Pigment Epithelial-Derived Factor in Pancreatic and Liver Cancers-From Inflammation to Cancer

Abstract

Gastrointestinal (GI) cancers are among the leading causes of mortality worldwide. Despite the emergence of new possibilities that offer hope regarding the successful treatment of these cancers, they still represent a significant global health burden. These cancers can arise from various cell types within the gastrointestinal tract and may exhibit different characteristics, behaviors, and treatment approaches. Both the prognosis and the outcomes of GI treatment remain problematic because these tumors are primarily diagnosed in advanced clinical stages. Current biomarkers exhibit limited sensitivity and specificity. Therefore, when developing strategies for the diagnosis and treatment of GI cancers, it is of fundamental importance to discover new biomarkers capable of addressing the challenges of early-stage diagnosis and the presence of lymph node metastases. Pigment epithelial-derived factor (PEDF) has garnered interest due to its inhibitory effects on the migration and proliferation of cancer cells. This protein has been suggested to be involved in various inflammation-related diseases, including cancer, through various mechanisms. It was also observed that reducing the level of PEDF is sufficient to trigger an inflammatory response. This suggests that PEDF is an endogenous anti-inflammatory factor. Overall, PEDF is a versatile protein with diverse biological functions that span across different tissues and organ systems. Its multifaceted activities make it an intriguing target for therapeutic interventions in various diseases, including cancer, neurodegeneration, and metabolic disorders. This review, for the first time, summarizes the role of PEDF in the pathogenesis of selected GI cancers and its potential utility in early diagnosis, prognosis, and therapeutic strategies for this malignancy.

Keywords: PEDF; biomarkers; cancer; gastrointestinal malignancies; hepatocellular carcinoma; pancreatic cancer.

Figure 1

The schematic structure of PEDF consists of several distinct domains and regions, each of which is responsible for specific biological activities, such as antiangiogenic, neurotrophic, and anti-tumor effects. Abbreviations: LRP6—LDL Receptor-Related Protein 6, PNPLA2—photoreceptor cells express the patatin-like phospholipase domain-containing 2, RCL—reactive center loop.

Figure 2

PEDF plays an important role in microcirculation, which refers to the circulation of blood in the smallest blood vessels, including arterioles, capillaries, and venules. PEDF primarily exerts its effects through antiangiogenic, anti-inflammatory, and antioxidant actions, which influence the behavior of endothelial cells, vascular permeability, and overall vascular health in the microcirculatory system. Abbreviations: 67LR—67 kDa laminin receptor, AKT—protein kinase B, AQP4—aquaporin-4, BBB—blood–brain barrier, BCL2—B-cell lymphoma 2, BRB—blood–retina barrier, DN—diabetic nephropathy, EC—endothelial cells, eNOS—endothelial nitric oxide synthase, MAPK—mitogen-activated protein kinase, NADPH—nicotinamide adenine dinucleotide phosphate hydrogen, NOXO1—NADPH oxidase organizer 1, PEDF—pigment epithelium-derived factor, PI3K—phosphoinositide 3-kinases, VEGF—vascular endothelial growth factor [15,16,21,22,23,24].

Figure 3

The effect of PEDF on tumors. These effects contribute to its overall anti-tumor activity by targeting both the tumor cells and the surrounding microenvironment, particularly through the regulation of angiogenesis, apoptosis, and immune responses. Abbreviations: PEDF—pigment epithelium-derived factor.

Figure 4

The influence of PEDF through VEGF, JNK, p38/MAPK and AKT signaling in cancer. Abbreviations: AKT—Protein Kinase B, c-Jun—N-terminal Kinase, JNK—c-Jun N-terminal Kinase, MAPK—mitogen-activated protein kinase, PEDF—Pigment Epithelium-Derived Factor, PNPLA2—patatin-like phospholipase domain containing 2 (also known as adipose triglyceride lipase, ATGL), VEGF—vascular endothelial growth factor.