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Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2

Ali, Haytham ; AbdelMageed, Manar ; Olsson, Lina ; Lindmark, Gudrun LU ; Hammarström, Marie Louise ; Hammarström, Sten and Sitohy, Basel (2023) In Frontiers in Oncology 13.
Abstract

Introduction: Approximately 25% of colon cancer (CC) patients having curative surgery will relapse. Therefore, it is crucial to identify patients with increased recurrence risk to offer them adjuvant chemotherapy. Three markers with prominent expression in fibroblasts: forkhead box Q1 (FOXQ1), matrix metalloproteinase-11 (MMP11), and thrombospondin-2 (THBS2), and the fibroblast expressed chemokine CXCL12 were selected for studies because of the critical role of fibroblasts in the microenvironment of the tumor. Methods: The expression levels of the biomarkers were assessed in primary CC tumors, lymph nodes of CC patients and controls, and CC cell lines at mRNA and protein levels by real-time qRT-PCR and immunohistochemistry,... (More)

Introduction: Approximately 25% of colon cancer (CC) patients having curative surgery will relapse. Therefore, it is crucial to identify patients with increased recurrence risk to offer them adjuvant chemotherapy. Three markers with prominent expression in fibroblasts: forkhead box Q1 (FOXQ1), matrix metalloproteinase-11 (MMP11), and thrombospondin-2 (THBS2), and the fibroblast expressed chemokine CXCL12 were selected for studies because of the critical role of fibroblasts in the microenvironment of the tumor. Methods: The expression levels of the biomarkers were assessed in primary CC tumors, lymph nodes of CC patients and controls, and CC cell lines at mRNA and protein levels by real-time qRT-PCR and immunohistochemistry, respectively. Results: FOXQ1, MMP11, and THBS2 mRNAs were expressed at significantly higher levels in primary tumors compared to normal colon (P=0.002, P<0.0001, and P<0.0001, respectively). In contrast, CXCL12 mRNA levels were higher in normal colon tissue. FOXQ1, MMP11, and THBS2 levels were also expressed at significantly higher levels in metastasis-positive lymph nodes compared to both metastasis-negative- and control nodes (P<0.0001/P=0.002, P<0.0001/P<0.0001, and P<0.0001/P<0.0001, respectively). Immuno-morphometry revealed that 30–40% of the tumor cells expressed FOXQ1, MMP11, and THBS2. FOXQ1 and THBS2 were barely detected in normal colon epithelium (P<0.0001), while MMP11 was expressed in normal colon epithelium at high levels. Discussion: We conclude that CC tumor cells show ectopic expression of FOXQ1 and THBS2 possibly making these tumor cells independent of fibroblast cell support. The high expression levels of these two biomarkers in metastatic lymph nodes suggest that they are potential indicators of patients at risk for recurrence.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
colon cancer, CXCL12, fibroblasts, FOXQ1, immunohistochemistry, MMP11, qRT-PCR, THBS2
in
Frontiers in Oncology
volume
13
article number
1297324
publisher
Frontiers Media S. A.
external identifiers
  • pmid:38156105
  • scopus:85180658536
ISSN
2234-943X
DOI
10.3389/fonc.2023.1297324
language
English
LU publication?
yes
id
3d66a56e-5596-4f79-8ddc-f22a08345d3a
date added to LUP
2024-02-08 15:42:13
date last changed
2024-04-24 22:17:35
@article{3d66a56e-5596-4f79-8ddc-f22a08345d3a,
  abstract     = {{<p>Introduction: Approximately 25% of colon cancer (CC) patients having curative surgery will relapse. Therefore, it is crucial to identify patients with increased recurrence risk to offer them adjuvant chemotherapy. Three markers with prominent expression in fibroblasts: forkhead box Q1 (FOXQ1), matrix metalloproteinase-11 (MMP11), and thrombospondin-2 (THBS2), and the fibroblast expressed chemokine CXCL12 were selected for studies because of the critical role of fibroblasts in the microenvironment of the tumor. Methods: The expression levels of the biomarkers were assessed in primary CC tumors, lymph nodes of CC patients and controls, and CC cell lines at mRNA and protein levels by real-time qRT-PCR and immunohistochemistry, respectively. Results: FOXQ1, MMP11, and THBS2 mRNAs were expressed at significantly higher levels in primary tumors compared to normal colon (P=0.002, P&lt;0.0001, and P&lt;0.0001, respectively). In contrast, CXCL12 mRNA levels were higher in normal colon tissue. FOXQ1, MMP11, and THBS2 levels were also expressed at significantly higher levels in metastasis-positive lymph nodes compared to both metastasis-negative- and control nodes (P&lt;0.0001/P=0.002, P&lt;0.0001/P&lt;0.0001, and P&lt;0.0001/P&lt;0.0001, respectively). Immuno-morphometry revealed that 30–40% of the tumor cells expressed FOXQ1, MMP11, and THBS2. FOXQ1 and THBS2 were barely detected in normal colon epithelium (P&lt;0.0001), while MMP11 was expressed in normal colon epithelium at high levels. Discussion: We conclude that CC tumor cells show ectopic expression of FOXQ1 and THBS2 possibly making these tumor cells independent of fibroblast cell support. The high expression levels of these two biomarkers in metastatic lymph nodes suggest that they are potential indicators of patients at risk for recurrence.</p>}},
  author       = {{Ali, Haytham and AbdelMageed, Manar and Olsson, Lina and Lindmark, Gudrun and Hammarström, Marie Louise and Hammarström, Sten and Sitohy, Basel}},
  issn         = {{2234-943X}},
  keywords     = {{colon cancer; CXCL12; fibroblasts; FOXQ1; immunohistochemistry; MMP11; qRT-PCR; THBS2}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Oncology}},
  title        = {{Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2}},
  url          = {{http://dx.doi.org/10.3389/fonc.2023.1297324}},
  doi          = {{10.3389/fonc.2023.1297324}},
  volume       = {{13}},
  year         = {{2023}},
}