Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors

Abstract

In recent years, growing research interest has focused on the so-called liquid biopsy. A simple blood test offers access to a plethora of information, which might be extremely helpful in understanding or characterizing specific diseases. Blood contains different molecules, of which circulating free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and extracellular vesicles (EVs) are the most relevant. Conceivably, these molecules have the potential for tumor diagnosis, monitoring tumor evolution, and evaluating treatment response and pharmacological resistance. This review aims to present a state-of-the-art of recent advances in circulating DNA and circulating RNA in gastrointestinal stromal tumors (GISTs). To date, progress in liquid biopsy has been scarce in GISTs due to several issues correlated with the nature of the pathology. Namely, heterogeneity in primary and secondary mutations in key driver genes has greatly slowed the development and application in GISTs, unlike in other tumor types in which liquid biopsy has already been translated into clinical practice. However, meaningful novel data have shown in recent years a significant clinical potential of ctDNA, CTCs, EVs and circulating RNA in GISTs.

Keywords: CTCs; GIST; circulating tumor cell; ctDNA; epigenetics; gastrointestinal stromal tumor; liquid biopsy; personalized medicine; precision medicine; soft tissue sarcoma.

Figure 1.

Patients’ management: standard biopsy versus liquid biopsy. Potentially, a simple blood test may promote the identification of tumors at an early stage, in contrast with standard biopsy, which can be done only with advanced disease. Moreover, liquid biopsy has the advantage of providing a dynamic picture of the tumor, whereas standard biopsy may give only a static image, resulting from the small tumor tissue collected. Finally, liquid biopsy can be helpful to monitor the therapy response, due to the fact that it can detect novel resistance mutations which suggest the tumor is no longer responding to the treatment.

Figure 2.

Schematic representation of extracellular vesicle (EV) release. Left panel: Exosomes (30–100 nm in size) are released in extracellular space from multivesicular bodies (MVBs) through exocytosis. MVBs contain various intraluminal vesicles (ILVs) which are generated by the inward budding of the endosome membrane. Exosome cargo may include different kind of RNAs, such as miRNA, lncRNAs, mRNAs, otherwise quickly degraded if free. Right panel: Microvesicles (100–1000 nm in size) originate through a finely regulated budding/blebbing of the plasmatic membrane involving the Golgi apparatus. According to the classical secretory pathway, vesicles with their protein cargo, are sorted and packed in the Golgi apparatus, and then transported to the plasma membrane. In cancer, it has been proposed that there is an additional mechanism of EV release. Specifically, cancer cells may produce multivesicular spheres (MVSs), which contain many spheresomes.

Figure 3.

Pros and cons of liquid and standard biopsy in GIST. GIST, gastrointestinal stromal tumor.