Role of Epithelial-Mesenchymal Plasticity in Pseudomyxoma Peritonei: Implications for Locoregional Treatments

Abstract

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial-mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal-epithelial transition, MET), now collectively called epithelial-mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial-mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Keywords: CRS/HIPEC; EMP; EMT; PMP; cytoreductive surgery; epithelial-mesenchymal plasticity; epithelial-mesenchymal transition; hyperthermic intraperitoneal chemotherapy; pseudomyxoma peritonei.

Figure 1

(a) Intraoperative view of abdominal mucin accumulation in pseudomyxoma peritonei (PMP) and (b) appendiceal mucinous neoplasia with mucocele.

Figure 2

Transcoelomic spread of tumor cells, PMP development and progression. Tumor cells induced to undergo an epithelial–mesenchymal transition (EMT) detach from the primary tumor and invade the peritoneal cavity through the serosal wall. The malignant seeding of mucin-producing single cells and cell clusters into the abdominal cavity is regulated by peritoneal fluid dynamics. Ascitic fluid flow is influenced by the movements of the diaphragm and the abdominal muscles, the peristaltic movements of the intestinal tract and by gravity. The presence of signet-ring cells denotes an aggressive, high-grade PMP. Peritoneal implants are generated by the attachment of tumor cells mainly at sites of fluid reabsorption. The tumor cells invade the subserosal extracellular matrix (ECM) and proliferate. Tumor progression is accompanied by massive mucin accumulation, inflammation and fibrosis of the mesothelial lining.

Figure 3

EMT profile in single and clustered PMP cells. Scattered cells in mucin pools are characterized by a more mesenchymal state (red triangle), whereas cell clusters show a more epithelial profile (green triangle). Single cells are frequently associated with a more aggressive clinical behavior, and more frequently show signet-ring morphology, indicated by the arrow. CK: Cytokeratin.

Figure 4

Ectopic ossification in PMP. The tumor microenvironment is composed of cellular and acellular elements, whose interaction may create a dynamic landscape in which EMP takes place. Cytokines and chemokines initially expressed by tumor cells and then induced in the attracted stromal and immune cells may promote cell plasticity. In the context of PMP, TGF-β/BMP9 secreted by PMP cells and expressed by stromal cells may induce EMT in an autocrine and/or paracrine loop. Tumor cells, after having transitioned into a more mesenchymal state, may differentiate towards an osteoblast-like phenotype. In a similar manner, mesenchymal stromal cells, influenced by the same stimuli, may undergo a transition to osteoblast-like cells. These cells were shown to express osteoblastic markers and are very likely responsible for pathologic formation of extraskeletal bone. TGF-β/BMP9: Transforming growth factor-beta/Bone morphogenetic protein 9; BGLAP: Bone γ-carboxyglutamic acid-containing protein or Osteocalcin; OPN: Osteopontin.