Tumors Talk in a Language That Looks Like Viruses- Muting Them Could Prevent Progression & Metastasis

Author: Daniel S, PhD; Last update: January 31st, 2021

Update

Dear Friends,

With this post, I am going to address a subject that may be key in oncology and that it is rarely discussed as it is related to a relatively new area of science. However, even if relatively new, it has already led to a Nobel Prize in Medicine.

Before addressing the subject of this post, here is an update on my activity:

While there is a lot to write about the latest oncology research that we can translate fast to the real world and apply it, which is my pleasure to address, these days I allocated most of my time and energy for helping our supplement company MCS Formulas get momentum. There is no other option, since the success of MCS Formulas is key for me staying in the oncology field and continuing to do my best to uncover, and accelerate new treatment options, as I did for he past 5 years. 

Therefore, you helping with buying your supplements from MCS Formulas is not only contributing back to the oncology as we will Donate 50% of profits to oncology projects (the remaining goes in the growth of the company), but will also help me stay in oncology field and do so much more for cancer patients.

Before going to the oncology related content I like to share with you today, I have some great news regarding MCS Formulas:

• We do our best for people buying supplements at MCS Formulas, and the result of that is reflected in many 5 star review we received (reviews collected by a third party internationally recognized company)
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• As we deliver Worldwide, during the first months we had challenges with delivery in some areas across the World due to the carriers we initially used. There were some very good carriers which we would not expect to create challenges. But they did, and we changed them. Now, I am so happy to say that we have a great support from FedEx, to deliver very fast across the world, very reliable and at a great price. We ship from Amsterdam, and with FedEx we now deliver orders to nearly all locations around the World in just a few days! I am so happy with that and I wish to thank FedEx for their great support.

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Exosomes: The Inter-cellular Communication System

It is often the case, that if a cancer patient has multiple tumors, when one tumor awakes and becomes painful immediately the others may start to be active as well. This can be explained by mechanisms related to general inflammation and immune system activity. However, this synchronization made me often think that tumors may be able to communicate between themselves.

Can tumors communicate between themselves? This was a question that was for sometime in my mind.

The answer is YES. Tumors, as all cells in our body, can communicate between themselves and a major group of messengers is called Exosomes (Ref.).

Exosomes are little bubbles (~20 to ~150 nanometers size) made of a fat membrane, and containing various elements such as proteins, DNA, and RNA. Yes, this sounds like a virus when looking at it’s structure and behavior, but it is not a virus as it is created by our own body, with a different purpose (Ref.). So exosomes are essentially little bubbles that are traveling around the body. They are produced inside the cells and release in to the extracellular space and blood stream to be taken up by distant cells, where they can affect cell function and behavior.

Therefore, they are little messengers carrying cargo (proteins and genetic information) between both neighboring and distant cells. They deliver messages at the right place and right time within the human body, and the importance for the discovery of how this process works has led to the 2013 Nobel Prize in Physiology or Medicine (Ref.).

Because of exosomes, cells do not require physical contact in order to communicate. This is why, communication of cells via exosomes is a fundamental process in the human body (and not only).

Both normal cells and cancer cells use these exosomes for cell-to-cell communication (i.e. intercellular communication).

The Essential Role of Exosomes in Cancer

While exosomes and the related mechanisms have been studied for about 3 decades now, the role of exosomes in cancer is a new subject to science. Most of the literature on this subject has been published during the past 5-10 years. This is why, this subject is not yet one addressed in the clinical world, while the importance of exosomes has been highlighted by the 2013 Nobel Prize in Physiology or Medicine, as discussed above.

The effect of exosomes from different cells varies significantly depending on their cell of origin. Exosomes release by the tumor cells are known to play important role in angiogenesis and maybe more importantly, in metastasis (Ref.). They help cancer cells communicate with fibroblasts and immune cells within the tumor micro-environment, mediating immunosuppression through various mechanisms including the promotion of expansion of regulatory T-cells (Ref.). However, note that not only the tumor cells produce tumor-promoting exosomes. For example, exosomes secreted by macrophages are able to promote breast cancer invasion and metastasis (Ref.).

It has been shown that exosomes generated by the tumors (that carry cancer-specific RNAs and proteins) are released in the blood and are traveling to distant targeted organs preparing the local environment before the arrival of the first cancer cells (Ref.1, Ref.2). The preparation involves stimulation of fibroblasts at distant sites by tumor-derived factors and chemokines that attract tumor cells (Ref.).

Extremely interesting in my view, it has been reported that exosomes can even transfer mutations from one cell to another (Ref.). Furthermore, exosomes have been found to contain e.g. GLUT1 and PKM2, and influencing the metabolism of target cells. Recipient cells exhibited high expression of GLUT1 and PKM2, which indicated the occurrence of glycolysis, namely the Warburg effect. (Ref.) Now imagine what is the implication of this knowledge: tumors produce viral-like particles that have the right size and structure not to be recognized by the immune system and they can transfer mutations and influence metabolism of the target cells. A taste of the implications of this is reflected by a recent study (2020) reported in Nature magazine, where scientist were able to have exosomes transfer a disease phenotype from a human to a mouse (Ref.).

