Hypoxia, cytokines and stromal recruitment: parallels between pathophysiology of encapsulating peritoneal sclerosis, endometriosis and peritoneal metastasis

Abstract

Peritoneal response to various kinds of injury involves loss of peritoneal mesothelial cells (PMC), danger signalling, epithelial-mesenchymal transition and mesothelial-mesenchymal transition (MMT). Encapsulating peritoneal sclerosis (EPS), endometriosis (EM) and peritoneal metastasis (PM) are all characterized by hypoxia and formation of a vascularized connective tissue stroma mediated by vascular endothelial growth factor (VEGF). Transforming growth factor-β1 (TGF-β1) is constitutively expressed by the PMC and plays a major role in the maintenance of a transformed, inflammatory micro-environment in PM, but also in EPS and EM. Persistently high levels of TGF-β1 or stimulation by inflammatory cytokines (interleukin-6 (IL-6)) induce peritoneal MMT, adhesion formation and fibrosis. TGF-β1 enhances hypoxia inducible factor-1α expression, which drives cell growth, extracellular matrix production and cell migration. Disruption of the peritoneal glycocalyx and exposure of the basement membrane release low molecular weight hyaluronan, which initiates a cascade of pro-inflammatory mediators, including peritoneal cytokines (TNF-α, IL-1, IL-6, prostaglandins), growth factors (TGF-α, TGF-β, platelet-derived growth factor, VEGF, epidermal growth factor) and the fibrin/coagulation cascade (thrombin, Tissue factor, plasminogen activator inhibitor [PAI]-1/2). Chronic inflammation and cellular transformation are mediated by damage-associated molecular patterns, pattern recognition receptors, AGE-RAGE, extracellular lactate, pro-inflammatory cytokines, reactive oxygen species, increased glycolysis, metabolomic reprogramming and cancer-associated fibroblasts. The pathogenesis of EPS, EM and PM shows similarities to the cellular transformation and stromal recruitment of wound healing.

Pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) in patients with gastric cancer and peritoneal metastasis: a phase II study

“…Moreover, the mesothelial-mesenchymal transition of the peritoneum and associated fibrosis are central features of carcinogenesis of PM, but also of wound healing. 32 Therefore, we do not trust PCI as a response criteria for PIPAC therapy and prefer the objective histological assessment by an independent pathologist. 33 In the future, this approach combining radiology, laparoscopy and histological regression grading might overcome current limitations of imaging in assessment of therapy response in PM.…”

Identification of Differentially Expressed Genes and Signaling Pathways Related to Ovarian Endometriosis by Integrated Bioinformatics Analysis

“…Endometriosis was characterized by chronic in ammation, hypoxia and cellular transformation which was related to AGE-RAGE pathway. Activation of receptor for advanced glycation end products (RAGE) dramatically upregulated multiple intracellular signal pathways including protein kinase C and MAPK/NF-κB which promoted expression of pro-in ammatory cytokines [17]. In addition, PI3K-Akt-dependent pathways were involved in degradation of extracellular matrix and cell apoptosis which facilitated the implantation and invasiveness of endometriosis [18].…”

Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis

“…Aerobic glycolysis is 90% less efficient, but at the same time 10–100 times more rapid in producing ATP when compared to mitochondrial OXPHOS (2 ATP vs. 30 ATP per glucose molecule) [20]. Thus, a major upregulation of glucose transporters and glucose usage, glycolytic enzymes, and lactate production is required for the maintenance of ATP production to ensure tumor cell survival [24,29]. Variations of the glycolytic ratio within tumors (from 0 to 100%) can alter the energy cost of tumors over a 2- to 3-fold range [20].…”

“…The export of lactic acid into the extracellular space by CAFs and uptake of the lactate by adjacent cancer cells also maintains an acidic extracellular tumor microenvironment (pHe) and alkaline intracellular CAF environment (pHi). This enables tumor cell intravasation, immune evasion, angiogenesis, and chemotherapy drug resistance and is fundamental to the survival and progression of PM [29] (Figure 2).…”

“…By combining IL-6 inhibition with programmed death ligand-1 (PDL-1) targeted therapy in pancreatic adenocarcinoma, improved overall T-cell activation, and anti-tumor response was achieved in a murine model [53,54]. This is relevant to patients with PM and CAS, as cancer cells in the peritoneum recruit peritoneal mesothelium, fibroblasts, monocytes, adipocytes, and endothelial cells to form a supporting stroma, which enables resistance to anoikis and evasion of T cell immunosurveillance [24,29].…”