INTRODUCTION

Liver cancer is a common malignancy and the fourth leading cause of cancer death worldwide[1].It is one of the most challenging cancers to treat.For patients with an early stage of liver cancer,surgical treatment is the standard of care.However,most patients with liver cancer are already in the advanced stage at the initial diagnosis,which results in a poor prognosis[2].Currently,α-fetoprotein (AFP) is the most commonly used serum marker for liver cancer[3].However,AFP has a sensitivity of 41%–64% and a specificity of 80%–94%,which is often missed diagnosis,especially in the early stages of liver cancer[4].Therefore,it is vital to develop more sensitive and specific liver cancer biomarkers to improve patient survival.

Recent studies have shown that exosomes have potential as biomarkers for liver cancer[5].Once considered cellular waste,exosomes are rich in bioactive molecules,such as proteins,lipids,and nucleic acids[6,7].Almost all human cells can secrete exosomes.Tumor cells release more exosomes than normal cells,and the exosome contents of tumor cells are different from those of normal cells[8,9].Additionally,the exosomal envelope protects proteins,nucleic acids,and other substances in exosomes from degradation by extramembrane enzymes[10].The stability and abundance of exosome contents show the advantages of its unique liver cancer biomarkers.

On the other hand, without encouragement talented students may never be motivated to learn, develop skills, or reach their full potential. For example, at the same high school, there was a teacher whose Spanish language classes I attended but from whom I, unfortunately learned very little simply because of the woman’s cold sarcastically8 critical attitude. She seemed to know nothing about encouraging students, and she was gifted speaking contemptuously of those of us who weren’t learning fast enough. Her negativism drove me away. Partly because of this teacher’s negative influence, I am not fluent in Spanish today.

Exosomes are widely involved in cell-to-cell communication.They can deliver their functional RNAs and proteins to recipient cells and affect their physiological functions[11].Therefore,exosomes can also serve as drug delivery vehicles.Here,we summarize the potential of exosome contents in the diagnosis and treatment of liver cancer,provide new ideas for the diagnosis and treatment of liver cancer,and promote further research on the potential clinical applications of exosomes.

MATERIALS AND METHODS

Literature search

According to the conventional research methods of systematic review[12],a systematic literature search was conducted in PubMed and Web of Science using the following keywords:"exosomal biomarkers","exosomal therapy","exosomal therapy" and "liver cancer" or "HCC".The EndNote software was used to delete duplicate data[13].The latest literature was published in June 2021.Literature search focused on full texts.Two reviewers independently screened the references of each article to remove the irrelevant studies according to our inclusion criteria.The inclusion criteria were as follows:(1) Detection of exosomes or their contents in clinical samples (body fluid or tissue);or (2) Exosomes served as drug carriers or therapeutic factors.Two authors(Xiao-Cui Wei and Li-Juan Liu) independently reviewed the full texts of all retained literature and analyzed the information.

Data extraction

The data collected from each study included the clinical sample,expression level,and application of exosomes divided into three major segments.The first part involved the exosomes isolated from the body fluid samples.The second part meant the data that were relevant to the detection of exosomal contents in the clinical tissue samples.The third part included the collection of data pertinent to the application of exosomes.

RESULTS

Literature selection

A total of 1295 studies were identified using the systematic literature search.After 835 duplicate studies were found and omitted,460 were screened by two independent reviewers.A further 402 irrelevant studies were excluded,including review articles,other diseases,records containing neither clinical samples nor animal experiments,exosome-independent studies,methods for detecting exosome or articles in Chinese.Finally,58 published papers were included in the study (Figure 1).

Exosomes are identified as potential biomarkers or potential biotherapeutics

The expression of exosomal contents was detected in liver cancer clinical tissue samples,and cytology or animal experiments were used to identify the role of exosomal contents.Upregulated exosomal contents might enhance hepatocellular carcinoma (HCC) progression,angiogenesis,and drug resistance,while downregulated exosomal contents might attenuate angiogenesis.In Table 3[57-66],all these abnormally expressed exosomal contents may become novel therapeutic targets for liver cancer.

