Open access peer-reviewed chapter
Abstract
High-grade glioma (HGG) such as glioblastoma multiforme (GBM) is an aggressive brain tumor that is still associated with poor prognosis. With the discovery and advancement in understanding of cancer stem cells (CSC) in glioma, these cells have emerged as seed cells for tumor growth and recurrence and appear as a potential target for therapeutics. Glioma stem cells (GSCs) demonstrate capacity of self-renewal, proliferation, and differentiation into multiple cell types and can contribute to tumor heterogeneity. Their role is established in tumorigenesis, metastasis, chemo- and radio-resistance and appears as a major cause for tumor recurrence. Thus, targeting GSCs by various therapeutics may improve effectiveness of the drugs in use alone or in combination to significantly improve patient survival outcome in GBM cases. In this chapter, we have discussed various mechanisms that drive GSC including signaling pathways and tumor microenvironment. We have also discussed the mechanism behind resistance of GSCs toward therapeutics and the pathways that can be targeted to improve the outcome of the patients.
Keywords
- Glioblastoma multiforme
- cancer stem cells
- glioma stem cells
- signaling pathways
- chemotherapeutics
- tumor microenvironment
- resistance to therapy
1. Introduction
Glioblastoma multiforme (GBM), classified as grade IV glioma, is highly invasive, heterogeneous, and malignant primary brain tumor. It accounts for ~57% of all gliomas and ~ 48% of all primary malignant central nervous system (CNS) tumors [1, 2]. Such tumors are associated with poor quality of life of the patient due to progressive decline in neurologic function, thus making a huge impact on the patients, care givers, and their families. The standard treatment includes multimodal approach involving maximal surgical resection followed by radiotherapy, systemic therapy (chemotherapy, targeted therapy), and supportive care; however, long-term survival is exceptional. Despite the treatment, these tumors regrow and that too with aggressive phenotype, which worsen the symptoms leading to prognosis with average overall survival time < 14.6 months for primary GBM patients and < 6.9 months for recurrent GBM patients [3]. Understanding the molecular mechanism involved in therapeutic resistance and tumor regrowth despite standard treatment is imperative.
In this regard, researchers have identified existence of cancer stem cells (CSCs) in a variety of cancers that play crucial role in tumor initiation, maintenance, resistance to therapy, recurrence, metastasis, and generation of more aggressive phenotype [4]. These properties of CSC are manifested by their potential to self-renew, proliferate, ability to differentiate in multiple phenotypes, plasticity, quiescence, and dormancy. It is suggested that these CSCs originate either from normal stem cells that were already present in tissue or can be generated from dedifferentiation of somatic cells from bulk of tumor. Based on the properties of CSCs, they pose not only a barrier for anticancer therapy but also are responsible for recurrence into more aggressive phenotype. Various researchers have shown that CSC escape anticancer therapy due to their ability to enter dormancy, plasticity, renewal, and regrowth into heterogeneous group of tumor cells. Of interest, recent evidences have suggested that these CSCs are further enriched in response to standard radio-chemotherapy, which may be responsible for tumor regrowth and aggressive phenotype. These enriched CSCs might be result from the existing population of CSCs that evades the therapy or as per recent evidences, can be generated from non-CSCs from the bulk of tumor in response to therapy. Of note, CSCs have been identified in HGG cases also known as glioma stem cells (GSCs) that contribute to tumor heterogeneity and resistance to therapies, thus a major contributor of tumor recurrence. These GSCs are considered as a potential therapeutic target, therefore understanding the molecular pathways that drive GSCs becomes imperative [5]. In this book chapter, we have discussed about the properties of cancer stem cells, cell surface markers, signaling pathways, and mechanism of resistance to therapies and ways by which these pathways can be targeted using different chemotherapeutic agents.
2. Biology of cancer stem cells
Stem cells are specialized cells present in our body that possess properties such as capacity to self-renew, proliferate, and differentiate into multiple cell types. This quality of self-renewal along with associated signaling pathways is shared between both stem cells and cancer stem cells with added feature of oncogenicity in CSCs. The most common pathways that drive multipotency and self-renewal of stem cells include the Notch, Sonic hedgehog (Shh), and Wnt signaling pathways [4]. Due to activation of oncogenic pathways, CSCs can give rise to tumor mass consisting of heterogeneous cell population. Initially, Bonnet and Dick characterized CSCs in acute myeloid leukemia as leukemia-initiating cell that possessed properties of leukemia stem cell [6]. Later, such cells were also identified in a variety of solid tumors, including prostate [7], colon [8], lung [9], ovarian [10], and brain [11] tumors. It is hypothesized that CSCs are the seed of a tumor that are responsible for tumorigenesis by initiation, maintenance, propagation, resistance to therapy, recurrence as well as progression of the tumor [12].
