Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

Abstract

Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME's cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal-cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs "re-education" and/or targeting tumour progression inhibition.

Keywords: cancer cell; cancer-associated fibroblast; inflammation; magnification; metastasis; tumour microenvironment.

Figure 1

Fibroblasts’ phenotype adapts in response to external aggression. Activation of quiescent fibroblasts to a myofibroblast phenotype to repair tissue damage by wound healing is triggered by microenvironmental signals. Myofibroblasts should disappear by apoptosis (nemosis) after punctual aggression, but if fibroblasts are subjected to constant stress, they could evolve into a FAF or CAF phenotype.

Figure 2

Major pathways involved in CAF development. (A) Cytokines and growth factors: Regulation of CAF-specific gene expression through TGF-β signalling via Smad-dependent and Smad-independent pathways. In the canonical pathway, Smad2/3-Smad4 translocate to the nucleus and bind to a specific DNA sequence, being possibly inhibited by Smad7. In the non-canonical pathway, TGF-β promotes the activation of several signalling pathways, other than Smad, including PI3K kinases, MEK, and Rho-Rock, among others. (B) miRNAs signalling: miRNAs and lncRNAs transform NAFs into CAFs through downstream signalling involving JAK/STAT, NF-κβ, and MAPK cascades. (C) Paracrine activation: Through the PDK1/AKT signalling pathway, in which tumour exosome miRNA-21 inhibits it and PI3K promotes it. Notch signalling via AKT signalling pathway controls AKT phosphorylation and mTOR activation. As a result, mTOR regulates the expression of targeted genes associated with differentiation into CAFs; in addition, expression of tumour cell-derived SHH has been confirmed to modulate CAFs via paracrine activation of HH signalling, and the overexpression of SMO in CAFs contributes to HH signal transduction and GLI1 activation. Fibroblasts can also be metabolically reprogrammed via cancer cell-derived mitochondrial transfer and the TGF-β signalling pathway derived from cancer cells. (D) Auto CAFs-conversion: A self-propelled conversion induced by changes in cellular homeostasis, which controls the activation of cytoskeletal proteins and the secretory phenotype via the YAP1/TEAS1 and JAK2/STAT3 signalling pathways. EMT is facilitated by an activated CXCL12 signal via the ERK/AKT-Twist1-MMP1 pathway. TIMP-1 is related to collagen contractility and CAF proliferation and migration through the ERK1/2 signalling pathway in CAFs (Table 1).

Figure 3

CAF “education” by the cancer-derived factors (extension of section C) in Figure 2). Cancer-derived exosomes carry elements such as miRNA and lncRNA that promote the transformation of NAF to CAF through downstream signals that include cascades such as TGF-β/Smads, JAK/STAT, NF-κB, and MAPK. NAF-CAF conversion may also be driven by the reprogramming of glucose metabolism and the HIF-1α signalling pathway involved in glycolysis. Both the canonical TGF-β signalling pathway (TGF-β/Smads) and the non-canonical pathway (with activation of TGF-β but not Smads) are actively involved in the malignancy of NAFs. In CAFs, while miRNA-21 can attenuate the inhibition of PTEN on PDK1/AKT, the receptor–ligand binding-activated PI3K can promote it. As a result, through the PDK1/AKT signalling cascade mTOR protein is transported into the nuclei, and subsequently, the mTOR protein regulates the expression of targeted genes associated with CAFs differentiation. Notch signalling pathway is also involved in CAF differentiation via AKT. In turn, CAF-mediated PI3K/AKT signalling pathway regulates cell proliferation, migration, and stemness in cancer cells. EGFR/ERK signalling in CAFs is stimulated by E2 and G1 and upregulates fatty acids metabolism. Further, PDGF-BB and SDF-1 stimulate a higher invasive and migratory capability of CAFs via ERK1/2 phosphorylation (Table 1).

Figure 4

Heterogeneous cellular origin of CAFs. Within the TME, CAFs can be derived from a wide variety of cells: activated resident fibroblasts, bone marrow-derived mesenchymal stem cells, endothelial cells, epithelial cells, adipocytes, pericytes, and stellate cells. Depending on the origin, CAFs have distinctive characteristics, functions, and locations.

Figure 5

Crosstalk between tumour cells and CAFs at the primary tumour and metastatic site. Factors derived from cancer cells activate local fibroblasts to become CAFs. CAFs, in turn, produce interleukins to activate signalling in cancer cells increasing their metastatic potential. CAFs are chaperons of tumour cells as they support their survival and extravasation to the metastatic site, as well as preparing the premetastatic niche.

Figure 6

Strategies for CAF-targeted anticancer therapy. (1) Reprogramming to a non-CAF phenotype using epigenetic modifiers or TGF-β inhibitors. In addition, the use of anti-miRNAs, miRNA mimetics, or siRNA administration to reverse CAFs phenotype. (2) Blocking all signalling emitted by CAFs either by targeting crucial molecules (IL-6, TGF-β, CXCL12) or signalling pathways such as CCL2 and CCR2 signalling axis, JAK-STAT3, TGF-β, and the Hedgehog signalling pathway, or FAK signalling pathways to restrict ECM remodelling along with TN-C, MMPs, and HA. (3) Targeting αSMA or membrane markers such as FAPα, GPR77, or CD10 to eradicate CAFs populations.