Table 2[22,35,39,47-56] includes potential biotherapeutics of exosomal contents for liver cancer.Those downregulated exosomal contents in blood liver cancer samples might serve as possible biotherapeutic drugs.

5.Into the forest:The forest is a place of change. It can also be a place of danger. There is also a connection to meeting gods in the forest, and when the devil appears in the forest he is being connected to the old gods (Biedermann 158).Return to place in story.

Exosomal contents are identified as potential therapeutic targets

In some literature,exosomes were isolated from liver cancer patients’ blood samples.Then,the level of exosomal molecular contents was detected.Table 1[14-46] lists the potential biomarkers for liver cancer.In these studies,exosomal contents that were upregulated in blood exosomes might be potential exosomal biomarkers.

Exosomes serve as drug carriers and therapeutic factors

In addition to being carriers,some researchers have reported the therapeutic effect of exosomes.As early as 1998,Zitvogel

[86] found that dendritic-cell-derived exosomes (DEXs) could activate tumor-specific cytotoxic T lymphocyte response and inhibit tumor growth

.DEXs have been used in several clinical trials.Researchers have processed DEXs derived from melanoma patients,loaded them with melanoma antigens,and observed an enhanced antimelanoma immunity after selfinoculation[87].Another trial indicated that DEX therapy increases natural killer cells(NKs) lytic activity in patients with non-small cell lung cancer (NSCLC)[88].Besse’s group has conducted phase II clinical trials in NSCLC and confirmed the capacity of DEXs to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC[89].In addition to injecting DEXs,Dai and colleagues have found that the immunotherapy of colorectal cancer (CRC) with ascites-derived exosomes in combination with granulocyte–macrophage colony-stimulating factor can serve as a choice for immunotherapy of advanced CRC[90].In liver cancer,however,there have been no such clinical trials.

The main result that the authors are concerned about is discovering the great potential of exosomes in the diagnosis and treatment of liver cancer.

Table 5[70,71] shows the self-derived exosomes from dendritic cells as potential therapeutic factors.Data showed exosomes isolated from dendritic cells could inhibit tumor growth and improve the immune response.This indicated that exosomes serve as potential therapeutic factors.

DISCUSSION

Liver cancer is a global disease with high morbidity and mortality[72].Despite the continuous development of novel treatment options,the 5-year survival rate of liver cancer patients is still low because of the delayed diagnosis[73,74].Scientists are still trying to find new markers for early diagnosis and individualized treatments.

Over the past decade,exosomes have received widespread attention.Many studies have found that the differential expression of exosome proteins and RNAs has diagnostic significance for various cancers.Previous studies have suggested that exosomes may serve as liquid biopsies to help diagnose malignancies such as breast,pancreatic and lung cancer,and glioblastoma[75-78].Here,we listed exosomal contents that have been identified as possible biomarkers for liver cancer in recent years.We found multiple research reports about miR-21[21-24,46] and LINC00161[37,38].There are five papers on exosomal miR-21.These studies indicate that expression level of miR-21 in serum exosomes of liver cancer patients is higher than that of healthy people,suggesting that it is the most likely marker for early liver cancer screening.Among the contents of liver cancer serum with downregulated exosomal expression,miR-122 has been reported most often.These studies suggest that miR-122 may be the most likely biotherapeutic drug for liver cancer[22,47].

The servants came to the door, and finding it locked, they knocked; but the frozen breath on the window replied in Prince Milan s voice, I am coming directly

In addition to serving as disease markers in patients’ serum,exosomes are involved in the occurrence,development and prognosis of various cancers[79].Bai

[80] have shown that exosomes secreted by gastric cancer cells deliver miR-135b to tumor cells and promote angiogenesis by negatively regulating intracellular forkhead box O1.This study provides a potential target for antiangiogenic therapy.Huang and his collaborators demonstrated that colon cancer cells secrete Wnt4-rich exosomes delivered to normoxic cells to activate β-catenin signaling and enhance their metastatic behavior.They found that β-catenin inhibitors ICG-001 can inhibit this metastatic behavior,which provides a new target for treating metastatic colon cancer[81].In this paper,we listed the previous studies on the mechanism of exosomal contents involved in the development of liver cancer.Therefore,developing drugs targeting these exosomal contents may be a potential therapy for liver cancer.

