University of Western Australia Library. University of Wollongong Library. Blood vessel tortuosity selects against evolution of aggressive tumor cells in confined tissue environments: Gale Eastern Regional Libraries. Neoplasms Search for additional papers on plastiicity topic.
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Received Nov 6; Accepted Feb This article has been cited by other articles in PMC. Associated Data Not applicable. Abstract Exosomes are small extracellular vesicles that contain genetic material, proteins, and lipids. They function as potent signaling molecules between cancer cells and the surrounding cells that comprise the tumor microenvironment TME.
Exosomes derived from both tumor and stromal cells have been implicated in all stages of cancer progression and play an important role in therapy resistance. Moreover, due to their nature as mediators of cell-cell communication, they are integral to TME-dependent therapy resistance.
In this review, we discuss current exosome isolation and profiling techniques and their role in TME interactions and therapy resistance. We also explore emerging clinical applications of both exosomes as biomarkers, direct therapeutic targets, and engineered nanocarriers.
In order to fully understand the TME, careful interrogation of exosomes and their cargo is critical. This understanding is a promising avenue for the development of effective clinical applications.
Keywords: Exosomes, Tumor microenvironment, Therapy resistance, Biomarkers Background The tumor microenvironment TME is a complex ecosystem and an active participant in all stages of cancer initiation and progression [ 1 , 2 ]. Comprised of diverse cell types in a variety of functional niches, the TME modulates a plethora of cell-cell interactions.
These interactions orchestrate reprogramming into cancer-permissive environments and can have significant impacts on cancer development [ 3 ], progression [ 4 ], and treatment success [ 5 ].
Therapies targeting the immune compartment of the TME are promising, especially in combinatorial approaches. However, the TME has been implicated as a major source of therapy resistance, especially due to its inherent heterogeneity and adaptability [ 6 ]. With the advent of single-cell technologies, cancer heterogeneity has been interrogated in cancer cells [ 7 , 8 ] and the surrounding TME [ 9 — 11 ].
This heterogeneity is complicated by dynamic signaling. Cells in the TME exchange information through a variety of signaling networks, ranging from juxtacrine interactions such as desmosomes and cell-cell junctions, to secreted factors such as cytokines, chemokines, and extracellular vesicles such as exosomes [ 12 ].
Exosomes and other extracellular vesicles highlight the complexity of dynamic cell-to-cell interactions that make up the TME. In this review, we focus on our growing understanding of the biogenesis and functions of exosomes originating from cancer cells and the TME and their ability to mediate paracrine signaling and influence cancer progression. In total, the TME can amplify critical oncogenic pathways in cancer cells to promote tumor progression, dissemination, and therapy resistance.
Exosomes are an intriguing component of TME signaling and represent a growing body of research that may lead to exciting clinical applications and therapies. In the process of endosomal maturation, intraluminal vesicles form via ESCRT-dependent and independent processes [ 14 ].
The late intraluminal vesicle-containing endosomes are referred to as multivesicular endosomes or multivesicular bodies. The contents of the intraluminal vesicles that become exosomes contain directly sorted and sometimes stochastically acquired cytoplasmic and membrane-bound contents. Generally, multivesicular bodies will fuse with lysosomes to degrade or recycle their contexts. Extracellular vesicles released from multivesicular bodies that fuse with the plasma membrane are known as exosomes [ 13 , 14 ].
These are not to be confused with microvesicles, which form by budding from the plasma membrane. The term exosome is often incorrectly used interchangeably with extracellular vesicle. In contrast, exosomes are a subset of extracellular vesicles that originate from endosomes and are difficult to distinguish from other small extracellular vesicles by common isolation methods.
While this does not detract from previous findings on exosomes, it is important to note. Exosome isolation techniques Exosomes can be isolated from cell culture supernatants and biological fluids using a variety of techniques Fig. In tissue culture models, exosomes are classically separated from input media by differential high-speed ultracentrifugation, including steps to clear cells, cell debris, and larger microvesicles [ 15 ]. While this technique is most prevalent, it can result in inconsistent yield and purity, and the harsh nature of ultracentrifugation can destroy exosomes [ 15 ].
Another isolation technique is polyethylene glycol-based low-speed centrifugation — however, it is unclear if this method interferes with the functionality of purified exosomes [ 16 ].
Several commercial exosome isolation kits are widely used, but their ability to yield pure and functional exosomes is poorly characterized. Further, antibody- and filter-based enrichment methods can produce pure populations of exosomes without harsh centrifugation [ 17 ].
These methods separate exosomes from cell culture or biological fluids in a label-free and contact-free manner [ 18 , 19 ]. Acoustofluidic approaches use acoustic waves in the context of a microfluidic device to perform size-based separation from whole blood [ 19 ].
Fluidic techniques, such as ExoTIC exosome total isolation chip use a step-wise nanoporous membrane approach to enrich and then further purify extracellular vesicles in the nm range [ 18 ].
Once widely available, acoustofluidic or fluidic methods may be the most accurate approaches to isolate reproducible quantities of functional and intact exosomes.
Exosomes in the tumor microenvironment as mediators of cancer therapy resistance
Received Nov 6; Accepted Feb This article has been cited by other articles in PMC. Associated Data Not applicable. Abstract Exosomes are small extracellular vesicles that contain genetic material, proteins, and lipids. They function as potent signaling molecules between cancer cells and the surrounding cells that comprise the tumor microenvironment TME. Exosomes derived from both tumor and stromal cells have been implicated in all stages of cancer progression and play an important role in therapy resistance.
CANCER INVASION AND THE MICROENVIRONMENT PLASTICITY AND RECIPROCITY PDF
The sections were deparaffinized, rehydrated, and subjected to antigen retrieval combined with signal detection, as previously described [ 14 , 15 ]. The antibodies used were mouse monoclonal anti-CD dilution, aa, clone 9E5, cat no. After the sections were rinsed three times in TBST for 5 min each time, the sections were incubated with HRP- and AP-labeled secondary antibodies premixed at a ratio for 1 h at room temperature. Immune signal evaluation For each sample, the immunoreactivity levels of COX2 were estimated under a light microscope by assessing the average signal intensity on a scale of The intensity and percentage scores were subsequently multiplied to obtain a composite score; a score of 0 to 3 was defined as negative, while a score of 4 to 12 was defined as positive. CD is known to be a specific marker for M2-type macrophages. The average counts were recorded as M2 macrophage counts for each patient.
Cancer Invasion and the Microenvironment-Plasticity and Reciprocity
Cancer cells are located in a very complex microenvironment together with stromal components that participate to enhance oxidative stress to promote tumor progression. Indeed, convincing experimental and clinical evidence underline the key role of oxidative stress in several tumor aspects thus affecting several characteristics of cancer cells. Oxidants influence the DNA mutational potential, intracellular signaling pathways controlling cell proliferation and survival and cell motility and invasiveness as well as control the reactivity of stromal components that is fundamental for cancer development and dissemination, inflammation, tissue repair, and de novo angiogenesis. Introduction With over 3 million novel cases each year in Europe, cancer is a main public health hitch with a vital need for new therapies. Hanahan and Weinberg defined in the s the so-called hallmarks of cancers, mandatory characteristics of virtually all neoplastic cells, enabling them to grow in a foreign and hostile environment and allowing escaping endogenous protective systems .