During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro- and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.

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Role of Matrix Metalloproteinases in Angiogenesis and Cancer.

Extracellular-vesicle-based cell-to-cell communication is conserved across all kingdoms of life. There is compelling evidence that extracellular vesicles are involved in major (patho)physiological processes, including cellular homoeostasis, infection propagation, cancer development and cardiovascular diseases. Various studies suggest that extracellular vesicles have several advantages over conventional synthetic carriers, opening new frontiers for modern drug delivery. Despite extensive research, clinical translation of extracellular-vesicle-based therapies remains challenging. Here, we discuss the uniqueness of extracellular vesicles along with critical design and development steps required to utilize their full potential as drug carriers, including loading methods, in-depth characterization and large-scale manufacturing. We compare the prospects of extracellular vesicles with those of the well established liposomes and provide guidelines to direct the process of developing vesicle-based drug delivery systems. In this Review the authors discuss the biological role of extracellular vesicles and how they can be applied as drug carriers, focusing on the current state of their manufacturing and existing challenges.

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Extracellular vesicles as a next-generation drug delivery platform.

The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8+ T cells with genetically modified receptors-chimaeric antigen receptors-to specify and enhance CD8+ T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment.

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Cytotoxic CD8 + T cells in cancer and cancer immunotherapy

Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nanosized membrane vesicles derived from most cell types. Carrying diverse biomolecules from their parent cells, EVs are important mediators of intercellular communication and thus play significant roles in physiological and pathological processes. Owing to their natural biogenesis process, EVs are generated with high biocompatibility, enhanced stability, and limited immunogenicity, which provide multiple advantages as drug delivery systems (DDSs) over traditional synthetic delivery vehicles. EVs have been reported to be used for the delivery of siRNAs, miRNAs, protein, small molecule drugs, nanoparticles, and CRISPR/Cas9 in the treatment of various diseases. As a natural drug delivery vectors, EVs can penetrate into the tissues and be bioengineered to enhance the targetability. Although EVs' characteristics make them ideal for drug delivery, EV-based drug delivery remains challenging, due to lack of standardized isolation and purification methods, limited drug loading efficiency, and insufficient clinical grade production. In this review, we summarized the current knowledge on the application of EVs as DDS from the perspective of different cell origin and weighted the advantages and bottlenecks of EV-based DDS.

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.

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Exosome-based immunotherapy: a promising approach for cancer treatment

Hypoxic tumor microenvironment is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. A continuous interference between cancer cells and stromal cells within the hypoxic microenvironment has been uncovered for its importance in cancer development and treatment responsiveness. Exosomes, initially considered as “garbage bins” for unwanted material from cells, are now elucidated to perform a variety of functions that involve interactions within the cellular microenvironment due to their ability to carry numerous cargoes, including lipids, proteins, nucleic acids, and metabolites. Exosome-mediated continuous interference between cancer cells and stroma are believed to regulate hypoxia-adaptation and to rebuild the microenvironment in return. In this review, we will discuss the knowledge in literature with respect to the exosome-mediated multi-directional and mutual signal transmission among the variety of cell types within hypoxic cancer microenvironment.

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Exosome-orchestrated hypoxic tumor microenvironment.

Radiotherapy is one of the most effective treatment methods for various solid tumors Bidirectional signal transduction between cancer cells and stromal cells within the irradiated microenvironment is important in cancer development and treatment responsiveness Exosomes, initially considered as "garbage bins" for unwanted from cells, are now understood to perform a variety of functions in interactions within the tumor microenvironment Exosome-mediated regulation processes are rebuilt under the irradiation stimuli, because the exosome production, uptake, and contents are markedly modified by irradiation In turn, irradiation-modified exosomes may modulate the cell response to irradiation through feedback regulation Here, we review current knowledge and discuss the roles of exosome-mediated interactions between cells under radiotherapy conditions

http://www.cancerbiomed.org/index.php/cocr/article/download/1768/1725

Exosome-mediated cellular crosstalk within the tumor microenvironment upon irradiation.

Small extracellular vesicles containing miR-192/215 mediate hypoxia-induced cancer-associated fibroblast development in head and neck squamous cell carcinoma

Small extracellular vesicles (sEVs) operate as a signaling platform due to their ability to carry functional molecular cargos. However, the role of sEVs in hypoxic tumor microenvironment-mediated premetastatic niche formation remains poorly understood. Methods: Protein expression profile of sEVs derived from normoxic and hypoxic head and neck squamous cell carcinoma (HNSCC) cells were determined by Isobaric Tagging Technology for Relative Quantitation. In vitro invasion assay and in vivo colonization were performed to evaluate the role of sEV-delivering proteins. Results: We identified lysyl oxidase like 2 (LOXL2) which had the highest fold increase in hypoxic sEVs compared with normoxic sEVs. Hypoxic cell-derived sEVs delivered high amounts of LOXL2 to non-hypoxic HNSCC cells to elicit epithelial-to-mesenchymal transition (EMT) and induce the invasion of the recipient cancer cells. Moreover, LOXL2-enriched sEVs were incorporated by distant fibroblasts and activate FAK/Src signaling in recipient fibroblasts. Increased production of fibronectin mediated by FAK/Src signaling recruited myeloid-derived suppressor cells to form a premetastatic niche. Serum sEV LOXL2 can reflect a hypoxic and aggressive tumor type and can serve as an alternative to tissue LOXL2 as an independent prognostic factor of overall survival for patients with HNSCC. Conclusion: sEVs derived from the hypoxic tumor microenvironment of HNSCC can drive local invasion of non-hypoxic HNSCC cells and stimulate premetastatic niche formation by delivering LOXL2 to non-hypoxic HNSCC cells and fibroblasts to induce EMT and fibronectin production, respectively.

Yaying Hao

Papers

Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source

Exosome-orchestrated hypoxic tumor microenvironment.

Exosome-mediated cellular crosstalk within the tumor microenvironment upon irradiation.

Small extracellular vesicles containing miR-192/215 mediate hypoxia-induced cancer-associated fibroblast development in head and neck squamous cell carcinoma

LOXL2-enriched small extracellular vesicles mediate hypoxia-induced premetastatic niche and indicates poor outcome of head and neck cancer.