3. Glioma stem cells
In brain tumors, presence of CSC has been identified and characterized by various groups and are defined as GSCs or glioma initiating cells [11]. When cultured, these cells grown into neurospheres that constitute of cells that express SC markers including Nestin and CD133. When these cells are injected into nude mice, they lead to tumor formation due to their SC properties [13]. To add further, various groups have utilized properties of stem cells that are present in brain predominantly in subventricular zone (SVZ) to initiate tumor by exposure to chemicals (ethylnitrosourea) or viruses (avian sarcoma virus) in animals that strongly support the importance of stem cells in tumor formation [7, 14, 15]. These cells contribute to tumor heterogeneity and plasticity and have shown resistance to therapies and thus have emerged as a major contributor of tumor recurrence [5, 16, 17]. These CSCs are also influenced by micro environmental conditions such as nutrient deprivation, hypoxia, pH, vasculature, radiation, and chemotherapeutic treatment (explained in detail in coming sections) [16, 17, 18, 19].
Several putative GSC surface markers, such as CD133, CD15, and CD44, and GSC transcription factors, such as SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and NANOG, have been discovered [20, 21]. However, before its clinical implication, higher sensitivity and specificity of these GSC markers need to be established [21, 22].
4. Major signaling pathways that drive glioma stem cells
In order to maintain stemness properties, GSCs depend upon number of signaling pathways that also support them to sustain under adverse conditions during tumorigenesis [23, 24, 25]. To understand the process of stemness in GSC, the signaling pathways that are also a part of normal neuronal stem cells are discussed. These pathways mainly include Notch, bone morphogenic proteins (BMPs), NF-
4.1 Notch signaling
Notch signaling pathway is crucial in developmental process and plays a major role during embryonic development. This pathway regulates cellular proliferation, differentiation, apoptosis, and cell lineage decisions. In GSCs, Notch signaling pathways are highly active, which in turn maintain stemness by inhibiting differentiation. Notch signaling is also involved in oncogenic transformation. It has been identified that inhibition of Notch signaling decreases oncogenic potential of GSCs [26, 27].
4.2 Bone morphogenetic proteins (BMPs)
BMP group of molecules belongs to the transforming growth factor-β (TGF-β) superfamily of proteins. BMPs plays role during embryogenesis, development as well as adult tissue homeostasis. It interacts with different signaling molecules including Wnt/
4.3 Wnt/β-catenin signaling
Wnt/β-catenin signaling is a highly conserved pathway that regulates cellular proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. This pathway also regulates NSC expansion and promotes astroglial lineage differentiation during neural development [33, 34]. In GSC,
4.4 Epidermal growth factor receptor (EGFR) signaling
The EGFR pathway is one of the most crucial pathways involved in cellular processes including proliferation, differentiation, migration, and apoptosis in a variety of cells including stem cells. Dysregulation of this pathway has been linked to cancer. Critical role of EGFR has been identified in NSCs as well [40, 41, 42]. In GSC EGFR works through activation of
4.5 Sonic hedgehog (Shh) signaling
The Shh signaling pathway is crucial for proper embryonic development as it governs tissue polarity, patterning maintenance, cellular proliferation, intercellular communication, and differentiation [44, 45]. Persistent Shh pathway signaling has been observed in the subventricular zone of adult brain where it plays a critical role in regional specification and maintenance of NSCs [46]. Aberrant regulation of the Shh pathway due to mutation has been identified to cause tumorigenesis in a wide variety of cancer tissues including gliomas and GSCs. This pathway is highly active in GSCs where it regulates stemness genes and thus maintains self-renewal of GSC and promotes tumorigenesis and inhibition of Shh signaling reduces both stemness as well as
5. Pathways that contributing to resistance of glioma stem cells toward therapies that lead to tumor regrowth
