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DOI: 10.32604/oncologie.2022.020993

REVIEW

Progression of Exosome-Mediated Chemotherapy Resistance in Cancer

Haojie Zhang1, Xiaohong Wang2,*, Yue Yu2 and Zhenlin Yang3,*

1Binzhou Medical University, Yantai, 264003, China
2Department of Breast Surgery, Binzhou Medical University Hospital, Binzhou, 256603, China
3Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, 256603, China
*Corresponding Authors: Xiaohong Wang. Email: wangxiaohong0607@126.com; Zhenlin Yang. Email: ikb0607@163.com
Received: 22 December 2021; Accepted: 12 April 2022

Abstract: Chemotherapy plays an important role in controlling cancer progression, but the long-term use of chemotherapeutic agents can lead to drug resistance and eventually treatment failure. Therefore, elucidation of the mechanism of drug resistance is the key to solve the problem of chemotherapy resistance. In recent years, exosomes derived from tumor cells have received extensive attention from researchers. In this paper, we reviewed the role and mechanism of exosome-mediated tumor drug resistance in recent years, summarized the related studies of exosome and chemotherapy drug resistance, and focused on several different ways by which exosomes participate in tumor drug resistance. It includes the transporters of non-coding RNAs (ncRNAs), active proteins, stromal cell-derived exosomes and exosomes that directly mediate the efflux of drug molecules. Our review suggests that exosomes can play a role in the treatment of tumor drug resistance by inhibiting the secretion of exosomes, providing a new idea for the prevention and treatment of tumor chemotherapy drug resistance.

Keywords: Exosomes; chemotherapy; drug resistance; tumor microenvironment

1  Introduction

Chemotherapy is one of the main treatments for controlling tumor progression [1–3]. However, the long-term application of chemotherapeutic agents usually results in chemotherapy drug resistance of tumor cells, and eventually treatment failure and disease progression [4–6]. Therefore, elucidating the mechanisms of action for chemotherapy drug resistance is essential for effective cancer prevention, evaluation, or reversal of resistance to chemotherapy. Tumor cell-derived exosomes (TDEs) have been shown to play a role as cargo carriers which mediate the transfer of chemoresistance information between cells.

Extracellular vehicles (EVs) usually refer to vesicles with a lipid bilayer membrane structure that are secreted by cells or shed from the cell membrane. EVs can be classified into exosomes, microvesicles, and apoptotic bodies according to their biogenesis, size, markers and contents. The diameter of exosomes (40–100 nm) is smaller compared to microvesicles (100–1000 nm) and apoptotic bodies (1–4 μm) [7,8]. Exosomes were first discovered by researchers during the transition from reticulocytes to mature red blood cells [9]. At early stage, exosomes were referred to as “garbage bags” to remove unwanted proteins from the body. Various cell types including lymphocytes, epithelial cells, immune cells, mesenchymal stem cells, nerve cells, and tumor cells can secrete exosomes. Exosomes can be found in body fluids (e.g., blood, saliva, and urine) and enter the circulatory system to reach distant sites, thereby producing remote control effects [10–13]. When exosomes are observed under a transmission electron microscope, they usually appear as “dish-shaped” or “cup-shaped” vesicles with a lipid bimolecular membrane structure [14]. There are a variety of specific proteins on the surface, such as transmembrane proteins CD9, CD63, CD81, CD82, fusion proteins (Flotillin, annexin), and heat shock proteins (Hsc70). Among these proteins, the four transmembrane proteins have been recognized as markers of exosomes to distinguish it from other vesicles [15,16]. Genetic cargo, protein and non-coding RNAs (ncRNAs), carried by exosomes have important biological significance in the development and progression of tumors and drug resistance [17–20].

