indicator in CRC. 2) Inflammatory infiltration at the tumor invasive margin is also an independent prognostic indicator in CRC. The lack of association between high inflammatory infiltration and MSI may help to explain the non-association of MSI with survival in CRC patients. 3) Angiogenesis and lymphangiogenesis occur in the early stage of CRC development, but do not associate with CRC progression and patients’ prognosis. 4) hRAD50/hMRE11/hNBS1 may act dependently and independently, playing different roles in MSS and MSI CRC development. In MSS CRC, the strong expression of the three proteins, associated with a favorable prognosis, may present the cellular response against tumor progression. Expression of hNBS1 may be a prognostic indicator for MSS CRC patients in the earlier tumor stage. In MSI CRC, the frameshift mutations at the coding region of hRAD50 may contribute to tumor development.

Place, publisher, year, edition, pages
Linköping University Electronic Press, 2008.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1029
Keyword [en]
Carcinogenesis, genetic alterations, colorectal cancer (CRC), cysteine-histidine rich protein (PINCH), Inflammatory infiltration, Angiogenesis, lymphangiogenesis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-10516ISBN: 978-91-85895-51-9 (print)OAI: oai:DiVA.org:liu-10516DiVA: diva2:17253
Public defence
2008-01-25, Eken, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2015-11-19
List of papers
1. Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer
Open this publication in new window or tab >>Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer
2004 (English)In: Neoplasia, ISSN 1522-8002, Vol. 6, no 6, 796-801 p.Article in journal (Refereed) Published
Abstract [en]

Particularly interesting new cysteine-histidine-rich protein (PINCH), a LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway, is upregulated in stroma associated with many common cancers. The finding suggested that PINCH may be involved in promoting tumor-stromal interactions that support tumor progression, and, if so, tumors with abundant PINCH stromal staining may have a worse prognosis. To test this hypothesis, 174 primary colorectal adenocarcinomas with 39 distant normal mucosa samples and 26 metastases in the lymph nodes were studied by immunohistochemistry, and 7 additional colon tumors were studied by Western blot analysis and immunofluorescence. The abundance of PINCH protein in stroma increased from normal mucosa to primary tumor to metastasis (P < .05), and was more intense at the invasive margin than it was in the intratumoral stroma. Strong stromal immunostaining for PINCH was shown to predict a worse outcome (rate ratio 2.1, 95% CI 1.16-3.37, P = .01), independent of Dukes stage, growth pattern, and tumor differentiation. PINCH was detected in fibroblasts, myofibroblasts, and a proportion of endothelial cells of the tumor vasculature, supporting the involvement of PINCH in promoting tumor-stromal interactions that support tumor progression. Interestingly, stromal staining for PINCH was an independent prognostic indicator in colorectal cancer.

Keyword
colorectal cancer, PINCH, prognosis, protein expression
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12867 (URN)10.1593/neo.04304 (DOI)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2009-08-18
2. Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers
Open this publication in new window or tab >>Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers
Show others...
2005 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, Vol. 11, no 14, 2179-2183 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however, the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TN) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival.

Methods: Three hundred and one colorectal adenocar-cinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope.

Results: Low infiltration at invasive margin (c2 = 3.94, P = 0.047) and in whole tumor stroma (c2 = 3.89, P = 0.049) was associated with MSI, but TN was not (c2 = 0.10, P = 0.75). Low infiltration was related to advanced stage (c2 = 8.67, P = 0.03), poorer differentiation (c2 = 8.84, P = 0.03), DNA non-diploid (c2 = 10.04, P = 0.002), higher S-phase fraction (c2 = 11.30, P = 0.004), positive p53 expression (c2 = 7.94, P = 0.01), and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (c2 = 17.74, P = 0.001) and worse survival (P = 0.02 for univariate, and P = 0.05 for multivariate analysis).

Conclusion: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.

