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Macrophage subtype predicts lymph node metastasis in oesophageal adenocarcinoma and promotes cancer cell invasion in vitro

View Article: PubMed Central - PubMed

ABSTRACT

Background:: Currently, there is a lack of ideal biomarkers for predicting nodal status in preoperative stage of oesophageal adenocarcinoma (EAC) to aid optimising therapeutic options. We studied the potential of applying subtype macrophages to predict lymph node metastasis and prognosis in EAC.

Material and methods:: Fifty-three EAC resection specimens were immunostained with CD68, CD40 (M1), and CD163 (M2). Lymphatic vessel density (LVD) was estimated with the staining of D2-40. Subsequently, we tested if M2d macrophage could promote EAC cell migration and invasion.

Results:: In EAC without neoadjuvant treatment, an increase in M2-like macrophage was associated with poor patient survival, independent of the locations of macrophages in tumour. The M2/M1 ratio that represented the balance between M2- and M1-like macrophages was significantly higher in nodal-positive EACs than that in nodal-negative EACs, and inversely correlated with patient overall survival. The M2/M1 ratio was not related to LVD. EAC cell polarised THP1 cell into M2d-like macrophage, which promoted EAC cell migration and invasion. Neoadjuvant therapy appeared to diminish the correlation between the M2/M1 ratio and survival.

Conclusions:: The ratio of M2/M1 macrophage may serve as a sensitive marker to predict lymph node metastasis and poor prognosis in EAC without neoadjuvant therapy. M2d macrophage may have important roles in EAC metastasis.

No MeSH data available.


Related in: MedlinePlus

M2-like macrophage is associated with poor overall survival, but not associated with lymph node spread in EAC patients without neoadjuvant therapy. (A) The count of M1 or M2 macrophage in tumour centre and at tumour edge is not significantly different between EACs with (EAC N1-3) and without lymph node metastasis (EAC N0). (B) Kaplan–Meier overall survival curves of 31 EAC patients stratified by the counts of M1-like and M2-like macrophage based on the median number.
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fig1: M2-like macrophage is associated with poor overall survival, but not associated with lymph node spread in EAC patients without neoadjuvant therapy. (A) The count of M1 or M2 macrophage in tumour centre and at tumour edge is not significantly different between EACs with (EAC N1-3) and without lymph node metastasis (EAC N0). (B) Kaplan–Meier overall survival curves of 31 EAC patients stratified by the counts of M1-like and M2-like macrophage based on the median number.

Mentions: To assure the specificity of the makers we chose for this study, immunofluorescence double staining (CD68/CD40 and CD68/CD163) was performed and showed that most CD40- or CD163-positive cells co-expressed CD68 (Supplementary Figure 1A). In addition, double immunofluorescence or immunohistochemical staining for CD40 and CD163 was conducted and demonstrated only rare cells expressed both CD40 and CD163 (Supplementary Figures 1A and 1B). The results suggested that the markers we used in the study for identifying M1-like and M2-like subtypes of macrophage should be feasible and reliable in EAC specimens. Compared with EACs without lymph node metastasis, M1- like or M2-like macrophage, either located in tumour centre or at tumour edge, was not increased in EACs with positive lymph node(s) (Figure 1A and Supplementary Figure 2). Nevertheless, M2-like but not M1-like macrophage was significantly associated with poor patient OS (Figure 1B). CD68+ MC did not show any difference between EACs with or without nodal spread in either location (Supplementary Figure 3A). CD68+ macrophage did not relate to patient prognosis (Supplementary Figure 3B).


Macrophage subtype predicts lymph node metastasis in oesophageal adenocarcinoma and promotes cancer cell invasion in vitro
M2-like macrophage is associated with poor overall survival, but not associated with lymph node spread in EAC patients without neoadjuvant therapy. (A) The count of M1 or M2 macrophage in tumour centre and at tumour edge is not significantly different between EACs with (EAC N1-3) and without lymph node metastasis (EAC N0). (B) Kaplan–Meier overall survival curves of 31 EAC patients stratified by the counts of M1-like and M2-like macrophage based on the median number.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559839&req=5

fig1: M2-like macrophage is associated with poor overall survival, but not associated with lymph node spread in EAC patients without neoadjuvant therapy. (A) The count of M1 or M2 macrophage in tumour centre and at tumour edge is not significantly different between EACs with (EAC N1-3) and without lymph node metastasis (EAC N0). (B) Kaplan–Meier overall survival curves of 31 EAC patients stratified by the counts of M1-like and M2-like macrophage based on the median number.
Mentions: To assure the specificity of the makers we chose for this study, immunofluorescence double staining (CD68/CD40 and CD68/CD163) was performed and showed that most CD40- or CD163-positive cells co-expressed CD68 (Supplementary Figure 1A). In addition, double immunofluorescence or immunohistochemical staining for CD40 and CD163 was conducted and demonstrated only rare cells expressed both CD40 and CD163 (Supplementary Figures 1A and 1B). The results suggested that the markers we used in the study for identifying M1-like and M2-like subtypes of macrophage should be feasible and reliable in EAC specimens. Compared with EACs without lymph node metastasis, M1- like or M2-like macrophage, either located in tumour centre or at tumour edge, was not increased in EACs with positive lymph node(s) (Figure 1A and Supplementary Figure 2). Nevertheless, M2-like but not M1-like macrophage was significantly associated with poor patient OS (Figure 1B). CD68+ MC did not show any difference between EACs with or without nodal spread in either location (Supplementary Figure 3A). CD68+ macrophage did not relate to patient prognosis (Supplementary Figure 3B).

View Article: PubMed Central - PubMed

ABSTRACT

Background:: Currently, there is a lack of ideal biomarkers for predicting nodal status in preoperative stage of oesophageal adenocarcinoma (EAC) to aid optimising therapeutic options. We studied the potential of applying subtype macrophages to predict lymph node metastasis and prognosis in EAC.

Material and methods:: Fifty-three EAC resection specimens were immunostained with CD68, CD40 (M1), and CD163 (M2). Lymphatic vessel density (LVD) was estimated with the staining of D2-40. Subsequently, we tested if M2d macrophage could promote EAC cell migration and invasion.

Results:: In EAC without neoadjuvant treatment, an increase in M2-like macrophage was associated with poor patient survival, independent of the locations of macrophages in tumour. The M2/M1 ratio that represented the balance between M2- and M1-like macrophages was significantly higher in nodal-positive EACs than that in nodal-negative EACs, and inversely correlated with patient overall survival. The M2/M1 ratio was not related to LVD. EAC cell polarised THP1 cell into M2d-like macrophage, which promoted EAC cell migration and invasion. Neoadjuvant therapy appeared to diminish the correlation between the M2/M1 ratio and survival.

Conclusions:: The ratio of M2/M1 macrophage may serve as a sensitive marker to predict lymph node metastasis and poor prognosis in EAC without neoadjuvant therapy. M2d macrophage may have important roles in EAC metastasis.

No MeSH data available.


Related in: MedlinePlus