Exosomes originate from the endolysosomal system which forms early endosomes during endocytosis. Exosomes are formed by cell membrane invagination to form endosomes, then form multivesicular bodies, and finally exosomes are formed in cell multivesicular bodies and are released into the extracellular environment through fusion with cell membranes [21]. Functional molecules such as DNA, ncRNA, mRNA, and protein enter into early endosomes and develop into late endosomes that are rich in intracavity vesicles, namely extracellular vesicles [22–28]. These small spherical vesicles between 40–100 nm in diameter are secreted by various cells types and carry a variety of biologically active small molecules to participate in cell-cell information transmission and the regulation of a variety of malignant biological behaviors of tumor cells in tumor chemotherapy resistance, invasion and metastasis, and immune escape [29–35]. Tumor-derived exosomes (TDE) can enhance or induce drug resistance in sensitive cells through the delivery of ncRNA, proteins, and other biological molecules [29,36–42]. When this transport system is activated, the internal chemotherapeutic drug molecules and their metabolites can be transported to the endosome by MDR-ABC. The endosome further aggregates to form MVBs. MVBs fuse with the cell membrane and release exosomes. The drug will be excreted from the intracellular to the extracellular, causing tumor cells to develop drug resistance [43–46]. This article reviews the role and mechanism of tumor resistance mediated by exosomes, and aims to provide new ideas for the prevention and treatment of tumor chemotherapy resistance.

2  Tumor Drug Resistance Mediated by Exosomes

2.1 Exosomes Participate in the Regulation of Tumor Microenvironment

The tumor microenvironment (TME) is the local pathological environment where tumor occur, develop and metastasize. The TME is mainly composed of tumor cells, immune cells, endothelial cells, fibroblasts, inflammatory cells and extracellular matrix [18,19]. Exosomes mainly participate in the material transportation and information exchange between tumor and non-tumor cells through three ways: 1) Phagocytosis of target cells and receptor-mediated endocytosis. 2) Antigen presentation and receptor-ligand interaction. 3) Direct membrane fusion with target cell. A large number of studies have shown that as a mediator of intercellular communication, exosomes shuttle within the TME and are absorbed by surrounding cancer cells or stromal cells, and can transmit information by releasing their contents to cause tumor cell proliferation, invasion and metastasis, and chemotherapy drug resistance [47,48].

Signal transduction via soluble signaling molecules (cytokines, growth factors, or hormones) by all multicellular organisms occurs through membrane adhesion molecules, gap junctions and nanotubes to maintain necessary homeostasis conditions. Exosomes can change the tumor phenotype through signal transduction between tumor cells or tumor-related stromal cells. TDEs carry a variety of stimulating and inhibiting biomolecules (mRNA, ncRNA, protein) to provide a signaling network for the tumor microenvironment in vivo and in vitro. These biomolecules regulate cell signaling pathways and influence biological functions [20]. For example, the Ca2+ influx induced by TDEs play an important role in the function of T-regs, and thus, the regulation of T-reg inhibitors by TDE are carried out through a cell signal-dependent mechanism, without the need for recipient cells to internalize exosomes [49].

After 30 years of extensive research, it has been confirmed that transcription regulators can activate other signaling pathways during cell development and progression, such as Notch, Hedgehog (HH) family secreted proteins, Wingless/WNT, epidermal growth factor (EGF) and fibroblasts growth factor (FGF) [50]. Pikkarainen et al. [51] found that WNT signaling and Mac-2BP expression in HEK293 cells were significantly up-regulated under the induction of exosomes. In addition, further studies showed that the four domains of the Mac-2BP protein bind to the C-terminal domain of WNT. In vitro studies have shown that after human mesenchymal stem cells (MSC) and breast cancer cells MCF-7 are co-cultured with exosomes, the WNT signaling pathway in the cells is up-regulated [52]. Similarly, Lin et al. [53] found that after co-cultivating THP-1 cells, exosomes activate cell signaling pathways by producing IL-1β, TNF-α and IL-6, thereby suppressing the immune system and enhancing resistance to cancer treatment.

2.2 Exosomes Participate in the Regulation of Tumor Local Immune Microenvironment

There are many immune cells in the local immune TME, such as T lymphocytes, B lymphocytes, macrophages, dendritic cells, mast cells, natural killer cells, and neutrophils. Among them, in tumorigenesis, invasion, metastasis and drug resistance of T lymphocytes and tumor-associated macrophages (TAMs) play a very critical role. Exosomes play a very important role in anti-tumor immunity and immune escape between tumor cells and immune cells, and the flow of information [50,54,55]. Evasion of immune surveillance is a crucial step to gain metastatic outgrowth. Many findings revealed that exosomes, using multiple mechanisms, can help cancer cells to exert immunomodulatory activities [56]. Exosomes released by murine mammary carcinoma cells TS/A or 4T1 induced cancer growth in a mouse model, inhibiting natural killer (NK) cell cytotoxic activity ex vivo and in vivo [57]. Recently, an elegant work of Dhouha and coworkers demonstrated that PDL1-expressing exosomes can inhibit antitumour immune responses [58]. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis [59].