Resistance of CSCs toward therapies resulting in their enrichment and regrowth of tumor due to proliferation of these cells has been suggested by various researchers [48, 49, 50]. In HGG, despite the effectiveness of TMZ in removing the bulk tumor cells, regrowth with a more aggressive phenotype is inevitable, and researchers have identified critical role of CSCs in such regrowth. For instance, in HGG, treatment with therapeutic doses of temozolomide (TMZ) leads to expansion of GSCs pool in both patient-derived and established glioma cell lines. Such expansions are reported not only due to enrichment and proliferation of existing CSCs but also due to interconversion between differentiated tumor cells and GSCs [18]. Similarly, bevacizumab (VEGF antibody) although reduces GBM tumor growth, it is followed by tumor regrowth where the role of autocrine signaling through the VEGF-VEGFR2-Neuropilin-1 (NRP1) axis leads to enrichment of active VEGFR2 GSC subset in human GBM cells [51]. It is evident that the therapeutics evoke enrichment of CSCs involving multiple mechanisms. Thus, understanding various ways by which CSCs escape the radio- and chemotherapy, more effective treatment modalities can be developed. Broadly, in CSCs various different mechanism such as epithelial-mesenchymal transition (EMT), multiple drug resistance (MDR) dormancy, tumor environment contribute to resistance toward therapeutics and other adverse conditions faced by them in tumor microenvironment and are discussed as follows.
5.1 DNA repair systems
GSCs possess better DNA repair capacity as compared with bulk tumor cells [52]. These cells express higher levels of DNA repair enzymes such as O6-methylguanine-methyltransferase (MGMT), which are responsible for therapy resistance against DNA alkylating agents such as TMZ [53, 54, 55, 56]. However, there are contradictory studies that also suggest that TMZ resistance in GSCs is independent of MGMT status and alternate pathways might be involved [57, 58]. Further, preferential expression of DNA checkpoint kinases 1 (Chk1) and 2 (Chk2) lead to more efficient repair of DNA damage in CD133-positive glioma cells than CD133-negative glioma cells [54]. Other transcriptional regulators such as BMI, DNA-PK, poly (ADP-ribose) polymerase-1, hnRNP U, and histone H1, which play a role in DNA double-strand break repair, are highly expressed in CD133-positive GBM cells and play pivotal role in GSCs’ functions [59, 60].
5.2 Epithelial-mesenchymal transition (EMT)
EMT involves phenotypic changes in cells from epithelial to mesenchymal type involving high expression of markers such as N-cadherin and vimentin under various physiological as well as pathological conditions including cancer [61]. Interestingly, CSCs also share the EMT-like cell features [62], and it is believed that the link between EMT and CSCs might be responsible for cancer drug resistance acquisition and plasticity resulting in cancer cells transformation into the malignant cells and
5.3 Dormancy of CSCs
As the understanding of CSC biology has improved, it has been identified that CSCs can exist in proliferative or dormant state. Dormant CSCs maintain a low metabolic activity, however, show similarities with the normal proliferative counterpart in terms of stemness and other signaling pathways. For instance, dormant stem cells are low in metabolic activity that preferentially utilize the glycolytic pathway and produce low levels of levels of reactive oxygen species (ROS) [68]. However, these dormant/quiescent cells demonstrate high plasticity and can be reactivated to reenter proliferative stage and lead to tumor formation. Such dormant cells are also chemoresistant due to their dormant nature; interestingly, proliferative CSC can also enter dormancy in response to chemotherapeutics agents. In GBM, existence of a relatively quiescent subset of GSCs has been observed, which is responsible for maintaining the long-term tumor growth and responsible for recurrence by entering into highly proliferative cells upon receiving proper signals [69].
5.4 Anti-apoptosis
Various anti-apoptotic protein such as B-cell lymphoma-2 (BCL-2), BCL2 like 1 (BCL2L1), myeloid cell leukemia-1, MCL1 and BCL-xL are highly expressed in GSCs than differentiated bulk tumor cells. These proteins not only play role in GSCs maintenance but also provide survival advantage to these cells against various chemotherapeutic agents [70]. Other mediator of GSCs resistance includes BMI1, a GSC-enriched protein that inhibits p53-mediated apoptosis against TMZ [71]. Inhibition of such anti-apoptotic pathways can increase sensitivity of GSCs against different therapeutic agents.
