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
Macrophage antigen expression in breast and colorectal cancers: A consequence of macrophage - tumour cell fusion?
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Carcinogenesis is a sophisticated biological process consisting of a series of progressive changes in somatic cells from premalignant to malignant phenotype. Despite the vast information available about cancer cells, the origin of cancer and cause of metastasis still remain enigmatic. The hypothesis of cell fusion is one of several models explaining the evolution of neoplasia into clinically significant cancer. This theory states that cancer cells through heterotypic fusion with host cells generate hybrids expressing traits from both parental cells, and acquire metastatic potentials and growth-promoting properties. The cell fusion theory is still unproven and speculative, but cell fusion is a common biological process in normal tissue. Accumulated evidence shows that macrophage-cancer cell fusion occurs in vitro and in vivo and produces hybrids with metastatic potential, but the clinical significant of cell fusion is unclear. The aim of this thesis is to test this hypothesis in clinical patient materials and to explore the clinical significance of macrophage phenotype traits in solid tumours.

Paraffin-embedded cancer and normal tissue specimens from patients with breast cancer (n=133) and colorectal cancer (two different patient materials with totally 240 patients) were immunostained for the macrophage-specific antigen, CD163. The expression of CD163 was tested in relation to macrophage infiltration and tumour stage, survival time, irradiation, DNA ploidy, cancer cell proliferation and apoptosis.

Phenotypic macrophage traits, such as the expression of CD163, were seen in both breast and colorectal cancers, and were correlated to advanced tumour stages and poor survival. CD163 expression was more frequent in rectal cancer after irradiation and was associated with decreased apoptosis. Cancer cell proliferation was correlated to both macrophage infiltration and CD163 expression. Multivariate analysis showed that CD163 is a significant prognostic factor in both breast and colorectal cancers.

In an attempt to examine factors related to the function of macrophage fusion, the expression of the signalling adaptor protein DAP12 was tested and related to CD163 expression in breast cancers from 133 patients. DAP12 was shown to occur in breast cancer cells and was related to high histologic tumour grade, skeletal and liver metastasis, and poor prognosis. The findings in this thesis support the cell fusion theory and illustrate its clinical impact on tumour progression and metastasis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1149
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54820ISBN: 978-91-7393-545-6 (print)OAI: oai:DiVA.org:liu-54820DiVA: diva2:310555
Public defence
2009-10-02, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-05-20Bibliographically approved
List of papers
1. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival
Open this publication in new window or tab >>Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival
Show others...
2008 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 123, no 4, 780-786 p.Article in journal (Refereed) Published
Abstract [en]

Cells of the monocyte/macrophage lineage are important for tumour cell migration, invasion and metastasis. Fusion between macrophages and cancer cells in animal models in vitro and in vivo causes hybrids with increased metastatic potential. Primary breast cancer cells were characterized for macrophage antigens to test if phenotypic resemblance to macrophages is related to early distant recurrence. Immunostaining for CD163, MAC387 and CD68 was performed in a breast cancer tissue micro array from 127 patients consequently followed up for a median of 13 years. Tumour-associated macrophages expressed all 3 antigens. The breast cancers expressed CD163 to 48%, MAC387 to 14% while CD68 was not expressed. TGF-β staining intensity was positively related to both CD163 and MAC387 expression. Expression of CD163 in the cancer cells was compared to their DNA ploidy, Nottingham Histological Grade, TNM-stage, node state, presence of estrogen receptors and occurrence of distant metastases and survival. Cancers of a more advanced histological grade expressed CD163 to a higher extent. Cells expressing MAC387 were more common in cancers with a high proportion of CD163 positive cells. Multivariate analysis showed that expression of the macrophage antigen CD163 in breast cancer cells has a prognostic impact on the occurrence of distant metastases and reduced patient survival time.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43420 (URN)10.1002/ijc.23527 (DOI)73820 (Local ID)73820 (Archive number)73820 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.
Open this publication in new window or tab >>Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.
2009 (English)In: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, no 8, 1826-1831 p.Article in journal (Refereed) Published
Abstract [en]

Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.

Keyword
rectal cancer • macrophages • metastasis • survival • cell fusion • radiotherapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21408 (URN)10.1002/ijc.24506 (DOI)19582880 (PubMedID)
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2010-04-14
3. Tumor cell expression of CD163 is an independent prognostic factor in colorectal cancer patients
Open this publication in new window or tab >>Tumor cell expression of CD163 is an independent prognostic factor in colorectal cancer patients
(English)Manuscript (preprint) (Other academic)
Abstract [en]

CD163 is a macrophage specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression, as a macrophage trait, and macrophage infiltration and their clinical-pathological significance in colorectal cancer. The hypothesis of macrophage-cancer cell fusion may explain the expression of CD163 in cancer cells.

