bims-exocan Biomed News
on Exosomes roles in cancer
Issue of 2023‒04‒09
thirteen papers selected by
Muhammad Rizwan
COMSATS University
  1. Exosomes as crucial emerging tools for intercellular communication with therapeutic potential in ovarian cancer.
  2. Exosomes and osteosarcoma drug resistance.
  3. Exosome-based nanoimmunotherapy targeting TAMs, a promising strategy for glioma.
  4. An update in the applications of exosomes in cancer theranostics: from research to clinical trials.
  5. Tumor cells-derived exosomal circVCP promoted the progression of colorectal cancer by regulating macrophage M1/M2 polarization.
  6. Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway.
  7. Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy.
  8. Cancer stem cell-derived exosome-induced metastatic cancer: An orchestra within the tumor microenvironment.
  9. The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.
  10. Transmission of Exosomal TPX2 Promotes Metastasis and Resistance of NSCLC Cells to Docetaxel.
  11. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials.
  12. Exosomal delivery of 7SK long non-coding RNA suppresses viability, proliferation, aggressiveness and tumorigenicity in triple negative breast cancer cells.
  13. Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner.
  1. Future Sci OA. 2023 Jan;9(1): FSO833
    Exosomes as crucial emerging tools for intercellular communication with therapeutic potential in ovarian cancer.
    Shika Hanif Malgundkar, Yahya Tamimi.
      More than two-thirds of epithelial ovarian cancer (EOC) patients are diagnosed at advanced stages due to the lack of sensitive biomarkers. Currently, exosomes are intensively investigated as non-invasive cancer diagnostic markers. Exosomes are nanovesicles released in the extracellular milieu with the potential to modulate recipient cells' behavior. EOC cells release many altered exosomal cargoes that exhibit clinical relevance to tumor progression. Exosomes represent powerful therapeutic tools (drug carriers or vaccines), posing a promising option in clinical practice for curing EOC in the near future. In this review, we highlight the importance of exosomes in cell-cell communication, epithelial-mesenchymal transition (EMT), and their potential to serve as diagnostic and prognostic factors, particularly in EOC.
    Keywords:  biomarkers; cell-free messengers; exosomes; molecular cargo; ovarian cancer
    DOI:  https://doi.org/10.2144/fsoa-2022-0032
  2. Front Oncol. 2023 ;13 1133726
    Exosomes and osteosarcoma drug resistance.
    Huichao Fu, Yunjiao Wu, Jianbai Chen, Xing Hu, Xiaoyan Wang, Gongping Xu.
      Osteosarcoma (OS) is a primary malignant tumor of bone characterized by the formation of bone tissue or immature bone by tumor cells. Because of its multi-drug resistance, even with the improvement of chemotherapy and the use of targeted drugs, the survival rate of osteosarcoma (OS) is still less than 60%, and it is easy to metastasize, which is a difficulty for many clinicians and researchers. In recent years, with the continuous research on exosomes, it has been found that exosomes play a role in the diagnosis, treatment and chemotherapy resistance of osteosarcoma due to their unique properties. Exosomes can reduce the intracellular accumulation of chemotherapeutic drugs by mediating drug efflux, thus inducing chemotherapeutic resistance in OS cells. Exosomal goods (including miRNA and functional proteins) carried by exosomes also show great potential in affecting the drug resistance of OS. In addition, miRNA carried by exosomes and exosomes exist widely in tumor cells and can reflect the characteristics of parent cells, so it can also be used as a biomarker of OS. At the same time, the development of nanomedicine has given a new hope for the treatment of OS. Exosomes are regarded as good natural nano-carriers by researchers because of their excellent targeted transport capacity and low toxicity, which will play an important role in the field of OS therapy in the future. This paper reviews the internal relationship between exosomes and OS chemotherapy resistance, discusses the broad prospects of exosomes in the field of diagnosis and treatment of OS, and puts forward some suggestions for the study of the mechanism of OS chemotherapy resistance.
    Keywords:  biomarkers; drug resistance; exosomes; osteosarcoma; treatment
    DOI:  https://doi.org/10.3389/fonc.2023.1133726
  3. Cell Death Dis. 2023 Apr 03. 14(4): 235
    Exosome-based nanoimmunotherapy targeting TAMs, a promising strategy for glioma.
    Hong Luo, Hao Zhang, Jinning Mao, Hui Cao, Yihao Tao, Guanjian Zhao, Zhiwen Zhang, Nan Zhang, Zaoqu Liu, Jian Zhang, Peng Luo, Yuguo Xia, Yuan Cheng, Zongyi Xie, Quan Cheng, Guodong Liu.
