Exosomes are endosomal-derived vesicles that play an important role in cell-to-cell communication. Multiple cells from different parts of our system secret these vesicles, and in this sense, exosomes derived from cancerous cells have shown that are involved in cancer progression and metastasis.
The growing interest in determining the clinical relevance of these particles in cancer disease has driven the relevance of identifying the content of these disease-specific exosomes, such as nucleic acids, proteins and lipids, as a source of new biomarkers that propose the diagnostic potential of exosomes in the early detection of cancers.
In this sense, exosomes have been considered ideal biomarkers in cancer diagnosis, due to their specific and unique characteristics. However, there is still so much work to do in the development of diagnostic tools, where exosome-based assays can play an important role.
This article pretends to summarize the key aspects about exosomes as biomarkers, including isolation techniques and its relationship with the early detection of diseases as cancer.
Exosome content depend on the cellular origin and curiously seems to change according to the physiological state of the cells, which means that the number of copies and type of molecules seems to vary according to the condition in which the cells are found. This means that there are differential patterns in each physiological state that will be reflected in differential content within the exosomes, where protein and RNAs abundance could lead to different molecular profiles
Diseases involve a disturbance in the cell physiological state that could affects systemically. If we think that cells are in constant exchange of molecules with their environment, it is possible to detect those groups of exosomes with different cellular origin and composition. Therefore, the analysis of exosome content can provide evidence of the events that are temporally occurring in its cell of origin
In other words, if the vesicular contents of control patients (without the disease) and affected patients are studied comparatively, a differential molecular profile could be made for both cases, which could be used for the differential diagnosis of the disease.
As exosomes are unique in their molecular composition and this molecular content is a reflection of the state of the cell at the time the exosome is produced, this make them potential biomarkers with high specificity and sensitivity which is a basic requirement for, for example, noninvasive cancer diagnosis though liquid biopsies.
Biomarkers are currently one of the main topics in biomedical research. Due to exosome characteristics and content, they have become research candidates, studied by numerous scientific research groups worldwide. But what make these exosomes so interesting as biomarkers? their composition, stability, abundance and origin.
One of the important questions in the field of biomedicine is whether it is possible to carry out early detection of various diseases in order to enhance the effectiveness of treatments improving patient quality of life.
Currently, many studies have focused their efforts on the molecular content characterization in commonly accessible fluids, such as blood, urine, saliva, etc. In this regard, a new focus of interest is the study of the composition of circulating extracellular vesicles in these fluids.
The pathological state correlates with changes in molecular content, both inside and outside the cells. Thus, early detection of these changes indicates the presence of certain diseases, with these molecules serving as biomarkers of each condition.
Exosomes offer three major advantages that are interesting when used as biomarkers.
► First, the abundance of mainly saturated lipids provides increased membrane rigidity, making exosomes more resistant vesicles and providing greater protection of the internal molecular content.
► Secondly, the differential presence of some proteins in the exosomal membrane may allow specific identification of the cellular source, allowing vesicles to be isolated using Isolation columns (SEC) or immunoprecipitation and their contents to be studied separately.
►Thirdly, once the cell source has been identified, the analysis of the content can reveal the cellular state of organs that are difficult to study in vivo (such as the brain), and groups of biomarkers of greater specificity can be identified allowing pathology subclasification.
On the other hand, one of the great challenges when studying exosomes as biomarkers is their isolation.
This isolation can be carried out by physical methods (such as gradient ultracentrifugation) or by the use of surface markers (use of anti-tetraspanin antibodies, such as CD63). These techniques involve a large investment in terms of equipment, reagents and time, which most times it does not allow its transfer to the clinical setting.
However, biotechnology companies (such as Immunostep) work non-stop in order to provide high purified exosomes standards from different type of biological samples and cell line origin in order to facilitate the use of this exosomes as reference material in research and diagnosis, as well as different ultracentrifugation free methods for the highly- sensitive biomarker detection, easily transferable to clinical use.
Cancer is the uncontrolled growth of cells. Among various types of cancer, we can highlight lung cancer, gastrointestinal cancers (GI cancer), including liver cancer, pancreatic cancer and colorectal cancer, and breast cancer are the most common cause of cancer-related death. Chemotherapy, targeted therapy, surgical recession and radiotherapy can effectively cure or prolong patient survival. Nevertheless, sometime the survival rate of cancer is still very poor.
One of the main reasons of this, is the diagnosis of cancer at a late stage, where patients already have advanced tumors and metastatic tumors.
Over half of all cancer patients present a local advanced or metastatic stage, which make early diagnosis and treatment fundamentally important to improve patient prognosis. Therefore, tumor makers in development become a real breakthrough in this regard, aiming to accurately detect various types of cancer and control disease progression.
However, the sensitivity of these cancer biomarkers has so far been unsatisfactory. Furthermore, fecal occult blood testing of colorectal cancer and invasive endoscopic detection of gastric and colon cancer represent a major inconvenience for patients. Therefore, highly sensitive and noninvasive diagnostic markers for early cancer detection are strongly necessary.
In this regard, exosomes play an important role in cancer development through intercellular communication, promotion of cell metastasis and development of drug resistance. Exosomes are frequently secreted by the cancers and are widely distributed in many body fluids. Therefore, they can be detected in blood, saliva and urine.
This is the reason why exosomal biomarkers have demonstrated great performance in cancer diagnosis and prognosis. However, the methods of isolating exosomes vary in different studies and are a major source of variability in liquid biopsy results. .
Thus, ultracentrifugation or the use of commercial isolation kits are common methods in extracting exosomes. While ultracentrifugation gives highly pure exosomes but the isolation efficiency is relatively low; commercial kits maximizes the efficiency.
Exosomes are an interesting source of biomarkers that, to date, continues to be under constant research. In this sense, to continue standardizing protocols for the detection of exosomal biomarkers become critical. A new biomarker appears every day in specialized publications in the field, but few of them offer as much versatility as do exosomes in terms of the study of groups of molecules.
Currently, we still have little information on the mechanisms involved in biogenesis, export, transport, delivery and cellular effects. No doubt, we still have many hours of important work ahead of us.
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