Immune-staining of CD163 and macrophage infiltration were evaluated in paraffinembedded specimens, earlier analyzed for Ki-67, CD31 and D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 77 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data.

CD163 is positive in cancer cells in 16-18% of the patients and it is related to advanced tumor stages (stage III-IV) and unfavorable prognosis. High macrophage infiltration may be related to lower survival but this relation was not statistically significant. The prognostic significance of CD163 expression is independent of tumor stage (p=0,015) and macrophage density in tumor stroma (p=0,007).

The expression of macrophage phenotype in colorectal cancer cells is associated with poor prognosis independently of tumor stage and macrophage density in the tumour stroma. Macrophages may promote tumour growth and progression by an autocrine interaction with cancer cells. Macrophage – cancer cell fusion may occur in colorectal cancer and contribute to tumour progression and metastasis.

Keyword
Colorectal cancer, tumour associated macrophages, macrophage infiltration, CD163, cell fusion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54818 (URN)
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-04-14Bibliographically approved
4. DAP12, a macrophage fusion receptor, is expressed in breast cancer cells and associated with skeletal and liver metastases and poor survival
Open this publication in new window or tab >>DAP12, a macrophage fusion receptor, is expressed in breast cancer cells and associated with skeletal and liver metastases and poor survival
(English)Manuscript (preprint) (Other academic)
Abstract [en]

DAP12 is a transmembrane receptor present in myeloid cells and is essential for the development of functionally mature osteoclasts and microglia, and for integrin signaling in macrophages and neutrophils. The macrophage specific antigen CD163 is expressed in breast and colorectal cancer and is associated with early cancer recurrence and poor prognosis. We hypothesize that macrophage traits in cancer cells may be explained by fusion between cancer cells and tumor associated macrophages. The role of DAP12 in the fusion between cancer cells and macrophages is not known. This study was performed to investigate the expression of DAP12 in breast cancer cells and its´ relation to macrophage trait manifested by CD163 expression.

Immunostaining of DAP12, CD163 and MAC387 were evaluated in paraffinembedded specimens from totally 133 patients with breast cancer. The outcomes were analyzed in relation to clinicopathological data.

DAP12 expression was positive in the majority of cases (64%) with breast cancer and associated with advanced tumor grade (p= 0.015) and liver metastasis (p= 0.0465) but not lung metastasis (0.997). It tended to correlate with skeletal metastases (p=0.0673). Patients with breast cancer expressing high DAP12 had poor prognosis with higher rates of skeletal (p=0.023) and liver metastases (p=0.028) and overall shorter distant recurrence free survival (p=0.0028). DAP12 expression was neither correlated to CD163 nor MAC387 expression. To our knowledge, this is the first study where DAP12 expression is reported in breast cancer.

In conclusion, DAP12 is expressed in breast cancer and is significantly related to skeletal and liver metastasis as well as poor prognosis. We hypothesize that DAP12 expression may promote fusion between breast cancer cells and macrophages. It may even promote homing of cancer cells in bone and liver tissue and result in increased metastasis at these sites.

Keyword
Breast cancer, tumour associated macrophages, DAP12, CD163, metastasis, cell fusion
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54819 (URN)
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-04-14

Open Access in DiVA

Macrophage antigen expression in breast and colorectal cancers : A consequence of macrophage - tumour cell fusion?(892 kB)1229 downloads
File information
File name FULLTEXT01.pdfFile size 892 kBChecksum SHA-512
82368ffaaa4af62105f5227361e5f3871d5e3beb3e2f5be338abdc3a031dfb087749f0cf199748186a235e2d4f27c56017afb9e4c661ac1d4726144e162286a4
Type fulltextMimetype application/pdf
Cover(87 kB)53 downloads
File information
File name COVER01.pdfFile size 87 kBChecksum SHA-512
5c0ea7bedaf30872a2398584e56608d786063b85d2816767eac562bab2cc2b2d05c7cf6affdc96f49ed6dbd84833515900b5a0c2e895e4229095413f59f6711c
Type coverMimetype application/pdf

Authority records BETA

Shabo, Ivan

Search in DiVA

By author/editor
Shabo, Ivan
By organisation
Surgery Faculty of Health SciencesOncology Centre
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 1229 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: 173 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