2.3 The Role and Mechanism of Exosomes in the Occurrence of Tumor Resistance

Researchers discovered that this non-spherical membrane structure of vesicles contains many proteins, lipids, and nucleic acids from parental cells [60,61]. The database shows that more than 1,639 RNAs, 764 microRNA, 4,653 protein, and 194 lipid types can be detected in exosomes from various eukaryotic cells. In the past few years, there has been new evidence that exosomes are involved in the occurrence and development of tumors through the transfer of nucleic acids and proteins between cells [62]. And a line of evidence suggested that the content of exosomes released from tumor cells in biological samples may be associated with the clinical outcomes of cancer patients [63].

Exosomes mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. Exosomes mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signaling, increased DNA-repair or delivering ABC transporters to drug sensitive cells, see Fig. 1 below.

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Figure 1: The role of exosomes in drug resistance of tumor

2.3.1 Exosomes Derived from Tumor Cells Participate in Drug Resistance by Transporting ncRNAs

The heterogeneity of tumor cells themself lead to differences of sensitivity of chemotherapy drugs According to this trait, tumor cells can be divided into drug-resistant cells and sensitive cells [64]. For example, exosomes secreted by drug-resistant tumor cells can release proteins and ncRNA (miRNA, lnc RNA) to sensitive cells, thereby acquiring drug resistance [2,65–68].

Non-coding RNA (ncRNA) is a type of small RNA that that does not encode protein. However, they are involved in the process of protein translation. ncRNA can be divided into short-chain (<200 nucleotides) non-coding RNA (sncRNA) such as tRNA and miRNA and long-non-coding RNA (lncRNA > 200 nucleotides) [69]. A large number of studies have shown that ncRNA plays an important role in the chemotherapy resistance of tumors, especially miRNA and lncRNA [70,71].

Liu et al. [72] confirmed that exosomes can target PDCD4 and PTEN in oral squamous cell carcinoma (OSCC) by releasing miR-21 to deliver cisplatin resistance. By using a nude mouse subcutaneous Xenotransplantation model, they injected cisplatin and exosomes derived from oral squamous carcinoma cisplatin-resistant cells HSC-3-R and parental OSCC cells HSC-3 into mice. The exosomes derived from HSC-3-R cell exosomes promoted tumor growth and enhance the resistance of cisplatin [72]. Accumulating studies have found that exosomes can transfer a variety of miRNAs to make cancer sensitive cells resistant to a variety of drugs in many cancers (Table 1).

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In addition, lncRNA also plays an important role in tumor resistance. In advanced renal cell carcinoma (renal cell carcinoma, RCC), Wang et al. [76] found that exosomes derived from drug-resistant cells can impart sunitinib resistance to sensitive cells by delivering lncARSR, and its mechanism is competitively inhibited with lncARSR. After miR-34/miR-449 promoted the expression of c-Met and AXL, the AXL/c-MET inhibitors or targeted lncARSR treatment of sunitinib-resistant RCC can effectively relieve RCC tumor cells are resistant to sunitinib [76]. LncRNAs are involved in chemotherapy resistance and transfers its resistance to recipient cells in various cancers, including renal cell carcinoma, bladder cancer, breast cancer (Table 1).

2.3.2 Exosomes Derived from Tumor Cells Participate in Drug Resistance by Transporting Active Proteins

TDEs can transfer proteins to recipient cells, so that tumor-sensitive cells can acquire drug resistance. Researchers in a colon cancer study found that after co-cultivating exosomes secreted by the drug-resistant cell line RKO and colon cancer sensitive cell line Coca-2, the drug resistance of Coca-2 increased. Further research found that the mechanism may be due to exosomes derived from the drug-resistant cell line RKO can down-regulate PTEN proteins and increase the level of phosphorylated Akt, thereby inducing Cetuzumab resistance in Coca-2 cells [85]. Lv et al. [86] found that compared with breast cancer sensitive cells MCF-7/S, breast cancer drug-resistant cell lines MCF-7/DOC derived exosomes contain high levels of P-glycoprotein (P-gp). Exosomes derived from these drug-resistant cells MCF-7/DOC can transmit docetaxel resistance to sensitive cells MCF-7/S by delivering P-gp. Ning et al. [87] found that breast cancer drug-resistant cells highly express UCH-L1 protein and release these proteins into the TME through exosomes, thereby transferring chemotherapy resistance to recipient cells. Subsequently, researchers further confirmed that the mechanism of its transmission of drug resistance may be that the highly expressed UCH-L1 activates the MAPK/ERK signaling pathway to up-regulate the expression of P-gp, thereby enhancing breast cancer drug resistance [88].