5.5 Multidrug resistance
Stem cells express higher levels of several ATP-binding cassette (ABC) transporters resulting in efflux ability for various antineoplastic drugs [72]. In GSCs, increased
5.6 Metabolism
GSCs show metabolic adaptations to survive adverse conditions of tumor microenvironment that includes low pH, hypoxia, and low nutrient supply; at the same time they proliferate at a high rate to maintain their stemness [16, 17]. Majority of GSCs rely on glucose uptake via high-affinity glucose transporter 3 (GLUT3) to provide carbon source for nucleotide biosynthesis for rapid proliferating cells along with high energy demands [78, 79, 80]. These cells also highly express glutamine synthetase as compared with differentiated glioma cells for higher glutamine uptake, which acts as preferential source for
5.7 Autophagy
Autophagy is a catabolic pathway which is a cellular stress response under physiological as well as pathological conditions. This pathways acts by removal of damaged macromolecules such as proteins, nucleic acid, and lipids and recycles them for cellular processes and thus promotes cell survival; however, defect or dysregulation of such pathway may lead to cell death [84]. Role of autophagy is well established in a variety of cancers including GBM where it can play a role in cell survival or cell death [84, 85]. Autophagy also contributes to the maintenance of stemness characteristics of GSCs as well as provides chemoresistance to CSC against therapeutic agents [19, 86]. Inhibition of autophagy sensitizes GSCs towards a variety of therapeutic agents [19, 87, 88, 89]. Interestingly, other studies demonstrated that induction of autophagy by mammalian target of rapamycin (mTOR) inhibitors as well as curcumin-induced autophagy shows anti proliferative effect, induces differentiation and also improves sensitivity of GSC towards DNA damaging agents [90, 91, 92]. Together, these results suggest that GSCs require a balanced level of autophagy, too much or too little can significantly affect their stemness potential and resistance toward therapeutics. Further, role of autophagy has also been shown to support motility/migration capacity of GSCs [93]. However, role of autophagy in suppression of the self-renewal ability and tumorigenicity of GSCs has also been demonstrated where autophagy mediates Notch1 degradation [94]. Thus, role of autophagy in GSCs is crucial for maintenance of stemness as well as chemotherapeutic agents; targeting such pathway appears as a p These cells also highly express glutamine synthetase otential strategy to make the existing treatment more effective.
5.8 Extrinsic chemoresistance
Besides the signaling pathways and genetic signature of GSCs, extracellular environment also called as microenvironment in which these cells resides also plays crucial role in its functions and determines response towards therapeutic agents [95]. It has been identified that GSCs reside in inner tumor mass where rapid growth and high energy requirement of these cells along with neovasculature result in hypoxic conditions as well as low pH [29, 96]. These adverse conditions further promote expression of GSC markers and associated phenotype [97]. Various hypoxia and acidic pH-induced genes such as hypoxia-inducible factor (HIF) 1 and 2alpha and vascular endothelial growth factor (VEGF) are highly expressed in GSCs that contribute to GSC functions [98, 99]. It has been shown that in GSCs Notch signaling and MGMT expression are also regulated by HIF-1α, resulting in GSC stemness and also resistance toward TMZ [100, 101]. Further, hypoxic GSCs release extracellular vesicles that deliver HIF-1α induced miR-30b-3p that further activates STAT3 pathway and promotes TMZ resistance [102]. Further, it has been identified that TMZ increases the GSC pool in non-GSC subpopulations, indicating that non-GSC shows plasticity and can be converted to GSCs that might be responsible for resistance as well as regrowth of the tumor [18, 19]. Together, these findings suggest that
5.9 Role of Notch and sonic hedgehog pathways in mediating chemoresistance
Various signaling pathways such as Notch and SHH are active in GSCs compared with bulk tumor cells [103]. Further, in response to TMZ treatment of GSCs from primary GBM cells resulted in upregulation of
6. Strategies targeting glioma stem cells
Despite extensive research in oncology, the target is being missed leading to recurrence in a variety of high-grade tumors including malignant gliomas. With advancement in understanding of GSCs and its capacity of initiation, progression, resistance as well as recurrence of tumor, they appear as most promising target to treat cancers such as HGG. The drugs that can target GSC are being developed using multiple strategist including molecular targeting, autophagy inhibition, drug repositioning, and indirect targeting of GSC niches [17, 21, 106].
