Development Of Cancer Stem Cells Research Articles

Tumor Shrinkage can be a Promising Diagnosis Toward Remission or can also be an Ominous Diagnosis Toward Fatality

The objective of this article is to rectify tumor shrinkage as a valid diagnosis of cancer therapy. Cancer incidence and cancer mortality keep on increasing, which are an indication that cancer has not been handled right. Perpetual proliferation of cancer cells (CCs) is the most outstanding feature of cancer. Elimination of CCs to shrink tumor became the commanding principle, which was wrong, because cancer evolved due to wound unhealing. Killing to create wound definitely is contra-indication of cancer therapy. The mistake was committed at a time when we did not have the full knowledge of cancer, which was excusable. Now we have better knowledge of cancer, but the mistake is carrying on to result in 10 million annual mortality worldwide in 2019 with an anticipated annual increment of 5%, which is not excusable. Cytotoxic therapies can only benefit a small minority of cancer patients in the early stage whose chem-surveillance have not yet fatally damaged, relying on the restoration of chemo-surveillance to subdue cancer stem cells (CSCs), which are resistant to cytotoxic agents. Under this circumstance, tumor shrinkage is a promising diagnosis toward remission. Cytotoxic therapies cause the death of a majority of cancer patients in the advanced stage whose chemo-surveillance have been fatally damaged. Under this circumstance, tumor shrinkage is an ominous diagnosis toward fatality. Tumor shrinkage should be used with discretion. Cancer is a disease created by multiple factors. The collapse of chemo-surveillance or immuno-surveillance, the evolution of cancer stem cells (CSCs) from progenitor stem cells (PSCs) due to wound unhealing, and the progression of CSCs to faster replicating CCs by the activation of oncogenes or the inactivation of suppressor genes all contribute significantly to the development of cancer. An effective cancer therapy must be able to rectify all these contributing factors. Focusing on a specific factor is insufficient. The obsession to eliminate CCs to achieve tumor shrinkage is a grave mistake of cancer establishments to result in ever-increasing cancer mortality. Actually, elimination of CSCs is more important than the elimination of CCs, because CSCs contribute most fatal effects of cancer such as metastasis, drug resistance, anti-apoptosis, angiogenesis and recurrence. Induction of terminal differentiation by cell differentiation agent (CDA) formulations is the only option to eliminate CSCs which are critically linked to wound unhealing at the primary site. Induction of terminal differentiation can also result in the elimination of CCs, which are not as tightly linked to wound unhealing as CSCs. Terminal differentiation of CSCs and CCs cannot make the tumor to disappear. Thus, CDAs violated the commanding principle of tumor shrinkage put up by the cancer establishments, and were blocked as acceptable cancer drugs. CDA formulations are obviously the only drugs that can save the lives of advanced cancer patients whose chemo-surveillance have been fatally damaged. Oncologists and advanced cancer patients must unite to push for the approval of CDA formulations to save advanced cancer patients.

Berberine Inhibits Breast Cancer Stem Cells Development and Decreases Inflammation: Involvement of miRNAs and Interleukin-6

Berberine Inhibits Breast Cancer Stem Cells Development and Decreases Inflammation: Involvement of miRNAs and Interleukin-6

Phytosesquiterpene lactones deregulate mitochondrial activity and phenotypes associated with triple-negative breast cancer metastasis

