The researcher has given an overview on the regulatory network of extracellular circRNAs in cancer and their impact on cancer drug resistance. In order to propagate malignancy, circRNAs shuttle through the blood circulation as cell-free molecules or in exosomes, small vesicles where they are transported to various cells. Published in ExRNA, the network of circRNAs has the potential to be used as therapeutic targets or diagnostic and prognostic biomarkers for cancer treatment strategies.
Cancer is a malignant disease which is caused by an uncontrollable proliferation of cells which acquire abnormal, malignant traits. Following infiltration in the surrounding microenvironment, they move through the blood and lymphatic circulation and spread to and metastasize in different organs of the body. Over the past years, improved detection of locally confined tumors and adjuvant therapies have extended the 5-year survival of tumor patients. However, the extensive therapies are also accompanied with enhanced immune suppression mechanisms and drug resistance leading to increased relapse rates. Therefore, new therapy approaches that overcome drug resistance by targeting cancer-associated cell components and signalling pathways have to be developed to fight cancer cell survival. Such treatment strategies could be carried out by circular RNAs (circRNAs)
CircRNAs are single-stranded, circular non-coding RNAs (ncRNAs), and regulate a variety of cellular events including cell division, apoptosis and cell mobility. They modulate signaling pathways those oncogenic signals activate downstream components that promote tumor progression and reduce the efficacy of drugs resulting drug resistance. CircRNAs activate gene transcription by binding to DNA polymerase II or conversely, inhibit mRNA translation. However, the majority of
circRNAs bind to another ncRNA, namely microRNAs (miRNAs). MiRNAs are able to bind to and consequently inhibit the translation of mRNAs. The interaction of circRNAs with miRNAs interferes this binding of the miRNA to its target RNA, leading to the re-established translation of the mRNA. Thus, circRNAs may abrogate the oncogenic or tumor suppressive behavior of miRNAs
The differentially expressed and aberrantly cancer-associated levels of circRNAs in blood may correlate with clinical parameters and drug resistance of the cancer patients. The dynamic surveillance of their expression levels could help to assess whether cancer patients respond to the therapy or not, thus serve as a biomarker for drug resistance. CircRNAs circulate as stable cell-free molecules or imbedded in exosomes through the bloodstream and lymphatic system. Besides, exosomes which act as intercellular communicators allow circRNAs to propagate chemoresistance, tumor progression and metastasis from cell to cell. In order to avoid the spread of cancer-associated features, novel therapeutic approaches that target exosome which contain oncogenic circRNAs or circRNAs are necessary. To date, there are numerous assays to target and degrade oncogenic circRNAs. These technologies comprise small interfering RNA (siRNA), short hairpin RNAs (shRNAs), antisense oligonucleotides and CRISPR/cas13a. In addition, delivery systems manipulated with cell-specific surface markers bring these antisense RNAs to cancer target cells. They include adenoviral, lentiviral vectors and nanoparticles, as well as exosomes with their high biocompatibility, and low immunogenicity.
CircRNAs mediate a broad spectrum of modulations in the cells. They are involved in a complex regulatory network, and regulate numerous signal pathways. In this network, other ncRNAs are involved, e.g. miRNAs, those functions are abrogated by circRNAs. Furthermore, munerous components of multiple signaling pathways may be modulated by a circRNA. Likewise, one signaling pathway can be disturbed by several circRNAs, and the pathways can even cross-talk with each other. This makes it particularly difficult to precisely define the consequence of the changes in the regulatory networks when a certain circRNA is inhibited and accordingly, serves as a therapeutic target. Consequently, there is a potential risk for the patients to suffer from severe adverse effects during the treatment using circRNAs as therapeutic targets. Therefore, establishment of biological network models in which the interplay of circRNAs with other factors is considered have to be designed, to create specific cancer-associated signatures that reveal the extent of action of circRNAs on downstream components that cascade further components. Clarification of the concentrations of circRNAs in both time and cellular location may facilitate to establish these assays.
Finally, circRNAs may particularly be eligible as non-invasive diagnostic and prognostic biomarkers. They circulate stably in the bloodstream, and their concentrations may correlate with the clinical parameters of the cancer patients. The surveillance of their concentration variations during the therapy may possibly give evidence of the response to the treatment. However, a variety of circRNAs for each cancer type and a total of more than 3000 circRNAs are registered in the circAtlas (http://circatlas.biol.ac.cn), and the one to find that is a better biomarker than the established marker for a specific cancer type is a challenging task.
However, considering the potential value of circRNAs as diagnostic and prognostic biomarkers and as therapeutic targets, several clinical trials have been registered by the United States National Library of Medicine (NLM) at the National Institutes of Health (NIH) (https://clinicaltrials.gov/). Unfortunately, the results of these studies are still not available to know whether circRNAs are applicable in the diagnosis, prognosis or therapy of cancer patients and whether they can replace or complement the routine biomarkers.
To sum up, this short overview on circRNAs represents the potential pros and cons for their clinical application. It is will be exciting to know their clinical value in the future.
The paper "Impact of exosomal and cell-free circRNAs on cancer drug resistance" from Heidi Schwarzenbach was published in ExRNA and gives an overview on a variety of circRNAs that target a variety of miRNAs in drug resistance.
Source:
Journal reference:
Schwarzenbach, H. (2024). Impact of exosomal and cell-free circRNAs on cancer drug resistance. ExRNA. doi.org/10.55092/exrna20240018.