CAF: The star regulator in cancer network

This review is guided and revised by Tianlin He, with the manuscript written by his graduate student, Keke Lv. The authors believe that the development of solid tumors is the result of communication and crosstalk among its components, arising from an imbalance between parenchymal cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), distinguished by their remarkable plasticity and heterogeneity, serve as pivotal mediators within the intricate tumor microenvironment. The authors conduct a comprehensive review of the origins, classifications, and multifaceted functions of CAFs in pancreatic cancer, rectal cancer, lung cancer, and breast cancer. Furthermore, they synthesize insights on how these heterogeneous CAFs engage in extensive interactions with immune cells, the extracellular matrix, and tumor cells, utilizing signaling pathways, metabolic adjustments, and various other mechanisms throughout the initiation and progression of tumors. Ultimately, these intricate interactions culminate in immunosuppression and the unrestrained proliferation of tumor cells.

TME has emerged as a research hotspot in recent years. Cancer researchers have analyzed the structure and cellular composition of the TME, elucidating the roles of its key components: immune cells, cancer cells, extracellular matrix, and CAFs. In this review, the authors profoundly recognize that the TME is a dynamically balanced network system, where various cellular components should be understood as a whole.

With CAFs as the central pivot, Tianlin He and Keke Lv summarized the interactions between CAFs and innate immune cells (such as macrophages, neutrophils, mast cells, etc.) as well as adaptive immune cells (T cells and B cells): CAFs stimulate the polarization of innate immune cells towards pro-tumor subtypes through direct contact, paracrine signaling, and other pathways; and further positively feedback this effect under the counteraction of immune cells, thereby achieving tumor immune escape. Moreover, CAFs closely interfere with the degradation and deposition of the extracellular matrix (ECM) by secreting cytokines such as TGF-β, proteases like MMP, and LOX, thereby disrupting the balance between ECM fiber formation and degradation, leading to ECM fibrosis. Simultaneously, the stiff ECM activates the YAP pathway in CAFs through integrins, exacerbating this process. Based on the role of metabolism in tumor progression, they outline the metabolic regulation process between CAFs and tumor cells under stress conditions(inflammation and hypoxia). By dividing the tumor into aerobic and hypoxic regions, they demonstrate the complete process through which CAFs and cancer cells facilitate energy material turnover and enhance nutritional metabolism through cytokines and metabolites.

Importantly, they provide a comprehensive summary of the dual-edged nature of CAFs, emphasizing the crucial need for CAF-targeted therapies. They meticulously outline the existing therapeutic drugs and the current status of clinical trials targeting CAFs, and offer insightful perspectives on the challenges and promising opportunities that lie ahead in the exploration of CAFs.

Drawing from their profound understanding of CAFs' function within the TME, and through a meticulous summation and examination of the communication signals and interactive mechanisms, Tianlin He and Keke Lv present novel perspectives on clinical cancer treatment, recognizing diverse approaches for targeting CAFs. This review significantly enhances our comprehensive appreciation of CAFs' role as pivotal connectors and offers valuable insights for restoring the balance of TME.

See the article: 

Cancer-associated fbroblasts: heterogeneity, tumorigenicity and therapeutic targets

https://doi.org/10.1186/s43556-024-00233-8