      Exosomes, the cell-derived small extracellular vehicles, play a vital role in intracellular communication by reciprocally transporting DNA, RNA, bioactive protein, chains of glucose, and metabolites. With great potential to be developed as targeted drug carriers, cancer vaccines and noninvasive biomarkers for diagnosis, treatment response evaluation, prognosis prediction, exosomes show extensive advantages of relatively high drug loading capacity, adjustable therapeutic agents release, enhanced permeation and retention effect, striking biodegradability, excellent biocompatibility, low toxicity, etc. With the rapid progression of basic exosome research, exosome-based therapeutics are gaining increasing attention in recent years. Glioma, the standard primary central nervous system (CNS) tumor, is still up against significant challenges as current traditional therapies of surgery resection combined with radiotherapy and chemotherapy and numerous efforts into new drugs showed little clinical curative effect. The emerging immunotherapy strategy presents convincing results in many tumors and is driving researchers to exert its potential in glioma. As the crucial component of the glioma microenvironment, tumor-associated macrophages (TAMs) significantly contribute to the immunosuppressive microenvironment and strongly influence glioma progression via various signaling molecules, simultaneously providing new insight into therapeutic strategies. Exosomes would substantially assist the TAMs-centered treatment as drug delivery vehicles and liquid biopsy biomarkers. Here we review the current potential exosome-mediated immunotherapeutics targeting TAMs in glioma and conclude the recent investigation on the fundamental mechanisms of diversiform molecular signaling events by TAMs that promote glioma progression.
    DOI:  https://doi.org/10.1038/s41419-023-05753-9
  4. J Cancer Res Clin Oncol. 2023 Apr 03.
    An update in the applications of exosomes in cancer theranostics: from research to clinical trials.
    Kourosh Shahraki, Paria Ghasemi Boroumand, Hajie Lotfi, Fatemeh Radnia, Hossein Shahriari, Saman Sargazi, Sedigheh Sadat Mortazavi, Milad Shirvaliloo, Sakine Shirvalilou, Roghayeh Sheervalilou.
      Exosomes are nanosized extracellular vesicles secreted by nearly all viable cells following the fusing of multivesicular bodies and the plasma membrane and discharged into the encircling bodily fluids. Exosomes can transport cell-specific components from the source cell to the target cell. Given the enormous potential of exosomes as non-invasive diagnostic biomarkers and therapeutic nanovehicles. Lately, accumulated evidence has demonstrated that exosomes serve an important role in prognosis, diagnosis, and even treatment strategies. While several reviews have collective information on the biomedical application of exosomes, a comprehensive review incorporating updated and improved methodologies for beneficial applications of such vesicles in cancer theranostics is indispensable. In the current review, we first provided a comprehensive review of the introduction of exosomes, featuring their discovery, separation, characterization, function, biogenesis, secretion. The implications of exosomes as promising nanovehicles for drug and gene delivery, application of exosome inhibitors in the management of cancers, completed and ongoing clinical trials on the biological relevance of exosomes are then discussed in detail. As the field of exosome research grows, a better understanding of the subcellular parts and mechanisms involved in exosome secretion and targeting of specific cells will help figure out what their exact physiological functions are in the body.
    Keywords:  Cancer; Exosomes; Theranostics
    DOI:  https://doi.org/10.1007/s00432-023-04701-6
  5. Gene. 2023 Apr 05. pii: S0378-1119(23)00254-8. [Epub ahead of print] 147413
    Tumor cells-derived exosomal circVCP promoted the progression of colorectal cancer by regulating macrophage M1/M2 polarization.
    Yuncheng Tang, Sheng Hu, Tian Li, Xiaofeng Qiu.
      BACKGROUND: Colorectal cancer (CRC) is among the most frequent tumors of the digestive tract and the second leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the most critical immune cells in the tumor microenvironment, which closely interact with tumor cells to promote tumor incidence and progression. However, the precise mechanism of action between CRC cells and TAMs polarization is still being investigated.METHODS: Transmission electronic microscopy (TEM), NanoSight and western blotting were used to characterize exosomes (Exo) isolated from the culture medium of CRC cells. The cellular uptake and internalization of Exo were detected by confocal laser scanning microscopy. M1/ M2 phenotype markers expression were examined by ELISA and flow cytometry. Cell migration, invasion and proliferation were determined by transwell and CCK-8 assay, respectively. A xenograft tumor model was established to explore the role of circVCP in vivo. The target genes of circVCP or miR-9-5p were predicted by StarBase2.0. The target association among miR-9-5p and circVCP or NRP1 was confirmed using the luciferase assay and RNA-pull down assay.
