Despite advancements in cancer treatments, drug resistance continues to pose a significant challenge across a range of different therapeutic approaches. Now, new research from investigators at Kunming Medical University in China, published in Medcomm-Oncology, details the central role played by extracellular vesicles (EVs) in facilitating cancer drug resistance. The study shows how these tiny lipid-bound particles act as “messengers” between cancer cells to facilitate the transfer of cancer drug resistance traits between cells.
EVs transfer proteins, RNA, DNA, and other molecule between cancer cells and their microenvironment and carry with them resistance-related factors that help sensitive cancer cells acquire drug resistance from cells that are already resistant. This activity is not isolated only to cancer cells, but also impacts other components of the tumor microenvironment (TME) including fibroblasts and immune cells, further promoting tumor growth and treatment resistance.
An example of this is resistance developed to chemotherapy, where cancer cells release extracellular vesicles loaded with long noncoding RNAs like AC116025 to development resistance to the widely used chemotherapy agent fluorouracil (5-FU), a topical chemotherapy used to treat skin cancer. In radiotherapy, EVs have been shown to carry microRNAs that inhibit apoptosis in cancer cells.
In addition to their roles in promoting treatment resistance, EVs are also emerging as potential biomarkers due to their abundance in body fluids. But challenges to achieving this are due to the complexity of the molecular cargo of EVs as well as the rapid changes that EVs can experience in response to different therapies.
Despite these challenges, study leader Jun Yang, a professor from Kunming Medical University noted that deepening the understanding of the role of EVs in cancer has broad potential. “Understanding the mechanisms of EV-mediated drug resistance opens up new avenues for treatment. By targeting EVs, we can potentially reverse resistance and improve the efficacy of current therapies.”
The potential to leverage extracellular vesicles for diagnostic tools is promising, particularly through liquid biopsies that may facilitate non-invasive early cancer diagnosis and therapeutic response evaluation. Nevertheless, successful implementation will require addressing issues of heterogeneity in EVs, optimizing isolation techniques, and developing analytical methods that can ensure accurate biomarker discovery.
The therapeutic potential of EVs is also compelling. They can be engineered to deliver specific therapeutic cargoes such as miRNAs, anti-miRNAs, siRNAs, proteins, and anticancer drugs directly to cancer cells, which could improve treatment efficacy. However, ensuring precise targeting and stability of these cargoes poses challenges.
“EVs must be engineered or selected to ensure they preferentially deliver their therapeutic cargo to the intended targets while minimizing off-target effects,” the researchers wrote. “Developing strategies for accurate targeting without inducing immune responses is crucial. Furthermore, loading therapeutic agents into EVs efficiently and in a controlled manner is challenging. Ensuring that the therapeutic payload remains stable, bioactive, and effective after loading requires optimized protocols and technologies.”
Emerging insights into the interplay between EVs and various biological processes, including phase separation, aging, and neuro-oncological interactions, are fertile avenues for further research. The intersection of aging and EV biology, for instance, may uncover how age-related changes in cellular function affect therapy resistance and guide the development of age-specific treatment strategies.
While ongoing challenges exist, including the variability of EV isolation methods and uncertainties surrounding clinical efficacy, the promising research into EVs could eventually lead to strategies to help overcome cancer therapy resistance. As such, a comprehensive understanding of EV-mediated communication in cancer is necessary to aid in the development of innovative diagnostic tools and therapeutic modalities that may ultimately improve treatment outcomes.