2.3.3 Exosomes Derived from Stromal Cells Participate in Drug Resistance

Not only can tumor cells exchange information through exosomes, but exosomes released by stromal cells can also mediate drug resistance in tumor cells by delivering drug-resistant active molecules. Studies have found that in pancreatic ductal adenocarcinoma (PDAC), the sensitivity of exosome-release-deficient mice to gemcitabine is significantly higher than that of wild-type mice. In addition, it was confirmed that macrophage-derived exosomes (MDE) can induce PDAC mice to be resistant to gemcitabine by transporting miR-365 [42]. Lobb et al. [89] have shown that exosomes derived from mesenchymal and oncogene-transformed lung cells can transport ZEB1 mRNA to tumor recipient cells, thereby transporting chemoresistance and mesenchymal phenotypes to tumor cells. Exosomes secreted by TAMs can deliver cell signaling molecule miR-21 to gastric cancer tumor cells, thereby enhancing the resistance of gastric cancer to cisplatin. In addition, miR-21 inhibits cell apoptosis and promotes the activation of PI3 K/AKT signaling pathway by down-regulating PTEN in gastric cancer [90]. Ji et al. [37,91] found that exosomes rich in human mesenchymal stem cells (MSC) can activate calcium/calmodulin-dependent protein kinase (CaMK) and Raf/MEK/ERK pathways, thereby antagonizing 5-fluorouracil-induced tumor cells apoptosis and further enhance the multi-drug resistance (MDR) protein in tumor cells, thereby promoting resistance of gastric cancer cells to 5-fluorouracil. Chi et al. [92] found that the expression level of miR-21 in exosomes derived from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) was higher than that in exosomes derived from ovarian cancer cells. In-depth studies have shown that miR-21 can transfer from CAAs or CAFs to ovarian cancer cells, thereby inhibiting the apoptosis of ovarian cancer cells and directly binding to its target molecule APAF1 to trigger drug resistance. The above data indicate in the microenvironment of omental tumors, exosomes released from adjacent stromal cells of the tumor can change the malignant biological behavior of metastatic ovarian cancer cells by transporting and inhibiting miR-21 in exosomes. Metastasis is another new way to treat highly metastatic and highly recurring ovarian cancer. Researchers from Wang et al. [93] found that the antagonism of PGE2/EP4 can induce exosome-mediated clearance of tumor stem cells, and this effect can weaken the resistance of MSCs to tumor chemotherapy drugs and enhance the sensitivity of tumor chemotherapy.

2.3.4 Exosomes Directly Mediate the Efflux of Drug Molecules

Exosomes encapsulate anti-cancer drugs in tumor cells and mediate the efflux of drug molecules, thereby reducing the treatment of anti-tumor drugs. Shedden et al. [94] tracked the anti-tumor drug doxorubicin via fluorescent pulse tracking and found that tumor cells can shed the drug by shedding vesicles (exosomes). At the same time, studies have found that many transporters such as multidrug resistance related protein 1 (MRP-1), P-gp, and ATP transport protein (ABCA3), breast cancer resistance protein (BCRP) and other proteins, this type of protein has the same transmembrane domain, also known as MDR-ABC transporter protein.