    RESULTS: circVCP was highly accumulated in exosomes derived from plasma of CRC patients and CRC cells. Additionally, exosomal circVCP derived from CRC cells promoted cell proliferation, migration and invasion by regulating the miR-9-5p/NRP1 axis, and induced macrophage M2 polarization and inhibited macrophage M1 polarization.
    CONCLUSIONS: Over-expressed exosomal circVCP promoted the progression of CRC by regulating macrophage M1/M2 polarization through miR-9-5p/NRP1 axis. CircVCP may be a diagnostic biomarker and potential target for CRC therapy.
    Keywords:  CRC; circVCP; exosome; macrophage polarization; molecular mechanism
    DOI:  https://doi.org/10.1016/j.gene.2023.147413
  6. Hum Mol Genet. 2023 Apr 03. pii: ddad052. [Epub ahead of print]
    Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway.
    Lu Xu, Lile Wang, Rongna Yang, Tianxiang Li, Xiaoli Zhu.
      BACKGROUND: There is increasing evidence that exosome-mediated transmission of microRNA (miRNAs) helps to connect tumor-associated macrophages and cancer cells, including lung adenocarcinoma (LUAD) cells.PURPOSE: To identify the role of miR-3153 in LUAD progression and M2 macrophage polarization and explore its regulatory mechanism.
    METHODS: The relevant molecular mechanisms were analyzed and validated through mechanistic assays. In vitro functional assays followed by in vivo experiments were implemented to evaluate the role of exosomes in mediating M2 macrophage polarization and LUAD progression.
    RESULTS: LUAD cells transmitted miR-3153 through exosomes. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) promoted miR-3153 biosynthesis and exosomal sorting. Exosomal miR-3153 targeted zinc finger protein 91 (ZFP91) to suppress the ubiquitination and degradation of misshapen-like kinase 1 (MINK1), thereby activating the c-Jun N-terminal kinase (JNK) signaling pathway and inducing M2 macrophage polarization. M2 macrophage polarization induced by LUAD cell-derived exosomes promoted the malignant process of LUAD cells.
    CONCLUSION: Transmission of exosomal miR-3153 by LUAD cells activates the JNK signaling pathway and induces M2 macrophage polarization, thus promoting the progression of LUAD.
    DOI:  https://doi.org/10.1093/hmg/ddad052
  7. Cancer Sci. 2023 Apr 03.
    Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy.
    Zi-Wu Ye, Zi-Li Yu, Gang Chen, Jun Jia.
      Tumor angiogenesis plays an important role in the development of cancer since it allows for the delivery of oxygen, nutrients, and growth factors as well as tumor dissemination to distant organs. Although anti-angiogenic therapy (AAT) has been approved for treating various advanced cancers, this potential strategy has limited efficacy due to resistance over time. Therefore, there is a critical need to understand how resistance develops. Extracellular vesicles (EVs) are nano-sized membrane-bound phospholipid vesicles produced by cells. A growing body of evidences suggest that tumor cell-derived EVs (T-EVs) directly transfer their cargoes to endothelial cells (ECs) to promote tumor angiogenesis. Importantly, recent studies have reported that T-EVs may play a major role in the development of resistance to AAT. Moreover, studies have demonstrated the role of EVs from non-tumor cells in angiogenesis, although the mechanisms involved are still not completely understood. In this review, we provide a comprehensive description of the role of EVs derived from various cells, including tumor cells and non-tumor cells, in tumor angiogenesis. Moreover, from the perspective of EVs, this review focuses on the role of EVs in the resistance to AAT and the mechanisms involved. Due to their role in the failure of AAT, we here proposed potential strategies to further improve the efficacy of AAT by inhibiting T-EVs.
    Keywords:  Anti-angiogenic therapy; Extracellular vesicles; Non-tumor cells; Resistance; Tumor angiogenesis; Tumor cells
    DOI:  https://doi.org/10.1111/cas.15801
  8. Biochimie. 2023 Apr 01. pii: S0300-9084(23)00076-7. [Epub ahead of print]
    Cancer stem cell-derived exosome-induced metastatic cancer: An orchestra within the tumor microenvironment.
