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Hema Saranya Ilamathi
Cancer can develop at any time and in any part of the human body once the conditions are favorable for their growth. They continue to multiply by utilizing nutrients available in their habitat. These cancerous cells form a mass called primary tumors. However, once their resources become limited, they start to build a new habitat elsewhere in the body — much like the nesting behavior of birds. Each year, birds migrate and prepare a new habitat for their young ones. They build nests using carefully chosen raw materials to create a safe environment for young chicks. Similarly, cancer cells prepare secondary nesting spots in other parts of the body. Unfortunately, once tumors spread to new nesting grounds, they can be challenging to treat. Hence, many researchers are focused on understanding the process of formation of secondary tumor nesting spots and the raw materials used to prepare them.
Generally, a primary tumor sends different raw materials such as proteins, lipids, nucleic acids (DNA, RNA), and other small molecules to a secondary nesting site. Some of the raw materials are released directly into the bloodstream. Recently, researchers identified a sophisticated transport system in the human body that shuttles raw materials safely to the secondary tumor nesting site. These transport carriers are called exosomes. Healthy cells use exosomes to communicate and signal neighboring cells. In contrast, cancer cells use exosomes to release different signaling molecules that help to prepare their future habitats.
Cancer cells have different challenges to tackle before successfully establishing secondary nesting sites. These challenges include finding ways to reach new nesting grounds and building a habitat that promotes their survival and growth. First, cancer cells build a pathway to leave their present habitat and reach a secondary nesting ground. Cancer cells must cross different barriers before entering into the bloodstream. Therefore, cancer cells initially release exosomes to breach this barrier and lay out the pathway for its migration. These exosomes carry molecules that reduce the availability of certain proteins essential for the formation of this protective barrier.
To successfully establish in secondary nesting spots, cancer cells require a conducive environment. So, cancer cells educate their future neighboring cells to create a favorable environment before their arrival. Exosomes facilitate this long-distance communication between cancer cells and future neighbors. Exosomes also carry molecules that completely alter the metabolic process of neighboring cells. This rewiring process promotes the release of components from neighbor cells necessary for the successful colonization of cancer cells in their new habitat. For example, cancer derived exosomes alter metabolism of stromal fibroblast cells to create a favorable acidic environment for cancer cell growth. Altogether, cancer cells exploit exosomes to manipulate future neighbors for their own benefit.
While fabricating secondary nesting spots, cancer cells can be threatened by the immune system. As a result, cancer cells employ different strategies to evade various immune system checkpoints. Cancer-derived exosomes inhibit the development of anti-tumor immune responses in their new nesting sites by blocking the activation of immune cells. These exosomes carry immunosuppressor molecules that suppress the function of immune cells. Alternatively, cancer-derived exosomes can also attract an immunosuppressor cell into the secondary nesting spot. Altogether, exosomes constitute an essential system responsible for escape, invasion, and the establishment of cancer cells at secondary nesting sites.
Exosomes are thus important markers of cancer progression and could be used in cancer diagnosis. These carriers can be non-invasively isolated from patient-derived blood samples rather than invasive biopsy procedures used to collect tumor tissue from organs. Furthermore, cargo carried by exosomes can be used to characterize cancer progression and gauge its aggressiveness. However, protocols for isolating cancer-derived exosomes from blood are limited and ineffective currently, restricting the practicability of liquid biopsy in clinical settings.
In addition to their use in diagnosis, exosomes can be repurposed to deliver drugs. Current cancer-treatment protocols are accompanied by undesirable side outcomes due to the non-specific activity of drug on normal cells. To reduce or eliminate off-target drug effects, exosomes could be specifically redirected to cancer cells by attaching a guide molecule on the exosome surface. Exosome-based therapy could one day be used to treat drug-resistant and invasive cancer.
Overall, exosomes play a crucial role in cancer progression. Further research on exosome formation, release from cancer cells, cargo content, and its implications for tumor progression could shed light on exosomes’ potential application in cancer diagnosis and treatment.
Edited by Carolyn Farnsworth
Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-mediated metastasis: communication from a distance. Dev Cell. 2019;49(3):347-360.
Liu Y, Shi K, Chen Y, et al., Exosomes and their role in cancer progression. Front Oncol. 2021;11:639159.