Cancer-associated fibroblasts: overview, progress, challenges, and directions

Abstract

Tumors are one of the main causes of death in humans. The development of safe and effective methods for early diagnosis and treatment of tumors is a difficult problem that needs to be solved urgently. It is well established that the occurrence of tumors involves complex biological mechanisms, and the tumor microenvironment (TME) plays an important role in regulating the biological behavior of tumors. Cancer-associated fibroblasts (CAFs) are a group of activated fibroblasts with significant heterogeneity and plasticity in the tumor microenvironment. They secrete a variety of active factors to regulate tumor occurrence, development, metastasis, and therapeutic resistance. Although most studies suggest that CAFs have significant tumor-promoting functions, some evidence indicates that they may have certain tumor-suppressive functions in the early stage of tumors. Current research on CAFs continues to face many challenges, and the heterogeneity of their origin, phenotype, and function is a major difficulty and hot spot. To provide new perspectives for the research on CAFs and tumor diagnosis and treatment, this review summarizes the definition, origin, biomarkers, generation mechanism, functions, heterogeneity, plasticity, subpopulations, pre-metastasis niches (PMN), immune microenvironment, and targeted therapy of CAFs, describes the research progress and challenges, and proposes possible future research directions based on existing reports.

Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC)

“…IL6 orchestrates MAPK-STAT3 signaling which in turn regulates the dynamic transition between 2 CAFs sub-populations, EMT-CAFs and proliferation-CAFs [48], rendering the IL6-TGFβ-EMT-CAFs cross-talk a valid therapeutic target. While targeting directly EMT via NOTCH or WNT has shown limited success in the clinic [49], microenvironment remodeling to reverse immunosuppression by inhibiting CXCL12 [50] or promoting T-cell infiltration [51] or function via engineered oncolytic adenovirus [52], has shown has shown promising results in reducing metastasis formation [53]. Additionally, we observed a positive correlation between gene expression of IL8, CXCL8, CXCR1 and CXCL10 and Fn / Fusobacteriales prevalence, corroborating findings from Casasanta assessing Fn in HCT116 CRC cells [54].…”

The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options

“…Fibroblasts are present in all solid organs, where they release several components of the matrix, cytokines and growth factors and play a role in the regulation of the homeostasis. In cancer, the activated fibroblasts have an important function in the regulation of tumor growth, dissemination and metastasis [24]. PDAC is characterized by a prominent desmoplasia where the stroma components occupy more than 70% of the total tumor volume [25].…”

Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models

“…In addition, leukemic blasts are readily accessible and relatively defenseless to circulating CAR T cells, which is in stark contrast to the complex tumor microenvironment (TME) of solid tumors. The latter contains a dense extracellular matrix, which poses physical obstacles [28,[41][42][43], as well as cancer-associated fibroblasts (CAFs) [44], tumor-infiltrating macrophages [45], and regulatory T and B cells that are potential negative immune regulators [46]. Thus, it appears that the decreased cytolytic activity of CM-enriched CAR T cells is sufficient for the eradication of leukemic blasts, but insufficient to overcome the immunosuppressive TME of solid tumors, which requires a stronger T cell activation.…”