Triple-negative breast cancer (TNBC) recurrence and metastasis are the major causes of failure in TNBC therapy. The difficulties in treating TNBCs may be because of increased cancer cell plasticity that involves the fine-tuning of cellular redox homeostasis, mitochondrial bioenergetics, metabolic characteristics, and the development of cancer stem cells (CSCs). To investigate the effects and the underlying mechanisms of the phytosesquiterpene lactone deoxyelephantopin (DET) and its semi-synthesized derivative (DETD-35) in suppressing different phenotypic TNBC cell populations that contribute to tumor metastasis. A timelapse microfluidic-based system was established to analyze the effects of DETD-35 and DET on cell migration behavior in an oxygen gradient. Seahorse real-time cell metabolic analyzer and gas chromatography/quadrupole-time-of-flight mass spectrometry (GC/Q-TOF MS) were utilized to analyze the effects of the compounds on mitochondrial bioenergetics in TNBC cells. A miRNA knockout technique and miRNA sponges were employed to evaluate the miR-4284 involvement in the anti-TNBC cell effect of either compound. DETD-35 and DET attenuated TNBC cell migration toward hypoxic regions under a 2-19 % oxygen gradient in a timelapse microfluidic-based system. DETD-35 and DET also suppressed CSC-like phenotypes, including the expression of Sox2, Oct4, and CD44 in TNBC cells under hypoxic conditions. DETD-35 and DET affected mitochondrial basal respiration, ATP production, proton leak, and primary metabolism, including glycolysis, the TCA cycle, and amino acid metabolism in the lung-metastatic TNBC cells. Furthermore, the expression of mitophagy markers PARKIN, BNIP3, PINK1, LC3-II, and apoptotic markers Bax, cleaved caspase 7, and cleaved PARP in hypoxic and lung-metastatic TNBC cells was also regulated by treatment with either compound. In miR-4284 knockout cells or miR-4284 inhibitor co-treated TNBC cells, DET- and DETD-35-induced over-expression of mitophagic and apoptotic markers was partially reversed, indicating miR-4284 involved with the compounds caused programmed cell death. This study demonstrated the novel activities of DETD-35 and DET in suppressing CSC-like phenotypes and metastatic TNBC cells through the de-regulation of mitochondrial bioenergetics.

Targeting CREB-binding protein (CBP) abrogates colorectal cancer stemness through epigenetic regulation of C-MYC.

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs.

Evaluation of Tumorigenic Properties of MDA-MB-231 Cancer Stem Cells Cocultured with Telocytes and Telocyte-Derived Mitochondria Following miR-146a Inhibition.

Telocytes have some cytoplasmic extensions called telopodes, which are thought to play a role in mitochondrial transfer in intercellular communication. Besides, it is hypothesized that telocytes establish cell membrane-mediated connections with breast cancer cells in coculture and may contribute to the survival of neoplastic cell clusters together with other stromal cells. The aim of this study is to investigate the contribution of telocytes and telocyte-derived mitochondria, which have also been identified in breast tumors, to the tumor development of breast cancer stem cells (CSCs) via miR-146a-5p. The isolation/characterization of telocytes from bone marrow mononuclear cells and the isolation of mitochondria from these cells were performed, respectively. In the next step, CSCs were isolated from the MDA-MB-231 cell line and were characterized. Then, miR-146a-5p expressions of CSCs were inhibited by anti-miR-146a-5p. The epithelial-mesenchymal transition (EMT) was determined by evaluating changes in vimentin protein levels and was evaluated by analyzing BRCA1, P53, SOX2, E-cadherin, and N-cadherin gene expression changes. Our results showed that miR-146a promoted stemness and oncogenic properties in CSCs. EMT (N-cadherin, vimentin, E-cadherin) and tumorigenic markers (BRCA1, P53, SOX2) of CSCs decreased after miR-146a inhibition. Bone marrow-derived telocytes and mitochondria derived from telocytes favored the reduction of CSC aggressiveness following this inhibition.

Machine Learning Model for Prediction of Development of Cancer Stem Cell Subpopulation in Tumurs Subjected to Polystyrene Nanoparticles.

Cancer stem cells (CSCs) play a key role in tumor progression, as they are often responsible for drug resistance and metastasis. Environmental pollution with polystyrene has a negative impact on human health. We investigated the effect of polystyrene nanoparticles (PSNPs) on cancer cell stemness using flow cytometric analysis of CD24, CD44, ABCG2, ALDH1 and their combinations. This study uses simultaneous in vitro cell lines and an in silico machine learning (ML) model to predict the progression of cancer stem cell (CSC) subpopulations in colon (HCT-116) and breast (MDA-MB-231) cancer cells. Our findings indicate a significant increase in cancer stemness induced by PSNPs. Exposure to polystyrene nanoparticles stimulated the development of less differentiated subpopulations of cells within the tumor, a marker of increased tumor aggressiveness. The experimental results were further used to train an ML model that accurately predicts the development of CSC markers. Machine learning, especially genetic algorithms, may be useful in predicting the development of cancer stem cells over time.

Metabolic vulnerability of cancer stem cells and their niche.

Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

Crosstalk between colorectal CSCs and immune cells in tumorigenesis, and strategies for targeting colorectal CSCs.