3  The Role of Exosomes in the Treatment of Tumor Resistance

Exosomes play an important role in the treatment of tumor resistance. Exosomes derived from tumor cells and stromal cells can transmit drug resistance, which reduces the efficacy of chemotherapy. Therefore, the drug resistance of tumor cells can be reversed by inhibiting the secretion of exosomes or using nanoparticles to deliver anti-miRNA and changing the composition of exosomes to improve the therapeutic effect. Studies have shown that rapamycin and U18666A can inhibit the release of exosomes by interfering with the synthesis of MVBs and the participation of cholesterol in the formation of cell membranes, respectively, thereby increasing the sensitivity of B lymphoma to rituximab [95]. At the same time, there are reports that exosomes can act as nanoparticles to encapsulate miRNA-214 and deliver it to cisplatin-resistant gastric cancer cells to reverse the resistance of gastric cancer to cisplatin [96]. Some researchers have also found that β-elemeneact on the target genes of drug-resistant breast cancer cell lines, thereby affecting the content of related drug-resistant miRNAs rich in exosomes, and thereby reducing the amount of external drug resistance transmission efficiency [97]. In addition, it has been reported that exosomal miR-567 is associated with inhibition of autophagy related 5 (ATG5) protein and reversal of resistance to trastuzumab in breast cancer [98]. Recently, a drug nanocarrier for targeted chemotherapy of liver cancer has been developed [99]. This novel strategy utilized homotypic HepG2 cell membrane as cloak and polylactic acid glycolic acid (PLGA) nanoparticles as core to prepare nano-carrier hepm PLGA, which is then to be used as carrier of doxorubicin. Their study has shown high release efficiency and significant therapeutic effect in vivo and in vitro for this strategy, highlighting the the promising role of this strategy for drug-resistant HCC. In 2021, it has been reported that iRGD-modified (iRGD: a 9-amino acid cyclic peptide) exosomes with siCPT1A, which is a key enzyme in the process of fatty acid oxidation (FAO), could specifically transport siCPT1A into colorectal cancer cells to suppress FAO. Given the crucial role of FAO in drug resistance of colorectal cancer cells, iRGD-modified exosomes can significantly suppress the expression of CPT1A in colorectal cancer cells and therefore reversed the resistance to oxaliplatin resistance by inhibiting FAO [100]. Moreover, Lima et al. [101] have suggested that accumulation of CCL2-modified exosomes will lead to the change in the immune environment of affected organs, thereby mediating the chemoresistance the chancer cells. Based on these above results, it is reasonable to believe application of exosomes can be considered as a novel strategy to overcome chemoresistance in cancer cells.

4  Prospects and Challenges

Exosomes are a communication tool for transporting substances and transmitting information between cells, and they play an important role in the progression of TME. Exosomes and their contents (miRNAs, lncRNAs, and proteins) are closely related to the occurrence of tumor resistance. They activate signal pathways in cells by fusion with target cells, antigen presentation, and receptor-ligand interactions. However, the physiological and pathological roles of exosomes in the TME need to be further explored.

The number and heterogeneity of exosomes in body fluids may be their shortcomings as biomarkers, that may lead to false negatives or positives in tumor diagnosis. To overcome these obstacles, the precise regulatory mechanism of exosomes in tumor progression needed to be well understood in assisting with cancer diagnosis and cancer prognosis. It is expected that in the near future, exosomes can be used as liquid biopsy and non-invasive biomarkers for early detection of tumors. In addition, exosomes as drug carriers to treat tumors will also become an effective treatment strategy. The review of exosomes-mediated tumor chemotherapy resistance provides insight to reveal the molecular mechanism of tumor resistance and motivation for the search for drug resistance markers and new treatment methods for tumors.

Author Contributions: Haojie Zhang and Xiaohong Wang conceived and designed the study. Yue Yu was responsible for materials. Haojie Zhang and Xiaohong Wang drafted the article. Xiaohong Wang and Zhenlin Yang revised the article critically. All authors had final approval of the submitted versions.

Ethic Approval and Informed Consent Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Availability of Data and Materials: All data generated or analysed during this study are included in this published article. And all the data is real and available.

Funding Statement: This work was supported by National Natural Science Foundation of China [Nos. 81902702, 31801085], Natural Science Foundation of Shandong Province [Nos. ZR2017LH072, ZR2017MH033], Projects of Binzhou Technology Development Program [No. 2015ZC0301], National Key Research and Development Project [No. 2018YFC0114705], Scientific Research Staring Foundation of Binzhou Medical University [Nos. BY2014KYQD36, BY2014KJ36, BY2017KJ01], Science and Technology Program of Universities in Shandong Province [No. J15LL51]. The Special Funds for the Qilu Health and Health Leading Talents Cultivation Project (Wang xiaohong).

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

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