Tumor cells are not alone in the tumor mass; in fact they are surrounded by a complex and active microenvironment, composed by fibroblasts and their extracellular matrix (ECM), immune cells, nerves, blood vessels, and secreted factors. It is now well recognized that the microenvironment plays an important role in tumor development and thus it is imperative for the comprehensive understanding of the interplay between cancer and its microenviroment for the development of better preventative and therapeutic strategies.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5 year survival rate of only 10% after diagnosis[1]. One of the main reasons for this outcome is the poor understanding of the unique microenvironment of PDAC, where up to 90% of the tumor mass can be composed by the stroma, with most of it being the expansion of activated fibroblasts and their ECM[2]. Even though CAFs represent an important component of PDAC (and other types of cancers), they are still incompletely understood. This can be partially explained by the fact that there are no specific markers to discriminate CAFs, and researchers need to rely on negative selections, absence of mutations that characterize the transformed epithelial cells plus the presence of mesenchymal markers, all together with the assessment of fibroblastic function2.
There are still controversies about the pro- and anti-tumor effects of CAFs and their origin. Recently, a consensus was published2, where authors suggest that CAFs are mostly originated by the local activation and proliferation of resident fibroblasts, stimulated by tissue injury, reactive oxidative species, growth factors and more. These CAFs are characterized by their plasticity, as they can interchange between functions according to the signals of the environment. Many are the functions attributed to these cells; CAFs produce a very dense ECM, which can lead to the collapse of blood vessels, thus affecting nutrient supply and the delivery of therapies to this environment[3]. Moreover, CAFs can be immunusuppressive, producing a millieu of cytokines and chemokines that can turn off anti-tumor immune cells and recruit pro-tumor ones[4]. Interestingly, CAFs can also contribute to the metabolic signature of the environment, as they produce and modify a large range of metabolites, often supporting cancer cell survival[5].
Recently, our research group uncovered the pro-tumor roles of the synaptic protein Netrin G1 in CAFs[6]. The expression of Netrin G1 in CAFs from PDAC patients inversely correlated with overall survival. Moreover, the loss of Netrin G1 in CAFs led to decreased production of immunosuppressive factors, allowing NK cells to kill PDAC cells in vitro. Netrin G1 expression was also important for the production of metabolites (mainly glutamine and glutamate) by CAFs and for the support of nutrient deprived PDAC cells. It is important to mention that the Netrin G1 related studies were perfomed using 3D co-cultures, and that its expression can only be detected in CAFs growing in their 3D environment, further reinforcing the need for better strategies to study and understand the tumor microenvironment in PDAC.
Therefore, CAFs can be seen as the major intermediaries of PDAC microenvironment and to target these cells in an attempt to normalize them rather than eliminate them, might be an effective strategy for PDAC therapy.
References:
[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020; 70: 7-30.
[2] Sahai E et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer, 2020; 20:174-186
[3] Provenzano et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 2012; 21:418-29.
[4] Ziani L, Chouaib S, Thiery J. Alteration of the Antitumor Immune Response by Cancer-Associated Fibroblasts. Front Immunol, 2018; 9:414.
[5] Lyssiotis CA and Kimmelman AC. Metabolic interactions in the tumor microenvironment.
Trends Cell Biol, 2017; 27: 863-875.
[6] Francescone et al. Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression. Cancer Discov. 2020 Oct 30:CD-20-0775. Epub ahead of print.
ZFP36L2promotes cancer cell aggressiveness and is regulated by antitumormicroRNA-375in pancreatic ductal adenocarcinoma