Cancer immunotherapy has emerged as a promising strategy in the treatment of colorectal cancer, and relapse after tumor immunotherapy has attracted increasing attention. Cancer stem cells (CSCs), a small subset of tumor cells with self-renewal and differentiation capacities, are resistant to traditional therapies such as radiotherapy and chemotherapy. Recently, CSCs have been proven to be the cells driving tumor relapse after immunotherapy. However, the mutual interactions between CSCs and cancer niche immune cells are largely uncharacterized. In this review, we focus on colorectal CSCs, CSC-immune cell interactions and CSC-based immunotherapy. Colorectal CSCs are characterized by robust expression of surface markers such as CD44, CD133 and Lgr5; hyperactivation of stemness-related signaling pathways, such as the Wnt/β-catenin, Hippo/Yap1, Jak/Stat and Notch pathways; and disordered epigenetic modifications, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA action. Moreover, colorectal CSCs express abnormal levels of immune-related genes such as MHC and immune checkpoint molecules and mutually interact with cancer niche cells in multiple tumorigenesis-related processes, including tumor initiation, maintenance, metastasis and drug resistance. To date, many therapies targeting CSCs have been evaluated, including monoclonal antibodies, antibody‒drug conjugates, bispecific antibodies, tumor vaccines adoptive cell therapy, and small molecule inhibitors. With the development of CSC-/niche-targeting technology, as well as the integration of multidisciplinary studies, novel therapies that eliminate CSCs and reverse their immunosuppressive microenvironment are expected to be developed for the treatment of solid tumors, including colorectal cancer.

Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation

Chronic metabolic stress paradoxically elicits pro-tumorigenic signals that facilitate cancer stem cell (CSC) development. Therefore, elucidating the metabolic sensing and signaling mechanisms governing cancer cell stemness can provide insights into ameliorating cancer relapse and therapeutic resistance. Here, we provide convincing evidence that chronic metabolic stress triggered by hyaluronan production augments CSC-like traits and chemoresistance by partially impairing nucleotide sugar metabolism, dolichol lipid-linked oligosaccharide (LLO) biosynthesis and N-glycan assembly. Notably, preconditioning with either low-dose tunicamycin or 2-deoxy-D-glucose, which partially interferes with LLO biosynthesis, reproduced the promoting effects of hyaluronan production on CSCs. Multi-omics revealed characteristic changes in N-glycan profiles and Notch signaling activation in cancer cells exposed to mild glycometabolic stress. Restoration of N-glycan assembly with glucosamine and mannose supplementation and Notch signaling blockade attenuated CSC-like properties and further enhanced the therapeutic efficacy of cisplatin. Therefore, our findings uncover a novel mechanism by which tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation.

Aldehyde Dehydrogenase-1A1 (ALDH1A1): The Novel Regulator of Chemoresistance in Pancreatic Cancer Cells.

Aldehyde dehydrogenase-1A1 (ALDH1A1), a member of a superfamily of 19 isozymes, exhibits various biological functions and is involved in several important physiological and pathological processes, including those associated with various diseases including cancers such as pancreatic cancer. Chemotherapy is one of the most important strategies for the treatment of pancreatic cancer; however, the chemoresistance exhibited by pancreatic cancer cells is a leading cause of chemotherapy failure. It has been reported that overexpression of ALDH1A1 significantly correlates with poor prognosis and tumor aggressiveness, and is clinically associated with chemoresistance. Additionally, ALDH1A1 may serve as a novel regulator for the diagnosis and prognosis of cancer resistance. In particular, ALDH1A1 can promote cancer progression by facilitating the manifestation of cancer stem cell properties. However, the molecular mechanism by which ALDH1A1 clinically regulates the development of chemoresistance, and its role in prognosis and cancer stem cells, including pancreatic cancer stem cells, remain unclear. Therefore, the current review aims to summarize the clinical functions of ALDH1A1 as a novel regulator of chemoresistance, prognosis, and cancer stem cell development in pancreatic cancer.

YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and invivo, revealing a significant inhibition of the Wnt family member 5a (Wnt5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing (scRNA-seq) on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of colorectal cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 cell balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.

N-Biphenyl Pyrrolinones and Dibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting the LIN28-Let-7 Interaction.

