As a nanoscale subset of extracellular vehicles, exosomes represent a new pathway of intercellular communication by delivering cargos such as proteins and nucleic acids to recipient cells. Importantly, it has been well documented that exosome-mediated delivery of such cargo is involved in many pathological processes such as tumor progression, cancer metastasis, and development of drug resistance. Innately biocompatible and possessing ideal structural properties, exosomes offer distinct advantages for drug delivery over artificial nanoscale drug carriers. In this review, we summarize recent progress in methods for engineering exosomes including isolation techniques and exogenous cargo encapsulation, with a focus on applications of engineered exosomes to target cancer metastasis.
Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow. Cancer cells and other cells can transduce physical stimuli into biochemical responses using the mechanosensitive ion channel Piezo1, which is activated by membrane deformations that occur when cells are exposed to physical forces. When active, Piezo1 opens, allowing for calcium flux into the cell. Calcium, as a ubiquitous second-messenger cation, is associated with many signaling pathways involved in cancer metastasis, such as angiogenesis, cell migration, intravasation, and proliferation. In this review, we discuss the roles of Piezo1 in each stage of cancer metastasis in addition to its roles in immune cell activation and cancer cell death.
Background T cell activation is a mechanical process as much as it is a biochemical process. In this study, we used a cone-and-plate viscometer system to treat Jurkat and primary human T cells with fluid shear stress (FSS) to enhance the activation of the T cells through mechanical means. Results The FSS treatment of T cells in combination with soluble and bead-bound CD3/CD28 antibodies increased the activation of signaling proteins essential for T cell activation, such as zeta-chain-associated protein kinase-70 (ZAP70), nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NF-κB), and AP-1 (activator protein 1). The FSS treatment also enhanced the expression of the cytokines tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2), and interferon gamma (IFN-γ), which are necessary for sustained T cell activation and function. The enhanced activation of T cells by FSS was calcium dependent. The calcium signaling was controlled by the mechanosensitive ion channel Piezo1, as GsMTx-4 and Piezo1 knockout reduced ZAP70 phosphorylation by FSS. Conclusions These results demonstrate an intriguing new dynamic to T cell activation, as the circulatory system consists of different magnitudes of FSS and could have a proinflammatory role in T cell function. The results also identify a potential pathophysiological relationship between T cell activation and FSS, as hypertension is a disease characterized by abnormal blood flow and is correlated with multiple autoimmune diseases.
Circulating tumor cells (CTCs) are exposed to fluid shear stresses (FSS) of >1,000 dyn/cm2 in circulation. Normally, CTCs that are exposed to FSS of this magnitude die. However, some CTCs develop resistance to this FSS, allowing them to colonize distant organs. We explored how prostate CTCs can resist cell death in response to forces of this magnitude. The DU145, PC3, and LNCaP human prostate cancer cell lines were used to represent cells of different metastatic origins. The cell lines were briefly treated with an average FSS of 3,950 dyn/cm2 using a 30 G needle and syringe pump. DU145 cells had no change in cell viability, PC3 cells had some cell death, and LNCaP cells exhibited significant cell death. These cell death responses correlated with increased cell membrane damage, less efficient membrane repair, and increased stiffness. Additionally, FSS treatment prevented the LNCaP FSS sensitive cell line from forming a growing tumor in vivo. This suggests that these properties play a role in FSS resistance and could represent potential targets for disrupting bloodborne metastasis.
Vaccines have been used to prevent and eradicate different diseases for over 200 years, and new vaccine technologies have the potential to prevent many common illnesses. Cancer, despite many advances in therapeutics, is still the second leading causes of death in the United States. Prophylactic, or preventative, cancer vaccines have the potential to reduce cancer prevalence by initiating a specific immune response that will target cancer before it can develop. Cancer vaccines can include many different components, such as peptides and carbohydrates, and be fabricated for delivery using a variety of means including through incorporation of stabilizing chemicals like polyethylene glycol (PEG) and pan-DR helper T-lymphocyte epitope (PADRE), fusion with antigen-presenting cells (APCs), microneedle patches, and liposomal encapsulation. There are currently five cancer vaccines used in the clinic, protecting against either human papillomavirus (HPV) or hepatitis B virus (HBV), and preventing several different types of cancer including cervical and oral cancer. Prophylactic cancer vaccines can promote three different types of adaptive responses: humoral (B cell, or antibody-mediated), cellular (T cell) or a combination of the two types. Each vaccine has its advantages and challenges at eliciting an adaptive immune response, but these prophylactic cancer vaccines in development have the potential to prevent or delay tumor development, and reduce the incidence of many common cancers.
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