Gastric cancer (GC) is an important disease with high morbidity and mortality. Due to a lack of relatively convenient and reliable biomarkers, large numbers of GC are diagnosed at an advanced stage, with poor prognosis . It is fundamentally important to develop reliable biomarker(s) with enough specificity, sensitivity and convenience for early diagnosis. Whilst cellmediated 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 . Chronic inflammation mediates tumourigenesis, including cellular survival, proliferation, migration, angiogenesis and metastasis via cytokine mediated signalling pathways.
The inflammatory microenvironment surrounding a tumour is a complex ecology of immune cells interconnected with tumour cells. Among the leucocytes present at the tumour site, macrophages are abundantly present at all stages of tumour progression . Tumour-associated macrophages (TAMs) are correlated with poor survival of GC patients, as TAMs promote invasion and metastasis through enhancing angiogenesis . However, others have reported a positive correlation between TAMs and five year survival rate of GC patients . Multiple factors may contribute to this discrepancy, including tumour type and stage .
Macrophage colony stimulating factor (M-CSF) is a growth factor important in the regulation of differentiation, proliferation and survival of haematopoietic cell lineages . Circulating MCSF is increased in many tumours (e.g. breast, prostate and pancreatic cancers) and is positively correlated with invasion, metastasis and poor survival of tumour patients [8–10]. By contrast, monocytes/macrophages are able to kill cancerous cells by paraptosis, driven by over-expression of membrane M-CSF .
IL-34 was first identified by Lin et al in 2008, as a protein that is able to bind to CD14+ monocytes in peripheral blood mononuclear cells. IL-34 stimulates the differentiation of monocytes into macrophages via the CSF-1 receptor . Subsequently, IL34, including mRNA and protein, can be detected in various tissues secreted by fibroblast-like cells. The order of the level of production in the tissues is: spleen, heart, brain, thymus, lung, kidney, liver, small intestine, colon, testes, ovary and prostate . Using an IL-34 reporter gene, IL-34 a high level of expression has been detected in the skin and in the brain compared to other non-lymphoid and lymphoid tissues .
IL-34 is also a ligand of the M-CSF receptor, and acts as a “twin” to the M-CSF cytokine, demonstrating overlapping and complimentary actions . IL-34 acts similarly to MCSF in promoting osteoclastic differentiation of giant cell tumours , but IL-34 also displays singular function during brain development . Furthermore, the role of IL-34 in tumours is controversial particularly in the development, metastasis and prognosis of cancers, although the response to MCSF is tumour-type dependant, possibly due to the levels of M-CSF receptors .
Studies have long sought specific biological markers that could characterize GC . However, no existing marker(s) have proven to be sufficiently specific to GC. While the IL34/M-CSF/MCSFR axis is very important for regulating macrophage differentiation , the specific interplay between these cytokines, macrophages and the development of tumours is unclear. Accordingly, a multi-factor evaluation could provide more objective utility, particularly for either prediction and/or prognosis of gastric cancer, compared to studies in the current literature.
Conventional chemotherapy kills cancers non-specifically, based on the high rate of cancer cell division. Precision medicine is becoming popular in the treatment of malignancy, which tailors intervention to the individual patient with customization of medical decisions and healthcare . However, the success of a precision medicine approach replies on the identification of highly specific targets in each specific tumour. Therefore, elucidating specific molecular signalling pathways in specific cancers is necessary to facilitate the success of a precision medicine approach.
In our current study, we determined the production of M-CSF and IL-34, and the number of infiltrating CD68+TAMs in GC. The relationship between M-CSF, IL-34 and CD68+TAMs infiltration in GC was explored with a view to elucidate potential molecular targets.