Exploiting inflammation for therapeutic gain in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

Figure 1

The role of inflammation in PDAC Initiation. PDAC evolution occurs from PanIN 1 through 3 to invasive PDAC with progressive accumulation of desmoplastic stroma (H&E, top panels). The leukocyte infiltration surrounding lesions changes as PanINs progress. Tumour-associated macrophage infiltration increases early in PDAC tumorigenesis as demonstrated by F4/80 immunohistochemistry (second row). Neutrophils (visualised by MPO staining) are abundant around developing PanIN lesions but sporadic within developed tumours (third row). Varying quantities of T cells are present within both PanINs and PDAC, as shown by CD3 immunohistochemistry (bottom row).

Figure 2

Targeting inflammation in the treatment of PDAC. Schematic illustrating progression to PDAC through PanIN stages, with potential therapeutic opportunities in both prevention and treatment of disease outlined.