Cancer associated fibroblasts in cancer development and therapy

Abstract

Cancer-associated fibroblasts (CAFs) are key players in cancer development and therapy, and they exhibit multifaceted roles in the tumor microenvironment (TME). From their diverse cellular origins, CAFs undergo phenotypic and functional transformation upon interacting with tumor cells and their presence can adversely influence treatment outcomes and the severity of the cancer. Emerging evidence from single-cell RNA sequencing (scRNA-seq) studies have highlighted the heterogeneity and plasticity of CAFs, with subtypes identifiable through distinct gene expression profiles and functional properties. CAFs influence cancer development through multiple mechanisms, including regulation of extracellular matrix (ECM) remodeling, direct promotion of tumor growth through provision of metabolic support, promoting epithelial-mesenchymal transition (EMT) to enhance cancer invasiveness and growth, as well as stimulating cancer stem cell properties within the tumor. Moreover, CAFs can induce an immunosuppressive TME and contribute to therapeutic resistance. In this review, we summarize the fundamental knowledge and recent advances regarding CAFs, focusing on their sophisticated roles in cancer development and potential as therapeutic targets. We discuss various strategies to target CAFs, including ECM modulation, direct elimination, interruption of CAF-TME crosstalk, and CAF normalization, as approaches to developing more effective treatments. An improved understanding of the complex interplay between CAFs and TME is crucial for developing new and effective targeted therapies for cancer.

Keywords: Cancer associated fibroblasts (CAFs); Cancer development; Cancer therapy; Extracellular matrix (ECM); Heterogeneity; Tumor microenvironment (TME).

Fig. 1

Origins of CAFs. CAFs may originate from various cell types including pericytes, adipocytes, stellate cells, mesothelial cells, epithelial cells, endothelial cells, mesenchymal Stem Cells (MSCs) and normal fibroblast. This figure was created with BioRender.com

Fig. 2

Methodology for studying CAFs. (A) CAFs may be obtained through primary culture, or transformation from other cells, such as normal fibroblasts or pancreatic stellate cells (PSCs), for further researches. (B) Animal models of CAFs include patient-derived xenografts (PDX) and transplanted tumor models established from cell lines. Genetically engineered mouse models (GEMMs) can spontaneously develop tumors, better simulating the interaction between CAFs and TME. These genetically engineered mice also allow for the specific elimination of CAF subsets using drugs such as diphtheria toxin, as well as lineage tracing of CAF subsets through the expression of specific markers. (C) In vitro approaches to study CAF-TME interactions include 2D/3D co-culture, conditioned media transfer, and tumor organoid models. In vivo methods involve co-inoculation of CAFs and tumor cells. (D) CAF research integrates techniques such as western blotting (WB), flow cytometry, and immunofluorescence. Advanced tools like single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics provide deeper functional insights. This figure was created with BioRender.com

Fig. 3

CAFs modulate ECM to promote tumor growth. (A) CAFs promote the deposition of extracellular matrix, forming a physical barrier that hinders immune cell infiltration and drug penetration, thereby creating obstacles for anti-tumor treatment. (B) CAFs remodel ECM, facilitating tumor cell invasion and metastasis. (C) CAFs regulate the balance between dense ECM and loose ECM, thus promoting cancer progression. This figure was created with BioRender.com

Fig. 4

CAFs modulate the tumor immune microenvironment (TIME). (A) CAFs inhibit the function of effector T cells by secreting IL-6, CXCL12, TGF-β, and by expressing PD-L1; they also recruit regulatory T cells (Tregs). (B) CAFs recruit macrophages through cytokines such as IL-6, CXCL12, and IL-33, and promote M2 polarization and inducing immunosuppresive subses like lipid-associated macrophages (LAMs). (C) CAFs promote N2 polarization of TANs, upregulate PD-L1, and stimulate neutrophil extracellular trap (NET) formation. (D) CAFs enhance infiltration of monocytic (M-MDSCs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via tumor-derived CSF-1. This figure was created with BioRender.com

Fig. 5

Interplays between CAFs and tumor cells. (A) CAFs fuel tumor cell glycolysis via CCL6 and CCL12 secretion; In addition, Abca8a + CAFs facilitate tumor cell growth by secreting lipid droplets. (B) CAFs enhance tumor proliferation and therapy resistance through IL-6, HGF, and FGF2 secretion, and via exosomal long non-coding RNAs (lncRNAs). (C) CAFs induce epithelial-mesenchymal transition (EMT) via Hedgehog ligands, TGF-β, and HGF. (D) CAF-derived exosomes containing miR-522 suppress lipid peroxidation to inhibit ferroptosis. (E) Complement component 5a (C5a) activates GPR77 + CAFs, inducing tumor stemness via IL-6, IL-8, and TGF-β. This figure was created with BioRender.com

Fig. 6

Therapeutic strategies targeting CAFs. (A) CAFs normalization. Treatments such as calcipotriol, ATRA, and minnelide are designed to convert activated CAFs into a more quiescent, normal fibroblast-like state. Another approach includes CAF subpopulations shift from tumor-promoting to tumor-restrain CAFs (TR-CAFs). (B) Targeting ECM generated by CAFs. Drugs such as pirfenidone, PEGPH20 and vismodegib modify ECM remodeling process to enhance vascular perfusion and oxygenation within the tumor, thereby facilitating drug delivery. (C) Direct depletion of CAFs., strategies utilizing CAR-T cells, radiopharmaceuticals, and monoclonal antibodies (ADCs) have been employed to deplete specific CAFs subgroups through markers such as FAP and GPR77. (D) Targeting cross-talk between CAFs and TME. Specific blockade of signal pathway involved in cross-talks between CAFs and TME such as TGF-β, LIF and mTOR, can exert targeted anti-tumor effects. This figure was created with BioRender.com