Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via exosomes in gastrointestinal tumors

Abstract

Gastrointestinal (GI) tumors are a significant global health threat, with high rates of morbidity and mortality. Exosomes contain various biologically active molecules like nucleic acids, proteins, and lipids and can serve as messengers for intercellular communication. They play critical roles in the exchange of information between tumor cells and the tumor microenvironment (TME). The TME consists of mesenchymal cells and components of the extracellular matrix (ECM), with fibroblasts being the most abundant cell type in the tumor mesenchyme. Cancer-associated fibroblasts (CAFs) are derived from normal fibroblasts and mesenchymal stem cells that are activated in the TME. CAFs can secrete exosomes to modulate cell proliferation, invasion, migration, drug resistance, and other biological processes in tumors. Additionally, tumor cells can manipulate the function and behavior of fibroblasts through direct cell-cell interactions. This review provides a summary of the intercellular crosstalk between GI tumor cells and CAFs through exosomes, along with potential underlying mechanisms.

Keywords: cancer-associated fibroblasts (CAFs); exosomes; gastrointestinal (GI) tumors; review; tumor microenvironment (TME).

Figure 1

The origin of cancer-associated fibroblasts (CAFs). CAFs can be formed from a variety of cellular precursors through specific mechanisms. Multiple signaling pathways in tissue-resident NFs can be activated in response to stimulation by growth factors, cytokines, and chemokines, as well as epigenetic modifications, and can lead to the conversion of these cells into CAFs. in addition, metabolic reprogramming induced by metabolites derived from cancer cells, senescent fibroblasts, inflammatory cells, and mechanotransduction in the ECM also mediate the transformation of NFs into CAFs. BMSCs and quiescent stellate cells are also recruited and activated to become CAFs in response to growth factors, cytokines, and chemokines. In addition, adipocytes, pericytes, endothelial cells, epithelial cells, and smooth muscle cells are also converted to CAFs.

Figure 2

The classification and function of CAFs. The numerous routes of origin of CAFs lead to the high heterogeneity of CAFs. Generally, CAFs can be classified into rCAFs, myCAFs, iCAFs and apCAFs. rCAFs mainly play an oncogenic role. myCAFs promote ECM remodeling by synthesizing collagen and regulating mechanotransduction. iCAFs regulate the immune process by altering secretory properties. apCAFs activate CD4+ T cells in an antigen-specific manner. myCAFs, iCAFs and apCAFs together can significantly activate CD4+ T cells. The combination of myCAFs, iCAFs and apCAFs significantly promotes cancer cell proliferation, migration, invasion, metastasis and drug resistance, thereby contributing to the progression of cancer.

Figure 3

The biological roles of CAFs in cancer. The tumor microenvironment is complex, and CAFs can influence multiple processes in the tumor microenvironment such as angiogenesis, decalcification, hypoxia, immune regulation, and EMT in cancer cells by orchestrating the interactions of multiple cell types and processes, leading to metastasis and high drug resistance.

Figure 4

The biogenesis of extracellullar vesicles (EVs). EVs including exosomes, microvesicles, and apoptotic vesicles, are lipid bilayer particles that are naturally released from cells. The formation of EVs involves double invagination of the plasma membrane and intracellularization of intraluminal vesicles (ILVs). The formation of EVs involves the double invagination of the plasma membrane and the intracellular formation of intraluminal vesicles (ILVs), which are released into the extracellular space when MVBs fuse with the plasma membrane. However, microvesicles are produced by direct outward budding of the plasma membrane. The cargo contents of EVs are selectively packaged and depend on the maternal cell type and functional status. EVs can transfer bioactive RNAs, proteins, lipids, and metabolites from the donor cell to the recipient cell and influence the biological properties of the latter.