Therefore, this is a major way for tumors to influence the environment locally but also at a distance. As a result, it has been concluded that crosstalk between primary cancer cells and micro environmental cells is a key step in cancer metastasis (Ref.).

There is a very large amount of recent literature that can be discussed here, but the conclusion is that in order to progress and advance to other locations (metastasis) tumors need to communicate. Exosomes is one major “language” tumors speak. Therefore, inhibiting exosome production may help stop progression of cancer or at least slow it down, depending on how effective we are in achieving that.

It is also expected that inhibition of exosomes may help increase the effectiveness of immunotherapies, since there is sufficient evidence that tumor-derived exosomes are forerunners of immune suppression (Ref.).

One mechanism for resistance of tumors to chemotherapy is by releasing exosomes that encapsulate chemo drugs and exports them outside of the tumor cell. It has been showed, that inhibition of this process with repurposed drug lead to the increase of chemo effectiveness (Ref.). Therefore, exosomes are responsible for an important mechanisms via which tumors resist to chemotherapy .

Finally, exosomes may play a key role in tumor-induced cachexia (Ref.). Cancer cachexia is a metabolic syndrome characterized by the rapid loss of skeletal muscle mass with or without the loss of fat mass. Indeed, it has been showed that breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression (Ref.)

In conclusion, exosome inhibition makes very much sense for cancer patients since exosomes play a key role in facilitating:

• tumor progression
• metastasis
• cachexia
• chemo-resistance
• resistance to immunotherapies 

The next question on this line is, what are the drugs and supplements available that could help us modulate and down-regulated the exosome production by tumors. Such modulators coudl than be considered to be introduced as a part of a more comprehensive treatment strategy or drug cocktail used to fight specific cancers.

How to Inhibit Exosome-based Communication

There are two major ways to inhibit exosome production:

1. We can inhibit the building blocks required by the cell to generate Exosomes
2. We can inhibit the intra-cellular mechanisms responsible for the Exosomes production and their release from the cell

Inhibiting the building blocks means inhibiting intracellular production of cholesterol. Indeed, lipid rafts are fundamental to the budding of the membrane and cholesterol plays key role (Ref.1, Ref.2). An extensive strategy to inhibit cholesterol production that can be relevant to address the down-regulation of exosome production has been discussed here (Ref.). Therefore, drugs such as Statins and food supplements such as Citrus Bergamot may help on this line. Indeed, Simvastatin exhibited the ability to inhibit the secretion of exosome (Ref.).

The inhibition of intra-cellular mechanisms responsible for the Exosomes production and release from the cell, can be addressed by various drugs and supplements:

Available Drugs

• Imipramine (Ref.) – an anti-depressant drug –  inhibitor of the activity on acid sphingomyelinase (aSMase), an enzymes that facilitates the conversion of sphingomyelin to ceramide, a process relevant for exosomes formation and release as it increases membrane fluidity
• Indomethacin/Indometacin (Ref.) – non-steroidal anti-inflammatory drugs (NSAID) family used to decrease prostaglandins production during inflammation, due to its ability to non-selectively inhibit cyclooxygenase I and II – downregulate transcription of the ABCA3 transporter, an intracellular protein involved in lipid transport (Ref.)
• Ketoconazole (Ref.) – an antifungal drug 
• Sulfisoxazole (Ref.) – an oral antibacterial drug – a specific inhibitor of the biogenesis and secretion of exosomes from cancer cells
• Ketotifen (Ref.) – antihistamine drug, has the ability to block exosome release. Ketotifen was reported to block calcium influx into cells. It is shown that exosome release is regulated by calcium-dependent mechanisms. Therefore, the mechanism of ketotifen inhibiting exosome release might due to its calcium channel blocking effect. (Ref.)
• microenvironmental pH of tumour cells is an essential factor for exosome traffic (Ref.) This means that all those drugs and supplements altering internal and external pH may be effective against exosomes. Example of drugs that we already discussed in this context are Lansoprazole, Amiloride, Acetozolamide and many more. Please read more about them here. Indeed it has been showed that proton pump inhibitors can be effective in lowering exosomes release and as a result increasing effectiveness of chemotherapy (Ref.)

