CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

Abstract

Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours. Cancer-Associated Fibroblasts: Major Players in Pancreatic Tumourigenesis PDAC is one of the most lethal solid malignancies, with a 5-year survival rate of $9% [1]. Widespread fibrotic desmoplasia is one of the cornerstones of PDAC development, progression, metastasis, and treatment resistance, where stromal components of the TME can have fundamental and integrated roles in promoting tumourigenesis [2-6]. This extensive desmoplastic reaction is characterised by the recruitment and activation of CAFs, aberrant extracellular matrix (ECM) deposition and remodelling, tumour angiogenesis, altered blood supply, as well as increased inflammation coupled with altered (and often impaired) innate and adaptive immune responses [4,5,7-9]. CAFs are one of the most prominent and active components in the pancreatic TME [4,5]. During early tumour initiation, reciprocal tumour-stroma signalling drives the reprogramming of mesenchymal cells, such as pancreatic stellate cells (PSCs), into CAFs [6], after which they can perform numerous anti-and protumourigenic functions in the TME. For instance, PDAC CAFs are the chief source of fibrotic matrisomal components, such as collagens, hyaluronic acid (HA), and fibronectin, among others, as recently described by Tian et al. [10]. This fibrosis has downstream biomechanical and biochemical effects in the TME [11], including impaired drug efficacy due to reduced interfibrillar spacing in the interstitium, which leads to reduced vascular patency and poor immune cell infiltration [12-17]. Moreover, CAFs produce several chemokines, cytokines, growth factors, miRNAs, exosomes, and metabolites that can instruct cancer cells and other TME components to promote malignant biology [4,5]. Given the central role of CAFs in the TME, there have been several attempts to target them in combination with other therapeutic approaches, such as chemotherapy or immunotherapy, for the treatment of PDAC. Thus far, this treatment approach has been largely unsuccessful and, in some preclinical studies, harmful. This is best exemplified through the studies of Ö zdemir et al. [18] and Rhim et al. [19], which both found that depletion of CAFs in genetically engineered mouse models (GEMMs) of PDA...

Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

“…Cancer associated fibroblasts (CAFs) are important stromal cells within the tumor microenvironment that can be educated and/or recruited by tumor secreted factors. The capacity of CAFs to synthesize and remodel ECM components critically effects tumor progression (14). Understanding the nature of the heterotypic interactions between tumor cells, the ECM, and CAFs within the tumor microenvironment will offer insights into the mechanisms underpinning tumor progression and metastasis.…”

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

“…The study of the cellular interactions taking place between the cancer and stroma has recently emerged as an important topic in pancreatic cancer research [43][44][45]. Multiple new stromal targets of potential clinical importance in PDAC are currently being investigated [46]. Of these, the activated PSCs, also denoted cancer-associated fibroblasts, have gained particular interest [47].…”

Fibroblasts direct differentiation of human breast epithelial progenitors

“…The cell lines established in the present study may prove valuable in determining such lineage relationships. It is also a possibility that phenotypic and functional CAF heterogeneity re ects plasticity in a broader sense, and in general may be governed more or less by the tumor genotype as suggested in mouse models of pancreatic cancer (reviewed in [65]). In this context, the cell lines may serve to decipher whether a speci c tumor genotype instructs development of a particular stromal response independent of recipient initial stromal cell type.…”