Exosomes in Cancer Progression and Therapy Resistance: Molecular Insights and Therapeutic Opportunities

Abstract

The development of therapy resistance still represents a major hurdle in treating cancers, leading to impaired treatment success and increased patient morbidity. The establishment of minimally invasive liquid biopsies is a promising approach to improving the early diagnosis, as well as therapy monitoring, of solid tumors. Because of their manifold functions in the tumor microenvironment, tumor-associated small extracellular vesicles, referred to as exosomes, have become a subject of intense research. Besides their important roles in cancer progression, metastasis, and the immune response, it has been proposed that exosomes also contribute to the acquisition and transfer of therapy resistance, mainly by delivering functional proteins and RNAs, as well as facilitating the export of active drugs or functioning as extracellular decoys. Extensive research has focused on understanding the molecular mechanisms underlying the occurrence of resistance and translating these into strategies for early detection. With this review, we want to provide an overview of the current knowledge about the (patho-)biology of exosomes, as well as state-of-the-art methods of isolation and analysis. Furthermore, we highlight the role of exosomes in tumorigenesis and cancer treatment, where they can function as therapeutic agents, biomarkers, and/or targets. By focusing on their roles in therapy resistance, we will reveal new paths of exploiting exosomes for cancer diagnosis and treatment.

Keywords: cancer; cancer therapy; exosomes; resistance transmission; therapy resistance.

Figure 1

(A) Schematic overview of exosome biogenesis via the endosomal pathway. Starting with (receptor-mediated) endocytosis (1.,2.), intracellular vesicles are formed (3.) and converge into early endosomes (4.). After maturation to late endosomes, intraluminal vesicles are formed through inward budding of the endosomal membrane, resulting in the MVB (5.). Upon fusion of the MVB with lysosomes (6a.), contents are typically recycled or degraded. Fusion of the MVB or lysosome with the plasma membrane (6b.) leads to the release of exosomes into the extracellular space (7.). (B) Schematic illustration of a single exosome and its bioactive cargo and components. MVB = Multivesicular body. TGN = Trans-Golgi network. Symbols indicate different endosomal cargoes, such as peptides and proteins, metabolites, and nucleic acids (as depicted in B). Purple squares symbolize ligand for receptor-mediated endocytosis. Created with BioRender.com.

Figure 2

Schematic overview of possible routes for exosome bioactivity. Interaction of exosomal ligands (green) and cellular receptors (red circle) can trigger downstream signaling cascades ((left); marked by an asterisk). Alternatively, exosomes can be internalized by endocytosis (receptor-ligand interaction in purple/blue) or phagocytosis (middle). Another possibility is the fusion of exosomal and cellular membrane, allowing the direct release of exosomal cargo (red triangle) into the cytoplasm (right). Created with BioRender.com.

Figure 3

Schematic overview of exosome-related mechanism contributing to therapy resistance. (A) Increased release of exosomes and export of active drug within exosomes facilitates chemotherapy resistance. Resistant cells can transfer their resistant phenotype to naïve cells via exosomal delivery of proteins and miRNAs. Upon uptake, this cargo can induce different cellular responses related to chemotherapy resistance. (B) Immunotherapy-resistant cells also show an increased release of exosomes. These exosomes can function as decoys for immunotherapeutic drugs or facilitate receptor–ligand signaling that increases therapy resistance. Uptake of exosomes shed by resistant cells can also induce immunotherapy resistance by delivering ncRNAs and proteins. (C) Radiotherapy-resistant cells also show an increased amount of exosome release. These exosomes contain ncRNAs and proteins that trigger resistance mechanisms if taken up by naïve cells. Created with BioRender.com.

Figure 4

Clinical use of exosomes. (A) After the diagnosis of cancer, an appropriate treatment strategy (surgery, chemotherapy, radiotherapy, immunotherapy, or a combination) is chosen based on the clinical gold standard. (B) Concurrent and recurrent analyses of exosomes allow treatment choices to be optimized and closely monitored, resulting in higher chances of remission and improved patient survival. Created with BioRender.com.