The RNA-binding protein LIN28 is a regulator of miRNA let-7 biogenesis. Inhibitors of LIN28 are highly sought after given the central role that LIN28 plays in tumorigenesis and development of cancer stem cells as well as LIN28's association with poor clinical prognosis. Although LIN28 inhibitors of different scaffolds have been reported, the potential of most LIN28 inhibiting small molecules was not fully explored since very limited structure-activity relationship (SAR) studies have been performed. We previously identified trisubstituted pyrrolinones as a new class of LIN28 inhibitors disrupting the LIN28-let-7 interaction. Here, we performed extensive SAR by evaluating 95 small molecules and identified new trisubstituted pyrrolinones featuring either an N-biphenyl or N-dibenzofuran substituent, overthrowing the existing conclusion that a salicylic acid moiety is indispensable for activity. Exchange of the negatively charged salicylic acid moiety in LIN28 inhibitors with a heterocyclic substituent is beneficial for membrane permeability, leading to increased activity in a cellular assay, and will potentially reduce toxicity.

Hepatitis C virus infects and perturbs liver stem cells.

The hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease. Here, we show that HCV maintains low-grade infections in liver organoids for the first time. HCV infection in liver organoids leads to transcriptional reprogramming causing cancer cell development and altered immune response. Our finding shows how HCV infection in liver organoids mimics HCV infection and patient pathogenesis. These results reveal that HCV infection in liver organoids contributes to liver disease progression.

Revolutionizing colorectal cancer treatment: unleashing the potential of miRNAs in targeting cancer stem cells.

Colorectal cancer (CRC) is a significant contributor to cancer mortality worldwide, and the presence of cancer stem cells (CSC) represents a major challenge for achieving effective treatment. miRNAs have emerged as critical regulators of gene expression, and recent studies have highlighted their role in regulating stemness and therapeutic resistance in CRC stem cells. This review highlights the mechanisms of CSC development, therapy resistance and the potential of miRNAs as therapeutic targets for CRC. It emphasizes the promise of miRNAs as a novel approach to CRC treatment and calls for further research to explore effective miRNA-based therapies and strategies for delivering miRNAs to CSCs in vivo.

Hypoxia-induced circSTT3A enhances serine synthesis and promotes H3K4me3 modification to facilitate breast cancer stem cell formation

Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1α)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management.

Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance.

The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.

Involving stemness factors to improve CAR T-cell-based cancer immunotherapy.

Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.

Clinical Theranostics Trademark of Exosome in Glioblastoma Metastasis.

Glioblastoma (GBM) is an aggressive type of cancer that has led to the death of a large population. The traditional approach fails to develop a solution for GBM's suffering life. Extensive research into tumor microenvironments (TME) indicates that TME extracellular vesicles (EVs) play a vital role in cancer development and progression. EVs are classified into microvacuoles, apoptotic bodies, and exosomes. Exosomes are the most highlighted domains in cancer research. GBM cell-derived exosomes participate in multiple cancer progression events such as immune suppression, angiogenesis, premetastatic niche formation (PMN), ECM (extracellular matrix), EMT (epithelial-to-mesenchymal transition), metastasis, cancer stem cell development and therapeutic and drug resistance. GBM exosomes also carry the signature of a glioblastoma-related status. The exosome-based GBM examination is part of the new generation of liquid biopsy. It also solved early diagnostic limitations in GBM. Traditional therapeutic approaches do not cross the blood-brain barrier (BBB). Exosomes are a game changer in GBM treatment and it is emerging as a potential platform for effective, efficient, and specific therapeutic development. In this review, we have explored the exosome-GBM interlink, the clinical impact of exosomes on GBM biomarkers, the therapeutics signature of exosomes in GBM, exosome-based research challenges, and future directions in GBM. Therefore, the GBM-derived exosomes offer unique therapeutic opportunities, which are currently under preclinical and clinical testing.

Histone modifications in drug-resistant cancers: From a cancer stem cell and immune evasion perspective.