Keyword
Inflammatory infiltration; Necrosis; Microsatellite instability; Prognosis; Colorectal cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12868 (URN)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2009-05-14
3. Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer
Open this publication in new window or tab >>Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer
Show others...
2009 (English)In: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 41, no 2, 116-122 p.Article in journal (Refereed) Published
Abstract [en]

Purpose. The aim of this study was to get a deeper understanding into how adults with cerebral palsy (CP) experience physiotherapy and physical activity in a perspective from childhood to adulthood; and how personal and environmental factors influence possibilities for physiotherapy and physical activity. Method. Data was collected through interviews with 22 community-living adults (35-68 years) with CP, from five counties in Sweden. The questions were open-ended and the interviews were taped and transcribed to written language. The material was analysed through qualitative content analysis, a classification process resulting in different themes. Results. The narratives from the 22 informants, based on experiences from childhood to adulthood, resulted in a description of prerequisites for carrying out physiotherapy and physical activity. Five different themes were identified: (i) Being enjoyable, (ii) Giving effects, (iii) Being comprehensible, (iv) Being integrated in daily life, and (v) Supportive healthcare with competent professionals. Conclusion. The information from the interviews elucidates the importance of a lifelong support from healthcare professionals. Physiotherapists with attentiveness to different life situations in combination with good understanding and knowledge in CP could facilitate continuous physical activity in people growing up and ageing with CP.

Keyword
Angiogenesis, Colorectal cancer, Lymphangiogenesis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16973 (URN)10.1016/j.dld.2008.07.315 (DOI)
Note
Original Publication:Jingfang Gao, Annica Knutsen, G Arbman, John Carstensen, B Franlund and Xiao-Feng Sun, Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer, 2009, DIGESTIVE AND LIVER DISEASE, (41), 2, 116-122.http://dx.doi.org/10.1016/j.dld.2008.07.315Copyright: Elsevier Science B.V., Amsterdamhttp://www.elsevier.com/Available from: 2009-03-24 Created: 2009-02-27 Last updated: 2011-03-04Bibliographically approved
4. The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers
Open this publication in new window or tab >>The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers
2008 (English)In: Disease Markers, ISSN 0278-0240, Vol. 24, no 2, 127-134 p.Article in journal (Refereed) Published
Abstract [en]

RAD50 protein is essential for DNA double-strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR-SSCP-DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)_{9} at coding region of hRAD50 were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs {may be a cellular response against tumor from further progression}, while hRAD50 mutation may be involved in the development of MSI CRCs.

Keyword
Colorectal cancer, hRAD50, immunohistochemistry, microsatellite instability, microsatellite stability
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12870 (URN)10.1155/2008/724796 (DOI)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2014-08-26
5. RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
Open this publication in new window or tab >>RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
2008 (English)In: Histology and Histopathology, ISSN 0213-3911, Vol. 23, 1495-1502 p.Article in journal (Refereed) Published
Abstract [en]

RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohisto-chemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n=208), the corresponding distant (n=41) and adjacent normal mucosa (n=130), and lymph node metastases (n=26), and investigated their clinicopathological significance in colorectal cancers (CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P<0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P<0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P<0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P<0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P=0.03; multivariate analysis: P=0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathlogical significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.

Keyword
RAD50, MRE11, NBS1, Prognosis, Colorectal cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12871 (URN)
Available from: 2008-01-07 Created: 2008-01-07 Last updated: 2009-04-28

Open Access in DiVA

cover(28 kB)42 downloads
File information
File name COVER01.pdfFile size 28 kBChecksum SHA-1
e14a37d67da37111c39cdba45e3b12320bd02d4fdd5e598e4eaa3e84121b77ba09b2595f
Type coverMimetype application/pdf
fulltext(430 kB)1409 downloads
File information
File name FULLTEXT01.pdfFile size 430 kBChecksum SHA-1
608344510d6ad12d317e61818bc110239cf02e13e3cbb3f0ed6e1955c5502d44e8d4275a
Type fulltextMimetype application/pdf

Authority records BETA

Gao, Jingfang

Search in DiVA

By author/editor
Gao, Jingfang
By organisation
OncologyFaculty of Health Sciences
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
Total: 1409 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1845 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf