Abstract
Extracellular vesicles (EVs) are involved in intercellular communication during carcinogenesis, and cancer cells are able to secrete EVs, in particular exosomes containing molecules, that can be transferred to recipient cells to induce pathological processes and significant modifications, as metastasis, increase of proliferation, and carcinogenesis evolution. FZD proteins, a family of receptors comprised in the Wnt signaling pathway, play an important role in carcinogenesis of the gastroenteric tract. Here, a still unknown role of Frizzled 10 (FZD10) protein was identified. In particular, the presence of FZD10 and FZD10-mRNA in exosomes extracted from culture medium of the untreated colorectal, gastric, hepatic, and cholangio cancer cell lines, was detected. A substantial reduction in the FZD10 and FZD10-mRNA level was achieved in FZD10-mRNA silenced cells and in their corresponding exosomes. Concomitantly, a significant decrease in viability of the silenced cells compared to their respective controls was observed. Notably, the incubation of silenced cells with the exosomes extracted from culture medium of the same untreated cells promoted the restoration of the cell viability and, also, of the FZD10 and FZD10-mRNA level, thus indicating that the FZD10 and FZD10-mRNA delivering exosomes may be potential messengers of cancer reactivation and play an active role in long-distance metastatization.
Highlights
Extracellular vesicles (EVs) are nanostructures derived from non-plasma membrane and exosomes represent a specific fraction of them that are, according to the established classification, characterized by an average diameter in the range between 50 and 200 nm [1,2]
Several studies proved that cancer cells are able to secrete exosomes that contain molecules, including non-coding RNA, miRNAs, mRNA, and proteins that can be transferred to recipient cells to induce new biological processes, causing significant modifications as angiogenesis, therapeutic resistance, formation of metastasis, and an increase of proliferation activity [7]
We proved that the modulation of the FZD10 expression level in small EVs strongly depends on the stage of disease, and that, the evolution of pathology can be monitored by evaluating the level of protein expression therein [8]
Summary
Extracellular vesicles (EVs) are nanostructures derived from non-plasma membrane and exosomes represent a specific fraction of them that are, according to the established classification, characterized by an average diameter in the range between 50 and 200 nm [1,2]. In our previous study we demonstrated the involvement of small EVs derived from human plasma in the carcinogenetic signal transmission in colon and gastric cancer. In different cancer cell lines such as colon, gastric, hepatic, and cholecystic cancer cell lines, a modulation of FZD10 protein expression depending on mRNA modulation [17] was demonstrated; very few evidences were found on the role of the FZD10 containing small EVs during the carcinogenesis or even, more in general, of the Frizzled proteins. The investigation of the specific genetic signal in such cell lines, and in the corresponding exosomes, demonstrated that the FZD10-mRNA expression level, reduced upon silencing, was restored after incubation with the exosomes of the untreated cell lines, reaching values comparable to those present in the pristine cells and their exosomes [19,20,21,22,23,24,25]. The study aimed to investigate the role of FZD10 on different cancer cell lines during the proliferation
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