    Khalid Rashid, Aqeel Ahmad, Semmal Syed Meerasa, Abdul Q Khan, Xiaobo Wu, Li Liang, Yuehong Cui, Tianshu Liu.
      Although the mechanisms as well as pathways associated with cancer stem cell (CSC) maintenance, expansion, and tumorigenicity have been extensively studied and the role of tumor cell (TC)-derived exosomes in this process is well understood, there is a paucity of research focusing specifically on the functional mechanisms of CSC-derived exosomes (CSC-Exo)/exosomal-ncRNAs and their impact on malignancy. This shortcoming needs to be addressed, given that these vesicular and molecular components of CSCs could have a great impact on the cancer initiation, progression, and recurrence through their interaction with other key tumor microenvironment (TME) components, such as MSCs/MSC-Exo and CAFs/CAF-Exo. In particular, understanding CSCs/CSC-Exo and its crosstalk with MSCs/MSC-Exo or CAFs/CAF-Exo that are associated with the proliferation, migration, differentiation, angiogenesis, and metastasis through an enhanced process of self-renewal, chemotherapy as well as radiotherapy resistance may aid cancer treatment. This review contributes to this endeavor by summarizing the characteristic features and functional mechanisms of CSC-Exo/MSC-Exo/CAF-Exo and their mutual impact on cancer progression and therapy resistance.
    Keywords:  CSC-Exos; CSC-Markers; Cancer stem cells; Chemoresistance; EMT; Metastasis; ncRNAs
    DOI:  https://doi.org/10.1016/j.biochi.2023.03.014
  9. Biochem Pharmacol. 2023 Apr 04. pii: S0006-2952(23)00130-2. [Epub ahead of print] 115539
    The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.
    Qian Li, Mengyuan Wang, Lingbo Liu.
      Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.
    Keywords:  Acute myeloid leukemia; Bone marrow niche; Drug resistance; Exosomes; Leukemic stem cells; Stemness maintenance
    DOI:  https://doi.org/10.1016/j.bcp.2023.115539
  10. Onco Targets Ther. 2023 ;16 197-210
    Transmission of Exosomal TPX2 Promotes Metastasis and Resistance of NSCLC Cells to Docetaxel.
    Jiaru Hu, Qing He, Tian Tian, Na Chang, Liting Qian.
      Background: Lung cancer, most of which is non-small cell lung cancer (NSCLC), is the most common tumor in the world, and drug resistance, as a major problem in clinical treatment, has attracted extensive attention. However, the role and mechanism of Targeting protein for Xenopus kinesin-like protein 2 (TPX2), which is highly expressed in NSCLC, is still unclear.Methods: Bioinformatics analysis was used to analyze the relationship between TPX2 and the clinicopathological features of NSCLC. Stable TPX2 overexpression cell lines with were constructed by lentivirus infection, and the effect of TPX2 on proliferation, migration, invasion and chemoresistance to docetaxel was characterized by the CCK8, wound healing, transwell, colony formation assay and FACS. An in vivo lung homing mouse model was used to further confirmed the role of TPX2 on metastasis. Exosomes were extracted by differential centrifugation from the culture supernatant, and their functions were investigated by co-culture with tumor cells. Gene expression was detected via Western blot and real time PCR (RT-qPCR).
    Results: Overexpression of TPX2 was related to the poor prognosis of NSCLC. Promoted migration, invasion and metastasis, and reduced the sensitivity of NSCLC cells to docetaxel. The abundance of TPX2 can be packaged in vesicles and transported to other cells. In addition, overexpression of TPX2 induced the accumulation of β-catenin and C-myc.
    Conclusion: Our findings indicated that intercellular transfer of exosomal TPX2 triggered metastasis and resistance against to docetaxel in lung cancer cells, through activating downstream WNT/β-catenin signaling pathway.
    Keywords:  NSCLC; TPX2; docetaxel; exosome; metastasis
    DOI:  https://doi.org/10.2147/OTT.S401454
  11. Stem Cell Res Ther. 2023 Apr 07. 14(1): 66
    Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials.
    Ahmed Lotfy, Noha M AboQuella, Hongjun Wang.
      Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy.
    Keywords:  Clinical trials; Exosomes; Extracellular vesicles; MSC; Mesenchymal stromal/stem cell
    DOI:  https://doi.org/10.1186/s13287-023-03287-7
  12. Life Sci. 2023 Apr 01. pii: S0024-3205(23)00280-1. [Epub ahead of print] 121646
    Exosomal delivery of 7SK long non-coding RNA suppresses viability, proliferation, aggressiveness and tumorigenicity in triple negative breast cancer cells.