6.1 Targeting GSC markers and related signaling pathways
GSCs are regulated by various pathways involving differential expression of epidermal growth factor receptor (EGFR), Notch1, sonic hedgehog (Shh), and STAT3, as well as related signaling pathways.
As discussed earlier, CD133 is the most well-characterized cell surface marker for GSCs, which has become a potential target for antibody-based therapy. Different immunotherapeutic approaches such use of synthetic monoclonal antibody, dual-antigen T cell engager, and chimeric antigen receptor (CAR) T cell have been utilized to target CD133+ GSCs. RW03 (anti-CD133 antibody) targets self-renewal ability of GSCs without effecting its proliferative capacity and could be a promising strategy in targeting GSCs [107]. Further, photothermal therapy has also shown selective efficacy in diminishing CD133-positive cells both
EGFR, a receptor tyrosine kinase, which is highly expressed in GSCs, is crucial for its survival, self-renewal, and tumorigenicity. Of importance, EGFR variant III (EGFRvIII) mutation is most commonly detectable (25–33%) in GBM cases [109]. Thus, EGFR inhibition becomes a potential target to inhibit GSCs proliferation, self-renewal, and induction of apoptosis [110]. EGFR inhibition in fact enhanced chemo- and radio-sensitivity of human glioma CSCs. Various reversible and irreversible inhibits of EGFR are available that can bind EGFR alone or along with its co-receptor HER2 [111, 112]. First-generation EGFR TKIs include gefitinib and erlotinib that can reversibly bind EGFR along with HER2; however, less than 20% of patients presented a response to these treatments [112, 113]. Irreversible inhibitor of EGFR, osimertinib, has shown efficiency in crossing the blood-brain barrier (BBB) and significantly inhibits GBM tumorigenesis
Various signaling pathways such as Notch and SHH are active in GSCs compared with bulk tumor cells [114]. Further, in response to TMZ treatment of GSCs from primary GBM cells resulted in upregulation of
Shh/Gli signaling that regulates GSCs cell proliferation, stem cell fate determination, and differentiation has also appeared as potential target for GSCs therapeutics [124]. Inhibition of hedgehog pathway by LDE225 induces autophagic cell death in GSCs with higher sensitivity of CD133-positive cells than CD133-negative cells [125]. LDE225 inhibits expression and nuclear translocation of Gli proteins, a transcriptional effectors of the Shh signaling pathway [126]. Casein kinase 2 (CK2) is another target to inhibit Shh/Gli signaling via transcriptional activation of β-catenin [127] and inhibition of CK2 by, CX-4945 (silmitasertib), reduces MGMT expression and sensitized tumor cells to TMZ [128].
Signal transducer and activator of transcription 3 (STAT3) that regulates multiple processes such as cell cycle and survival, regulation, immune response, and differentiation, tumorigenic transformation has also been implicated in GSC maintenance [129, 130]. Resveratrol (RV), a polyphenol present in grapes, a tumor preventive agent targets STAT3 signaling. In glioma, RV has shown antineoplastic actions by apoptosis induction and improving radio sensitivity of GSCs CD133+ cell population along with reducing of tumorigenic potential. Furthermore, RV also modulates Wnt signaling pathway and EMT activators, thereby regulating stemness of GSCs and reducing cellular motility [131, 132]. Another molecule that inhibits STAT pathway is WP1066, which is an analog of the natural product caffeic acid benzyl ester and targets GSCs. This molecule has shown promising results in clinical trial for patients with recurrent malignant glioma [133]. Other STAT3 inhibitors, STX-0119 and WP1066 have shown ability to suppress GSC proliferation
6.2 Targeting tumor microenvironment
GSCs are localized in specific niches, which have been identified as protective microenvironments in GBM. Five types of GSC niches have been identified where different cell types exists and have specific singling pathways: peri-vascular, peri-arteriolar, peri-hypoxic, peri-immune, and extracellular matrix out of which peri-vascular niche is the most frequently described GSC [135]. GSC microenvironment lacks organizations and has compromised BBB, higher levels of hypoxia, and excessive angiogenesis making it a target for anti-angiogenic therapy [136, 137].
