Impact of tumor‐associated macrophages on invasive ductal carcinoma of the pancreas head

Abstract

Tumor-associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumorassociated macrophages can be affected by cancer-related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM-related factors and the clinical impact of TAMs. CD68 (a pan-macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease-free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC. (Cancer Sci 2012; 103: 2012-2020 T he prognosis of patients undergoing resection for pancreatic invasive ductal carcinoma (IDC) remains poor.(1-5) Histological studies have been carried out to elucidate the aggressiveness of pancreatic IDC and have revealed prognostic factors including tumor size, lymph node involvement, nerve plexus invasion, positive resected margin, and low tumor grade.(1-8)Tumor-associated macrophages (TAMs) have recently been reported as a candidate factor in poor prognosis. (9) Macrophages are the most abundant cancer stromal cells involved in the host immune system, (10) and TAMs have been found to play important roles in tumorigenesis, angiogenesis, matrix remodeling, and metastasis.(11-13) Tumor-associated macrophages have a prognostic impact in prostate, breast, and lung cancers, as well as pancreatic IDC.(9,14-16) The heterogeneity of macrophages has been discussed with regard to their different responses to various microenvironmental stimuli. Macrophages are classically activated towards the M1 phenotype by lipopolysaccharide and interferon-c. M1 macrophages are characterized by high expression of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-12, and tumor necrosis factor. Alternatively, macrophages are activated towards the M2 phenotype by IL-4, IL-13, and IL-10. M2 macrophages are characterized by high expression of ...

Tumour‐educated macrophages display a mixed polarisation and enhance pancreatic cancer cell invasion

“…BxPC-3 cells co-cultured with PBMCs displayed significantly higher invasive capabilities than BxPC-3 cells cultured alone, in accordance with the tumour-promoting role of TAMs (P<0.001; Fig. 7a-b Previous studies on pancreatic cancer-related inflammation have shown enhanced leukocyte infiltration in the tumour microenvironment and elevated systemic cytokine levels in patients with pancreatic cancer [26][27][28][29][30] . Macrophages, in particular with an alternatively activated M2-associated phenotype, were among the most common leukocyte subsets infiltrating the tumour area 29, 30 .…”

“…7a-b Previous studies on pancreatic cancer-related inflammation have shown enhanced leukocyte infiltration in the tumour microenvironment and elevated systemic cytokine levels in patients with pancreatic cancer [26][27][28][29][30] . Macrophages, in particular with an alternatively activated M2-associated phenotype, were among the most common leukocyte subsets infiltrating the tumour area 29, 30 . This was further reflected in the systemic cytokine levels, where IL-6, IL-8 and IL-10 were elevated in pancreatic cancer patients [26][27][28] .…”

Distribution and Clinical Significance of Tumour-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: A Retrospective Analysis in China

“…The studies showing that high infiltration by M2 macrophages in tumour tissue is associated with poor prognosis in pdac patients 11,12,17 were conducted in Japan. Being that no study had yet been conducted in China, we set out to determine any correlations of tam and M2 macrophage counts with prognosis in Chinese patients with pdac.…”

“…Counting of CD68 and CD163 immunoreactivity-positive membrane or cytoplasm and nonreactive nuclei was performed under light microscopy (Olympus CX-40: Olympus, Tokyo, Japan). Macrophages were counted separately in the peripheral and central areas of lesions as described in an earlier study 17 . The means of the counts from 3 random high-power fields (400× magnification) were used in the analyses.…”

Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation

“…M1-like TAMs, however, are sparse and confined to the less hypoxic regions of tumors (15). The presence of M2-like TAMs in tumors correlates with poor prognosis (16,17), whereas the presence of M1-like TAMs correlates with longer survival for patients (18).…”