    Shohreh Farhadi, Samira Mohammadi-Yeganeh, Jafar Kiani, Seyed Mahmoud Hashemi, Ameneh Koochaki, Kazem Sharifi, Hossein Ghanbarian.
      AIMS: RN7SK (7SK), a highly conserved non-coding RNA, serves as a transcription regulator via interaction with a few proteins. Despite increasing evidences which support the cancer-promoting roles of 7SK-interacting proteins, limited reports address the direct link between 7SK and cancer. To test the hypothetic suppression of cancer by overexpression of 7SK, the effects of exosomal 7SK delivery on cancer phenotypes were studied.MATERIALS AND METHODS: Exosomes derived from human mesenchymal stem cells were loaded with 7SK (Exo-7SK). MDA-MB-231, triple negative breast cancer (TNBC), cell line was treated with Exo-7sk. Expression levels of 7SK were evaluated by qPCR. Cell viability was assessed via MTT and Annexin V/PI assays as well as qPCR assessment of apoptosis-regulating genes. Cell proliferation was evaluated by growth curve analysis, colony formation and cell cycle assays. Aggressiveness of TNBCs was evaluated via transwell migration and invasion assays and qPCR assessment of genes regulating epithelial to mesenchymal transition (EMT). Moreover, tumor formation ability was assessed using a nude mice xenograft model.
    KEY FINDINGS: Treatment of MDA-MB-231 cells with Exo-7SK resulted in efficient overexpression of 7SK; reduced viability; altered transcription levels of apoptosis-regulating genes; reduced proliferation; reduced migration and invasion; altered transcription of EMT-regulating genes; and reduced in vivo tumor formation ability. Finally, Exo-7SK reduced mRNA levels of HMGA1, a 7SK interacting protein with master gene regulatory and cancer promoting roles, and its bioinformatically-selected cancer promoting target genes.
    SIGNIFICANCE: Altogether, as a proof of the concept, our findings suggest that exosomal delivery of 7SK may suppress cancer phenotypes via downregulation of HMGA1.
    Keywords:  Exosome; HMGA1; Mesenchymal stem cell; RN7SK; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.lfs.2023.121646
  13. Cell Oncol (Dordr). 2023 Apr 04.
    Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner.
    Clarissa A Whitehead, Haoyun Fang, Huaqi Su, Andrew P Morokoff, Andrew H Kaye, Eric Hanssen, Cameron J Nowell, Katharine J Drummond, David W Greening, Laura J Vella, Theo Mantamadiotis, Stanley S Stylli.
      PURPOSE: The therapeutic efficacy of radiotherapy/temozolomide treatment for glioblastoma (GBM) is limited by the augmented invasiveness mediated by invadopodia activity of surviving GBM cells. As yet, however the underlying mechanisms remain poorly understood. Due to their ability to transport oncogenic material between cells, small extracellular vesicles (sEVs) have emerged as key mediators of tumour progression. We hypothesize that the sustained growth and invasion of cancer cells depends on bidirectional sEV-mediated cell-cell communication.METHODS: Invadopodia assays and zymography gels were used to examine the invadopodia activity capacity of GBM cells. Differential ultracentrifugation was utilized to isolate sEVs from conditioned medium and proteomic analyses were conducted on both GBM cell lines and their sEVs to determine the cargo present within the sEVs. In addition, the impact of radiotherapy and temozolomide treatment of GBM cells was studied.
    RESULTS: We found that GBM cells form active invadopodia and secrete sEVs containing the matrix metalloproteinase MMP-2. Subsequent proteomic studies revealed the presence of an invadopodia-related protein sEV cargo and that sEVs from highly invadopodia active GBM cells (LN229) increase invadopodia activity in sEV recipient GBM cells. We also found that GBM cells displayed increases in invadopodia activity and sEV secretion post radiation/temozolomide treatment. Together, these data reveal a relationship between invadopodia and sEV composition/secretion/uptake in promoting the invasiveness of GBM cells.
    CONCLUSIONS: Our data indicate that sEVs secreted by GBM cells can facilitate tumour invasion by promoting invadopodia activity in recipient cells, which may be enhanced by treatment with radio-chemotherapy. The transfer of pro-invasive cargos may yield important insights into the functional capacity of sEVs in invadopodia.
    Keywords:  Extracellular vesicles; Glioblastoma; Invadopodia; Radiotherapy; Temozolomide
    DOI:  https://doi.org/10.1007/s13402-023-00786-w
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