The Pancreatic Tumour Microenvironment. Influence by macrophages and glucose levels on tumourigenesis

University dissertation from Division of surgery, Department of clinical sciences Lund

Abstract: Pancreatic cancer is the fourth cause of cancer-related death with a 5-year survival rate less than 5%. Two of the risk factors are chronic pancreatitis and type 2 diabetes (T2D), which are believed to promote the tumour progression. Pancreatic cancer and its tumour microenvironment is characterised by a dense stroma, immune cell infiltration and poor vascularisation. This creates a favourable environment for cancer cells to grow, proliferate and invade surrounding tissue. The cell types orchestrating the local environment have shown to be pancreatic stellate cells and tumour-associated macrophages (TAMs), which control the local inflammation, provide growth factors and stimulate extra-cellular matrix (ECM) remodelling. In addition, the hypoxic environment induces a skewed metabolism in cancer cells due to the poor vascularisation, which creates dependencies on nutrients such as glucose. In this thesis, the role of the tumour microenvironment in pancreatic cancer was investigated, in particular the influence by hyperglycaemia and the interplay between pancreatic cancer cells and TAMs. High glucose levels was shown to promote proliferation, survival and enhanced invasion by pancreatic cancer cells. Pancreatic stellate cells induced epithelial-mesenchymal transition in pancreatic cancer cells and stimulated invasion into the ECM. Macrophages further enhanced the pancreatic cancer cell invasion and were found to be an indicator for survival in pancreatic cancer patients with T2D. In turn, pancreatic cancer cells were shown to stimulate macrophage differentiation with pro-tumour properties. Furthermore, the anti-diabetic drug metformin displayed direct anti-tumour and anti-inflammatory properties by inducing pancreatic cancer cell apoptosis and suppressing macrophage differentiation. In summary, the interplay between pancreatic cancer cells and its local environment is complex and of importance for tumour progression. Novel treatment strategies will need to broaden the view on cancer to also include the surrounding factors and cell types, to more efficiently treat cancer and create a better outcome for patients with pancreatic cancer.

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