Abstract
BackgroundGastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis. It is important to develop reliable biomarker(s) with specificity, sensitivity and convenience for early diagnosis. The role of tumour-associated macrophages (TAMs) and survival of GC patients are controversial. Macrophage colony stimulating factor (MCSF) regulates monocytes/macrophages. Elevated MCSF is correlated with invasion, metastasis and poor survival of tumour patients. IL-34, a ligand of the M-CSF receptor, acts as a “twin” to M-CSF, demonstrating overlapping and complimentary actions. IL-34 involvement in tumours is controversial, possibly due to the levels of M-CSF receptors. While the IL-34/M-CSF/M-CSFR axis is very important for regulating macrophage differentiation, the specific interplay between these cytokines, macrophages and tumour development is unclear.MethodsA multi-factorial evaluation could provide more objective utility, particularly for either prediction and/or prognosis of gastric cancer. Precision medicine requires molecular diagnosis to determine the specifically mutant function of tumours, and is becoming popular in the treatment of malignancy. Therefore, elucidating specific molecular signalling pathways in specific cancers facilitates the success of a precision medicine approach. Gastric cancer tissue arrays were generated from stomach samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, M-CSF, IL-34 and macrophages were determined.ResultsWe found that IL-34 may serve as a predictive biomarker, but not as an independent, prognostic factor in GC; M-CSF inversely correlated with survival of GC in TNM III–IV subtypes. Increased CD68+ TAMs were a good prognostic factor in some cases and could be used as an independent prognostic factor in male T3 stage GC.ConclusionOur data support the potency of IL-34, M-CSF, TAMs and the combination of IL-34/TAMs as novel biological markers for GC, and may provide new insight for both diagnosis and cellular therapy of GC.
Highlights
Gastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis
IL-34 and Macrophage colony stimulating factor (M-CSF) were decreased > 40% and > 95%, respectively, in GC compared to tumour adjacent gastric tissues (p < 0.05), whereas CD68+-Tumour associate macrophages (TAM) were increased 5.5 fold (p < 0.05) (Fig. 1)
Correlation between IL‐34, M‐CSF and C D68+‐TAMs in GC and clinicopathological parameters The median values obtained for IL-34, M-CSF and CD68+-TAMs expressions were found to significantly differ between subgroups defined by a range of clinicopathological parameters (Table 1, Fig. 2 and Additional file 1: Figure S1, Additional file 2: Figure S2)
Summary
Gastric cancer (GC) is a malignancy with high morbidity/mortality, partly due to a lack of reliable biomarkers for early diagnosis. It is important to develop reliable biomarker(s) with specificity, sensitivity and convenience for early diagnosis. The role of tumour-associated macrophages (TAMs) and survival of GC patients are controversial. Elevated MCSF is correlated with invasion, metastasis and poor survival of tumour patients. While the IL-34/M-CSF/M-CSFR axis is very important for regulating macrophage differentiation, the specific interplay between these cytokines, macrophages and tumour development is unclear. It is fundamentally important to develop reliable biomarker(s) with enough specificity, sensitivity and convenience for early diagnosis. Whilst cell-mediated immunity may exhibit anti-tumour activity, epidemiological, preclinical and clinical studies demonstrate that chronic inflammation plays a vital role in the initiation and/or development of gastric cancer [2]. Chronic inflammation mediates tumourigenesis, including cellular survival, proliferation, migration, angiogenesis and metastasis via cytokine mediated signalling pathways.
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