Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Abstract

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

“…Inter‐tumour stromal heterogeneity was reported in PDAC patients and enables patient stratification within prognosis groups (Moffitt et al , 2015; Puleo et al , 2018). Additionally, diverse subpopulations of CAFs were recently reported to co‐exist within a same PDAC tumour, being heterogeneous with regard to cell surface marker expression, cytokine production or cell signalling (Nielsen et al , 2018; Whittle & Hingorani, 2019; Norton et al , 2020). A recent publication identified, using molecular and functional analyses of several patient‐derived CAF primary cultures, four CAF sub‐groups that co‐exist within a tumour, each featuring specific phenotype and prognostic value (Neuzillet et al , 2019).…”

Stromal Protein-Mediated Immune Regulation in Digestive Cancers

“…It is now widely accepted that ECM proteins of the stromal TME have both pro- and anti-tumoral functions acting at different levels of tumor progression (e.g., epithelial-to-mesenchymal transition (EMT), proliferation, migration) [ 18 , 20 , 21 ]. However, a more detailed understanding of the acellular TME compartments could provide targets for selective therapeutic approaches [ 33 ]. Albeit there is long-standing knowledge of the immune modulatory functions of many ECM-associated proteins, namely cytokines and chemokines, such properties of core matrisome ECM proteins have only recently emerged [ 34 , 35 ].…”

“…Then, hedgehog inhibitors have been tested in patients with pancreatic and colorectal cancer but their administration was interrupted since they failed to reproduce promising pre-clinical results in a clinical setting and even paradoxically accelerated diseases progression [ 209 , 210 , 211 , 212 , 213 , 214 ]. These findings provided insight into the constitution of TME that comprises components that can either promote or restrain tumor progression, and that these components need to be targeted in a selective manner in order develop novel therapeutic agents [ 33 ]. Indeed, several pre-clinical and clinical studies addressed various ECM proteins as targets.…”

CD36 and CD97 in Pancreatic Cancer versus Other Malignancies

“…[227] "Anticancer compound Minnelide revealed deregulation of the TGFb signalling pathway in CAF, [228] resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state". [229] "This heterogeneity explains why one type of CAF is found to support cancer invasiveness and metastases while another type does not".…”