The emerging roles of exosomes in anti-cancer drug resistance and tumor progression: An insight towards tumor-microenvironment interaction.

The tumor microenvironment (TME) is a complex network of cellular organization consisting of fibroblasts, adipocytes, pericytes, immune cells endothelial cells, and extracellular matrix proteins. Besides communicating with each other, tumor cells are also involved in the tumor stroma interaction. Presently, most of the studies have focused on the contribution of TME in supporting tumor growth through intercellular communication by physical contact between the cells or through paracrine signaling cascades of growth factors and cytokines. The crosstalk between the tumor and TME has a pivotal role in the development of anti-cancer drug resistance. Drug resistance, be it against targeted or non-targeted drugs, has emerged as a major hurdle in the successful therapeutic intervention of cancer. Among the several mechanisms involved in the development of the resistance to anti-cancer therapies, exosomes have recently come into the limelight. Exosomes are the nano-sized vesicles, originated from the endolysosomal compartments and have the inherent potential to shuttle diverse biomolecules like proteins, lipids, and nucleic acids to the recipient cells. There are also instances where the pharmacological compounds are transferred between the cells via exosomes. For instance, the transfer of the cargoes from the drug-resistant tumor cells immensely affects the recipient drug-sensitive cells in terms of their proliferation, survival, migration, and drug resistance. In this review, we have discussed multiple aspects of the exosome-mediated bidirectional interplay between tumor and TME. Furthermore, we have also emphasized the contribution of exosomes promoting drug resistance and therapeutic strategies to mitigate the exosome induced drug resistance as well.

Jena BC ，Mandal M 《-》

Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance.

Santos P ，Almeida F 《Cells》

Communication in tiny packages: Exosomes as means of tumor-stroma communication.

Tumor-derived exosomes are nano-sized vesicles acting as multi-signal devices influencing tumor growth at local and distant sites. Exosomes are derived from the endolysosomal compartment and can shuttle diverse biomolecules like nucleic acids (microRNAs and DNA fragments), lipids, proteins, and even pharmacological compounds from a donor cell to recipient cells. The transfer of cargo to recipient cells enables tumor-derived exosomes to influence diverse cellular functions like proliferation, cell survival, and migration in recipient cells, highlighting tumor-derived exosomes as important players in communication within the tumor microenvironment and at distant sites. In this review, we discuss the mechanisms associated with exosome biogenesis and cargo sorting. In addition, we highlight the communication of tumor-derived exosomes in the tumor microenvironment during different phases of tumor development, focusing on angiogenesis, immune escape mechanisms, drug resistance, and metastasis.

Daßler-Plenker J ，Küttner V ，Egeblad M 《-》

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》

Functional roles of exosomal miRNAs in multi-drug resistance in cancer chemotherapeutics.

Recent understanding of different molecular aspects of tumor initiation and progression has led to the discovery of a growing list of drugs. While these drugs have shown promising effects on tumor cells, their widespread usage has been hampered by the acquisition of drug resistance in a subpopulation of tumor cells. A differential pattern in the secretion of specialized vesicles named "exosomes" in drug-resistant cancer cells have recently received much attention. In addition, microRNAs (miRNAs) have been shown to be enriched in exosomes. Exosomal miRNAs (also known as exo-miRs) could be shuttled to recipient cells and play a role in the regulation of post-transcriptional gene expression, which may exert certain effects on cancer drug resistance. Here, we have reviewed the role of exo-miRs in chemotherapeutic resistance in different cancer types. Besides, studies which have focused on predictive role of circulating exo-miRs in cancer drug resistance are reviewed.

Mowla M ，Hashemi A 《-》