Over the next few weeks we will be discusing about an interesting topic. It is the relationship between exosomes and one of the most common diseases of our era, cancer. We will start by introducing these small extracellular vesicles of between 40 and 150 nm in size, and then go into more detail, such as the early diagnosis of the disease thanks to exosomes.
Immunostep encourages all researchers to consider using exosomes to achieve better results in their projects. We hope this article sheds some more light on something that holds so much promise and so much potential.
At first glance, exosomes were described as a garbage bag of cellular waste, disposing excess and/or non-functional cellular components, such as poorly degraded molecules by lysosomal system; nowadays, it seems proven that exosomes also function as cellular shuttles that play a crucial role in cell-to-cell communication. Then, the main function consist in the transport of bioactive molecules between cells, including proteins, metabolites, RNA (mRNA, miRNA, long non-coding RNA), DNA (mtDNA, ssDNA, dsDNA) and lipids.
As exosomes are also present in healthy body fluids, it suggests a relevant role in the normal physiology such as immune system communication, tissue repair and communication within the nervous system, among others.
For instance, the immune response dependent of MHC, occurs after exosomes secrection in B and dendritic cells. About intercellular communication mediated by exosomes, it participates in the regulation of normal physiological processes, and also in the pathological processes of many diseases, including cancer.
You can find more interesting articles talking about this in our section «Publications».
Focusing on cancer, it is well-characterized that the stromal environment plays a pivotal role in tumor development and that tumors have a remarkable ability to modify the stroma for their own benefit.
Tumor cells alter surrounding normal cells to facilitate growth, invasion, chemo-resistance, immune evasion and tumor cells metastasis. Tumor cells also kidnap the normal vasculature and stimulate rapid formation of new blood vessels to supply nutrition to the tumor.
Although the immune system could initially suppress tumor growth, it is often progressively attenuated by the immunosuppressive signs from the tumor cells. In fact, tumoral cells release large amounts of exosomes compared to other cells due to factors such as the tumor microenviroment (acidic pH in the tumor microenviroment is directly related to tumor malignancy).
Hence, it has been described how acidity influences not only in number of released exosomes increase into the blood, but also type and in particular in exosomes expressing tumor markers, such as PSA, in cancer prostate.
Certainly, tumor exosomes are abundant in cancer patient’s peripheral blood, also in the central nervous fluid systems which contributes to spread their function from proximal to distance tissues. In particular, the role of tumor exosomes in the cancer progression might be very critical and important because mostly of the chemokines and growth factors are carried out. For example, tumor exosomes have been evaluated as cancer vaccines, via adaptive immune response for the proliferation of T cells mediated by DC, since their capacity to carry antigenic tumor material.
Conversely, numerous studies demonstrate a wide range of immunosuppressive functions, would help the tumor to evade immune attack in an autocrine or paracrine manner. Thus, it has been observed that serum exosomes from cancer patients, but not healthy donors suppresses CD8+effector T cells functions and induces their apoptosis.
Besides to inducing apoptosis in activated CD8+T cells through receptors such as FasL and TNF-related apoptosis-inducing ligand (TRAIL), tumor exosomes also inhibit NK cells functions, promotes differentiation, expansion and suppressive function of regulatory T cells and block myeloid precursor differentiation toward dendritic cells.
NKG2D is one of the main receptors involved in tumor recognition by NK cells and can be modulated by its ligands released in exosomes. It has been long known that soluble NKG2D-ligands in sera of cancer patients is co-related with advanced stages of cancer. Several NKG2D-ligands are recruited to exosomes. The role of soluble NKG2D-ligands in the context of immunotherapy has also been recently described.
Similarly, tumor exosomes can also support tumor progression and survival, contributing to the formation of a tumor microenvironment by stimulating angiogenesis, improving tumor metastatic dissemination, promoting tumor cells epithelial-mesenchymal transition and preparing the tumor niche in the new anatomic location, performing fibroblast and mesenchymal cells differentiation into myofibroblasts, as well as playing a role in drug resistance.
In this regard, it is well described how the microRNA content or tumor exosomal mRNA of different types of cancer can be transferred to the recipient cells and translated into functional proteins. Also, the protein content of the tumor exosomes can inhibit the apoptosis of the tumor cell through the Akt and ERK pathways or even the tumor-mediated transfer of an oncoprotein (MET) to bone marrow progenitor cells promotes the metastatic process, even for tumors with low metastatic capacity.
If you want to go deeper into this part, do not hesitate to read the complete article «Exosome beads array for multiplexed phenotyping in cancer».
One of the biggest challenges in oncology, it is the early diagnosis, for which new sensitive, specific, stable and easily sampled biomarkers are required; in addition it is also desired to avoid side effects of invasive biopsies and contribute to reduce excess treatment, psychological stress of the patients. But this is a point that we will continue in our next article.
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