Available Supplements:

• Pantethine (Ref.) – a pantothenic acid (vitamin B5) derivate found online as a food supplement  – pantethine has been shown to inhibit (by 80%) cholesterol synthesis in cultured skin fibroblasts (GM0043), as well as total fatty acids synthesis (Ref.)
• Cannabidiol (CBD) (Ref) – extract from Cannabis sativa available online, can block exosome release. CBD can block exosome release by 50% at 5 µM and it can selectively inhibit the release exosomes from cancer cell lines (e.g. prostate, breast, liver cancers, glioblastoma) (Ref.1, Ref.2)

Conclusion

In conclusion, there are two aspects that are extremely important here:

1. Exosomes produced by the tumors are major facilitators for tumor progression and their activity can be reduced with common drugs and supplements
2. When looking at how to inhibit exosomes products we find out that major strategies and drugs we already discussed as very relevant in the battle against cancer are also leading to exosome inhibition:
   • cholesterol strategy
   • ph strategy
   • calcium modulation

Could exosomes be the answer why all those strategies or drugs have been demonstrating to work against cancer? That remains to be seen. However, what is clear is that this is at least one other perspective we could take to look at cancer, learn and increase our effectiveness toward a successful treatment outcome. By doing that, we will be well ahead of the majority, since this is a field of science that from oncology point of view only recently started to receive good amount of attention from the scientific community.

References

Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589964/

Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.

Distinct Cargos of Small Extracellular Vesicles Derived from Hypoxic Cells and Their Effect on Cancer Cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404308/

Hypoxia is a common hallmark of solid tumors and is associated with aggressiveness, metastasis and poor outcome. Cancer cells under hypoxia undergo changes in metabolism and there is an intense crosstalk between cancer cells and cells from the tumor microenvironment. This crosstalk is facilitated by small extracellular vesicles (sEVs; diameter between 30 and 200 nm), including exosomes and microvesicles, which carry a cargo of proteins, mRNA, ncRNA and other biological molecules. Hypoxia is known to increase secretion of sEVs and has an impact on the composition of the cargo. This sEV-mediated crosstalk ultimately leads to various biological effects in the proximal tumor microenvironment but also at distant, future metastatic sites. In this review, we discuss the changes induced by hypoxia on sEV secretion and their cargo as well as their effects on the behavior and metabolism of cancer cells, the tumor microenvironment and metastatic events.

Exosomes in the tumor microenvironment as mediators of cancer therapy resistance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397467/

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.

Exosomes: Biological Carriers and Promising Tools for Cancer Immunotherapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565712/

Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190352/

Tumor–Stroma Interaction: Revealing Fibroblast-Secreted Exosomes as Potent Regulators of Wnt-Planar Cell Polarity Signaling in Cancer Metastasis https://cancerres.aacrjournals.org/content/73/23/6843

CD44v6 Dependence of Premetastatic Niche Preparation by Exosomes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745675/

Extracellular Vesicles in Cancer Metastasis: Potential as Therapeutic Targets and Materials https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352700/

The vast majority of cancer-related deaths are due to metastasis of the primary tumor that develops years to decades after apparent cures. However, it is difficult to effectively prevent or treat cancer metastasis. Recent studies have shown that communication between cancer cells and surrounding cells enables cancer progression and metastasis. The comprehensive term “extracellular vesicles” (EVs) describes lipid bilayer vesicles that are secreted to outside cells; EVs are well-established mediators of cell-to-cell communication. EVs participate in cancer progression and metastasis by transferring bioactive molecules, such as proteins and RNAs, including microRNAs (miRNAs), between cancer and various cells in local and distant microenvironments. Clinically, EVs functioning as diagnostic biomarkers, therapeutic targets, or even as anticancer drug-delivery vehicles have been emphasized as a result of their unique biological and pathophysiological characteristics. The potential therapeutic effects of EVs in cancer treatment are rapidly emerging and represent a new and important area of research. This review focuses on the therapeutic potential of EVs and discusses their utility for the inhibition of cancer progression, including metastasis.

Exosomal TGF-β1 is correlated with lymphatic metastasis of gastric cancers https://pubmed.ncbi.nlm.nih.gov/29218244/

Exosomes, Their Biogenesis and Role in Inter-Cellular Communication, Tumor Microenvironment and Cancer Immunotherapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313856/

Exosomes are extracellular vesicles ranging from 30 to 150 nm in diameter that contain molecular constituents of their host cells. They are released from different types of cells ranging from immune to tumor cells and play an important role in intercellular communication. Exosomes can be manipulated by altering their host cells and can be loaded with products of interest such as specific drugs, proteins, DNA and RNA species. Due to their small size and the unique composition of their lipid bilayer, exosomes are capable of reaching different cell types where they alter the pathophysiological conditions of the recipient cells. There is growing evidence that exosomes are used as vehicles that can modulate the immune system and play an important role in cancer progression. The cross communication between the tumors and the cells of the immune system has gained attention in various immunotherapeutic approaches for several cancer types. In this review, we discuss the exosome biogenesis, their role in inter-cellular communication, and their capacity to modulate the immune system as a part of future cancer immunotherapeutic approaches and their potential to serve as biomarkers of therapy response.

Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201802675R

Sulfisoxazole inhibits the secretion of small extracellular vesicles by targeting the endothelin receptor A https://www.nature.com/articles/s41467-019-09387-4

Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099119/

Advances in the discovery of exosome inhibitors in cancer https://www.tandfonline.com/doi/full/10.1080/14756366.2020.1754814

Extracellular vesicles and viruses: Are they close relatives? https://www.pnas.org/content/113/33/9155

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