Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets

Abstract

Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.

Keywords: Exosomal ncRNAs; Metastatic CRC; Therapeutic targets.

Fig. 1

Pathways involved in exosome biogenesis. Exosome biogenesis concludes several steps: [1] Endocytosis, the process of the plasma membrane's inward budding; [2] early endosome formation resulting from the inward budding of the plasma membrane; [3] late endosome: in this process, the early endosome membrane buds inward to start the process of cargo loading; [4] the ILV follows the previous process where cargo loading and scission of the ILVs occur; [5] the MVB contains all synthesized exosomes and will undergo two possible processes: (6a) where the plasma membrane is agitated by the MVB to secrete its exosomal cargo into the extracellular environment; (6b) where the MVB undergoes-lysosomal degradation from the step of the early endosome up to the formation of the MVB, several pathways are involved in the process of cargo sorting into late endosomes; namely, (2a) represents the classical ESCRT machinery pathway, where ubiquitinated cargo proteins rely on early functioning ESCRTs (ESCRT-I, II, and III) to be loaded into ILV, and ESCRT-III is involved in the scission of these ILV to form MVB. (2b) Represents the Syndecan-Syntenin-Alix pathway with its regulators, SRC and ARF6/PLD2. (2c) Represents the Alix-ESCRT–III–tetraspanin pathway. The 2a and 2b pathways depend on Alix's unique feature to deliver un ubiquitinated cargoes directly to ESCRT-III, escaping the need for early ESRTs. (2d) Represents an ESCRT-independent pathway mediated by Rab31 activating the EGFR receptor to later form a complex of Rab31-EGFR-FLOT and drive exosome biogenesis independently from all ESCRT machinery. Rab31 then conjugates with TBC1D2B to inactivate Rab7 and prevent its lysosomal degradation.

Fig. 2

Mechanisms by which exosomal proteins secreted from CRC cells promotes metastasis of CRC in recipient cells. (A) Exosomal secretion from non-mutated KRAS CRC cells.

Fig. 3

An illustration demonstrates the involvement of ncRNAs and oncogenic signaling pathways in CRC metastasis. NcRNAs (such as miRNAs, circRNAs, and lncRNAs) may stimulate CRC metastasis, and survival of tumor cells by focusing on specific genes and sponging different kinds of microRNAs, including miRNA-133a, miRNA-26a/26b, miRNA-329–3p, miRNA-139–5p, miRNA-342–3p, and miRNA-17. NcRNA may regulate a number of crucial signaling pathways, acting as an oncogene and encouraging CRC spread, such as the PI3K/Akt/mTOR, PTEN/PI3K/AKT, and (PI3K) γ/Akt/mTOR pathways.

Fig. 4

Illustration shows that by preventing biogenesis and secretion, exosome synthesis can be reduced. By directly lowering Rab5b mRNA stability and exosome formation in CRC cells, lncRNA-APC1, a crucial APC mediator, prevents the spread of CRC. ISG15 is expressed and coupled to MVB proteins, such as TSG101, by IFN-I. Inhibiting exosome secretion, ISGylation of MVB proteins encourages MVB fusion with lysosomes and destruction.