As drug carriers,exosomes have the characteristics of stability in circulation,good biocompatibility,low immunogenicity,and low toxicity[82,83].Liang

[84] have shown that exosomes loaded with 5-fluorouracil and miR-21 inhibitors can effectively improve cancer cell drug resistance and colon cancer treatment efficiency.Zhang and his group also found that HEK293T-cell-derived exosomes deliver exogenous si-c-Met to gastric cancer cells and enhance gastric cancer cell sensitivity to cisplatin[85].In this paper,we reviewed recent studies on the therapeutic effect of exosomes as carriers in HCC.

Table 4[67-69] focuses on the carrier roles of exosomes in HCC.Drug-carrying exosomes were injected into tumor-prone mice to observe the effects of the drugs.These studies indicated that exosomes could serve as drug carriers that made cancer cells sensitive to antitumor drugs or enhanced their antitumor efficacy.

22. Poisonous comb: The second temptation relates to Snow White s head and her hair. Combs were an attribute of Aphrodite, the Sirens and mermaids all symbols of female desirability. Hair is a symbol of fertility and virility, but the comb tames its wildness and its poison nearly kills her. IRReturn to place in story.

CONCLUSION

Exosomes are composed of a lipid bilayer membrane structure,which has the advantages of rich content,high stability,ability to reflect the state of disease,and cellular communication.These features make them a research hotspot for liver cancer for potential biomarkers,biotherapeutics,therapeutic targets,drug carriers,and therapeutic factors.

Although exosomes present good application value,there are still problems with their clinical application.Firstly,the separation and purification of exosomes are complex.Secondly,the contents in exosomes are not unique.Thirdly,not all exosomes secreted by cells are suitable for use as carriers.Although there are currently smallscale clinical trials,the actual application of exosomes in the clinical diagnosis and treatment of liver cancer still needs more in-depth studies.

ARTICLE HIGHLIGHTS

Research background

Liver cancer is one of the most common malignant tumors with high morbidity and mortality because of lacking early diagnosis and treatment.Exosomes have been a newly discovered cellular communication tool with high biocompatibility,low immunogenicity,and high transport efficiency.They show great potential for cancer diagnosis and therapy.

Research motivation

This review aimed to consolidate the evidence on exosomes as biomarkers for the diagnosis and therapeutics for liver cancer in a systematic fashion.

Research objectives

Then he summoned his son, and revealed to him that he had got the false bride, who was nothing but a waiting-maid, while the real one, in the guise31 of the ex- goose-girl, was standing at his side

Research methods

A systematic literature search was performed using PubMed and Web of Science.The latest literature was published in June 2021.

Research results

Fifty-eight studies were included in this systematic review.Blood-derived exosomes could be biomarkers or biotherapeutics.Cell-derived exosomes,which were used to explore underlying mechanisms of differentially expressed exosome contents in clinical tissue samples,might serve as potential therapeutic targets for liver cancer.Exosomes might also serve as drug carriers or therapeutic factors.

They took them both in their arms, and asked him to tell about his sorrowful lot during the twenty years he had lived in the forest as a hideous lindorm

Research conclusions

Existing studies show that exosomes have great potential for clinical application as potential novel diagnostic and therapeutic markers of liver cancer.

I advise you to do what you think will turn out to yourhappiness, said the girl. Be kind and good to her, but rememberthis; from the hour we part we shall never see each other again. Years passed; then one day she met the old friend and sweetheartin the street; he looked ill and miserable15, and she could not helpasking him, How are you?

Research perspectives

This present review might be helpful as a reference for clinical research on exosomes in liver cancer.

We are grateful to Wang Ying for her skillful statistical analysis guidance.

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