The development and immune evasion of cancer stem cells (CSCs) limit the efficacy of currently available anticancer therapies. Recent studies have shown that epigenetic reprogramming regulates the expression of characteristic marker proteins and tumor plasticity associated with cancer cell survival and metastasis in CSCs. CSCs also possess unique mechanisms to evade external attacks by immune cells. Hence, the development of new strategies to restore dysregulated histone modifications to overcome cancer resistance to chemotherapy and immunotherapy has recently attracted attention. Restoring abnormal histone modifications can be an effective anticancer strategy to increase the therapeutic effect of conventional chemotherapeutic and immunotherapeutic drugs by weakening CSCs or by rendering them in a naïve state with increased sensitivity to immune responses. In this review, we summarize recent findings regarding the role of histone modifiers in the development of drug-resistant cancer cells from the perspectives of CSCs and immune evasion. In addition, we discuss attempts to combine currently available histone modification inhibitors with conventional chemotherapy or immunotherapy.

Decoding of exosome heterogeneity for cancer theranostics.

Extracellular Vesicles (EVs) discovery establishes a new milestone in cancer research. It explains cancer biology in a new way. EVs classified some significant subclasses such as macrovesicle (originated from plasma membrane), apoptotic bodies (originated from the plasma membrane and endoplasmic reticulum), and exosomes (originated from endosomes).1 The theranostic signature of exosomes in cancer healing is impressive, but its heterogeneity leads most complicated domain of research. Therefore we comment on decoding exosome heterogeneity for future efficiency and effective cancer theranostics development. EVs are the cell-secreted one of the most important entities. The exosome attracted much attention due to its versatile uses. Overall, its participation in intercellular communication and its inner cargos (DNA, RNA, proteins, lipids and glycan)2 can reprogram the recipient cells. In addition, it also shows the healthy or pathologic complication status of the parent cells. In cancer, tumor and exosomes interlink a complex chapter of cancer biology. Exosomes play an important role in accelerated tumor growth, immune cell reprogramming,2 angiogenesis,3 extracellular matrix remodelling,4, 5 metastasis,4, 5 epithelial-mesenchymal transition (EMT),4, 5 organ-specific metastasis,5, 6 drug resistance and cancer stem cell development.3, 4 Clinically aspect, the exosome is the source of the cancer biomarkers.7-9 Exosome heterogeneity1 is evolving into a major conflict in cancer biomarker and therapeutic research.10 The exosome heterogeneity (Figure 1) is based on several facts such as origin, size, quantity, and internal molecular diversity.1 Exosome size distribution is the most complicated side of tumor-derived exosomes (TEXs). Scientific evidence shows that the same cells release differently-sized exosomes. This size-oriented biodiversity is reflected in using different isolation methods.9, 10 The tumor cells release more exosomes compared to healthy cells. The higher release of exosomes from tumor cells depends on several factors, such as drug and therapeutic exposures, hypoxic conditions, and senescence. The functional diversity of exosomes is related to the surface molecular expression and inner cargos of exosomes. All these complicated/complex parameters lead to a challenging ecosystem development of exosome-based cancer theragnostics (combination of biomarkers and therapeutics research). This scenario requires a solution to solve these challenges. Based on several innovative nano platform-based approaches transform these challenges into an opportunity for exosome researcher in a detailed exploration of exosome.11 Exosomes isolation, size and quantity related complication solved via microfluidic device, fluorescence antibody based exosome tracking, Nanoparticle tracking analysis (NTA) (above 60 nm exosome size challenging for its application),12, 13 magnetic and surface plasma resonance principle based single exosome screening,1 advanced sensitive flow cytometry (it is capable of the separation of exosome subpopulation) and electrophoresis chip. Molecular profiling of exosomes is one of the most critical tasks revealing the functional diversity of bioactive cargo molecules of exosomes. Droplet digital polymerase chain reaction (it is sensitive to the detection of rear mutations in tumor-derived exosomes),1 microfluidic technology combined with a chip system, and an electrochemical principle-based micro RNA profiling of exosomes explain the cancer complication of a new dimension.1 The downstream process of exosome profiling needs a muti-omics approach for proper molecular diversity to understand.1 The single cells exosome profiling approach combines with machine learning for more precision cancer marker development.14 All these technological advancements support constructing the next-generation promising cancer theranostic era based on exosomes.15, 16 Finally, decoding exosome heterogeneity opens a new door for exosome-based precision medicine17 and vaccines18 for cancer. We hope this article encourages large-scale EV research to explore a single exosome profiling approach and future exosome-based cancer precision medicine development. Not applicable. The authors declare no conflict of interest. There is no funding for this study.