Metastasis-associated fibroblasts in peritoneal surface malignancies

Abstract

Over decades, peritoneal surface malignancies (PSMs) have been associated with limited treatment options and poor prognosis. However, advancements in perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) have significantly improved clinical outcomes. PSMs predominantly result from the spread of intra-abdominal neoplasia, which then form secondary peritoneal metastases. Colorectal, ovarian, and gastric cancers are the most common contributors. Despite diverse primary origins, the uniqueness of the peritoneum microenvironment shapes the common features of PSMs. Peritoneal metastization involves complex interactions between tumour cells and the peritoneal microenvironment. Fibroblasts play a crucial role, contributing to tumour development, progression, and therapy resistance. Peritoneal metastasis-associated fibroblasts (MAFs) in PSMs exhibit high heterogeneity. Single-cell RNA sequencing technology has revealed that immune-regulatory cancer-associated fibroblasts (iCAFs) seem to be the most prevalent subtype in PSMs. In addition, other major subtypes as myofibroblastic CAFs (myCAFs) and matrix CAFs (mCAFs) were frequently observed across PSMs studies. Peritoneal MAFs are suggested to originate from mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, and omental-resident cells. This plasticity and heterogeneity of CAFs contribute to the complex microenvironment in PSMs, impacting treatment responses. Understanding these interactions is crucial for developing targeted and local therapies to improve PSMs patient outcomes.

Fig. 1. The sequence of events leading to development and establishment of peritoneal carcinomatosis.

(1) When the primary tumour overgrows and invades the visceral serosa, cancer cells can be shed into the peritoneal fluid and disseminate across the peritoneal cavity; (2) Tumour cells can enhance their survival by aggregating into multicellular clusters; (3) The increased survival allows the recruitment of immune cells (such as neutrophils) and fibroblast resulting in the formation of heterotypic clusters. (4) Those clusters also display an increased ability to attach to the peritoneum surface (mesothelial cells) and invade into the submesothelial space establishing a peritoneal metastatic tumour (5). Once tumour cell have invaded submesothelial stroma, they must modulate the peritoneal tissue in order to establish a supportive TME. As a consequence, resident fibroblast and other stromal cells are recruited, activated and converted into CAFs (6). The heterogeneity of cancer-associated fibroblasts is represented by the different colours attributed to CAFs.

Fig. 2. The most commonly found fibroblast subtypes in peritoneal surface malignancies.

In case a specific definition by the authors of the studies was missing, reported markers from each study were evaluated according to markers from Ma et al., Lavie et al. and Cords et al., in order to define the functional subtypes of the reported fibroblast groups. The most frequently reported definition markers per functional subtype among the PSM scRNAseq studies are shown [40, 41, 54]. myCAFs and mCAFs, modulate the extracellular matrix and generate a stiff tumour microenvironment, favouring tumour metastasis and chemoresistance. However, only myCAF express in addition ACTA2 and show a contractile phenotype. iCAF-secreted factors can induce inflammatory pathways, but they have also been reported to attract immunosuppressive regulatory T cells and promote anti-inflammatory polarisation of myeloid cells.

Fig. 3. The multi-cellular origins of cancer-associated fibroblasts (CAFs) in peritoneal surface malignancies.

Signals from the tumour microenvironment can activate precursor cells from different tissue sources: peritoneum, adipose tissue/omentum, and bone marrow. The potential sources include mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, mature adipocytes, adipose-derived mesenchymal stem cell, macrophages, and bone marrow-derived mesenchymal stem cells. The process which results from the conversion of those cellular precursors is indicated by the arrows. The diverse sources of CAFs lead to the emergence of diverse CAF subpopulations and heterogeneity within the tumour microenvironment.