Discovering the route from inflammation to pancreatic cancer

Abstract

Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this "injury-inflammation-cancer" pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy.

Figure 1

Oncogenic transformation from pancreatic injury to pancreatic cancer under the inflammation background. A) Usually, it takes decades for a subset of patients with chronic inflammatory diseases to develop pancreatic cancer (PC). Genetic susceptibility to pancreatic injury (KRAS, Id1/2, P53, P16, Cyclin D1, and DPC) plus the necessary environmental factors (alcohol abuse, smoking, age, obesity, and diabeties) repeatedly triggering pancreatitis (recurrent acute pancreatitis) plus an immune response leads to chronic inflammation and fibrosis rather than healing. These mutations are responsible for premature activation of trypsinogen and thus intrapancreatic autodigestion and pancreatitis. This prolonged inflammatory response initiates chronic pancreatitis (CP) and appears to progress unrelentingly toward accelerated inflammatory destruction of the total organ and provides a milieu for the development of PC. Overproduction of ROS and an increased cation overload due to enhanced Ca²⁺ release from the internal stores lead to mitochondrial stress and cell death. B) Tumor cells produce various cytokines and chemokines that allure leukocytes. Abundance of proinflammatory cytokines over anti-inflammatory cytokines leads to a level of inflammation that favors the neoplastic outcome. The expression of these pro-inflammatory proteins is regulated primarily by the transcription various factors (TFs) such as STAT3, NFκB, PPAR-γ. C) It is postulated that extensive and prolonged inflammation may result in a secondary damage, enriching the surrounding microenvironment leading to neovascularization. This leads to activation of PSCs and over-production of ECM proteins in the inflamed pancreas leading to an imbalance in the homeostasis. As cells progress towards dysplasia, tumor cells coupled with its stroma exhibit immune evasion. Tumor cells release pro-inflammatory cytokines (TNFα and IL-1β) that induce CAFs-mediated release of thymic stromal lymphopoietin (TSLP). TSLP-mediated expression of TSLP-Receptor on resident DCs leads to its activation and migration to draining LNs where they prime Th2 cells. Cytokine pool leads to the docking of the Th2 cells on the tumor cells, further fostering fibrosis by increasing ECM and activating the M2-TAM. D) Intensified DNA damage induced by inflammatory cells creates an environment with a deficient response to DNA damage, increased turn-over of cells aggravating the accumulation of the potential oncogenic mutations, hence amplifying the probability of malignant cells accumulation. Further, the DNA damage, which is beyond repair, triggers apoptotic dearth in mutated clones, eventually leading to increased proliferation of malignant cells. These events lead to organ regeneration in an oxidative-species-rich environment and ultimately lead to PC. Various therapeutic modalities against specific inflammatory mediators are demonstrated in green boxes. CAFs: cancer associated fibroblasts; DCs: dendritic cells; LNs: lymph nodes; MDC/CCL22: macrophage derived chemokine; PPAR-γ: peroxisome proliferator-activated receptor-γ; PSCs: pancreatic stellate cells; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription 3; TARC/CCL17: thymus and activation-regulated chemokine; TSLP: thymic stromal lymphopoietin; TSLPR: TSLP receptor.