The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators.

Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.

Ilkhani K ，Bastami M ，Delgir S ，Safi A ，Talebian S ，Alivand MR ... -  《-》

Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.

Cancer cells are well-known for adapting their metabolism to maintain high proliferation rates and survive in unfavorable environments with low oxygen and nutritional deficiency. Metabolic reprogramming most commonly arises from the tumor microenvironment (TME). The events of metabolic pathways include the Warburg effect, shift in Krebs cycle metabolites, and increase rate of oxidative phosphorylation that provides the energy for the development and invasion of cancer cells. The TME and shift in tumor metabolism shows a close relationship through bidirectional signaling pathways between the stromal and tumor cells. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in the TME and consist of a heterogeneous and plastic population that play key roles in tumor growth and metastatic capacity. Emerging evidence suggests that CAFs act as major regulators in shaping tumor metabolism especially through the dysregulation of several metabolic pathways, including glucose, amino acid, and lipid metabolism. The arrangement of these metabolic switches is believed to shape distinct CAF behavior and change tumor cell behavior by the CAFs. The crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to cancer cell growth, progression, and evasion from cancer therapies. But the mechanism and process of this interaction remain unclear. This review aimed to highlight the metabolic couplings between tumor cells and CAFs. We reviewed the recent literature supporting an important role of CAFs in the regulation of cancer cell metabolism, and the relevant pathways, which may serve as targets for therapeutic interventions.

Li Z ，Sun C ，Qin Z 《Theranostics》

Cancer associated-fibroblast-derived exosomes in cancer progression.

To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Li C ，Teixeira AF ，Zhu HJ ，Ten Dijke P ... -  《Molecular Cancer》

Metabolic Relationship between Cancer-Associated Fibroblasts and Cancer Cells.

Sazeides C ，Le A 《-》

A review on the role of CAFs and CAF-derived exosomes in progression and metastasis of digestive system cancers.

Zarin B ，Rafiee L ，Daneshpajouhnejad P ，Haghjooy Javanmard S ... -  《-》