6.3 Drugs targeting metabolic pathways
Drug repositioning also called as repurpose drugs is a growing concept that explores pre-existing a well-established drug to treat diseases aside from the intended ones. This concept results in lowering the overall developmental cost, time and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities [138]. In case of GSCs, repurpose drugs are being tested and have shown encouraging results. Especially, anti-diabetes drugs have been most well studied with promising results in GSCs targeting. Metformin, successfully used for type 2 diabetes mellitus, has entered phase I clinical trial for GBM in combination with TMZ [139]. Metformin preferentially acts in GSCs by inhibiting Akt activation and also induces conversion on GSCs to non-GSCs [140, 141]. Similarly glimepiride, another anti-diabetes drug, impairs GSCs by targeting glycolytic flux and increases its radio sensitivity to GBM [142]. Further, more repurpose drugs need to be identified that can effectively target GSCs along with its associated mechanism before it can be used in clinical application [138].
6.4 Targeting autophagy pathways
Autophagy is a cellular stress response, which can either promote survival or cell death. Our laboratory along with others has identified that autophagy is required for maintenance of GSCs and also plays a role in resistance of GSCs toward chemotherapy [19, 142, 143]. Targeting autophagy by commonly used agent chloroquine (CQ), which blocks the fusion of autophagosomes with lysosomes, has been shown to inhibit GSCs as well as sensitized them toward chemotherapeutic agents [19, 144]. This drug has also entered multiple clinical trials as an adjuvant treatment for GBM; where its antitumor effects of CQ are not limited to GSCs [145]. Further, combination of autophagy inhibitors with radiation effectively induced apoptosis and inhibited tumorosphere formation in GSCs [146, 147]. More selective autophagy inhibitor NSC185058, antagonist of autophagy-related 4B, inhibits tumorigenic potential of GSCs and enhances GBM sensitivity to radiotherapy in xenograft mouse models [148].
7. Conclusions and future directions
Treatment of HGG remains challenging. With identification of GSCs and their properties to resist treatment and repopulate the original tumor, a big momentum has been created in the development of novel therapeutics. Such therapeutic will involve a combination of drugs that controls the bulk tumor mass along with CSCs-directed agents. It has been identified that GSCs are responsible for tumorigenesis, therapeutic resistance, and tumor recurrence, and thus GSC-targeting drugs are being developed for improvement of treatment regime. These GSCs can survive cancer treatment by activating multiple mechanisms such as EMT, signaling pathways to regulate self-renewal, its interaction with tumor microenvironment, higher expression of drug transporters or detoxification proteins, plasticity, autophagy induction, anti-apoptotic mechanism, induction of dormant phenotype, and many others to overcome the toxic effects of therapeutics. With knowledge of these pathways, anticancer therapeutics are targeted against GSCs, which includes directing specific and pathways that regulate GSCs and protect them from therapeutic stress. Such GSC-directed drugs can be combined with agents that are currently in use to achieve better survival rates of cancer patients.
Identification of bioactive products and their molecular mechanisms that can modulate GSCs needs to be incorporated in treatment regime of HGG patients. With recent advancements in the field of high-throughput screening and genetic and epigenetic signatures, specific targeted drugs that can target bulk tumor with minimal generation of induced GSCs along with combination of drug that can target GSCs can be developed. Furthermore, tumor microenvironment that significantly regulates GSCs is also a potential target to prevent rate of dedifferentiation. It is important to consider that current therapeutic can result in conversion of non-GSC to GSCs; therefore, newer drugs or combinations need to be developed that can prevent this detrimental conversion. More stringent strategies involving GSC-targeted therapy along with glioma molecular subtypes need to be designed for selective and effective clinical trials.
However, most therapeutic agents have failed to be approved for clinical application or during clinical trials due to lack of understanding of the underlying mechanisms or failure to consider individual characteristics of the tumor. Further investigation of the molecular pathways that drive GSCs and make them resistant to therapies along with subtype-specific pathways of GSCs is required. Such studies will significantly improve not only the understanding of disease but will also direct the development of highly specific drugs with minimal side effects along with improved patient outcome.
Acknowledgments
The authors would like to acknowledge the funding support from Department of Biotechnology Bio-CARe grant, Govt. of India (BT/P19357/BIC/101/927/2016 to M.T.) and Intramural Research Grant by SGPGIMS (PGI/DIR/RC/36/2021) to LKS.
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