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Iacono, M.L.;  Gaggianesi, M.;  Bianca, P.;  Brancato, O.R.;  Muratore, G.;  Modica, C.;  Roozafzay, N.;  Shams, K.;  Colarossi, L.;  Colarossi, C.; et al. CSCs is The Main Players in Drug Resistance. Encyclopedia. Available online: https://encyclopedia.pub/entry/38817 (accessed on 04 July 2024).
Iacono ML,  Gaggianesi M,  Bianca P,  Brancato OR,  Muratore G,  Modica C, et al. CSCs is The Main Players in Drug Resistance. Encyclopedia. Available at: https://encyclopedia.pub/entry/38817. Accessed July 04, 2024.
Iacono, Melania Lo, Miriam Gaggianesi, Paola Bianca, Ornella Roberta Brancato, Giampaolo Muratore, Chiara Modica, Narges Roozafzay, Kimiya Shams, Lorenzo Colarossi, Cristina Colarossi, et al. "CSCs is The Main Players in Drug Resistance" Encyclopedia, https://encyclopedia.pub/entry/38817 (accessed July 04, 2024).
Iacono, M.L.,  Gaggianesi, M.,  Bianca, P.,  Brancato, O.R.,  Muratore, G.,  Modica, C.,  Roozafzay, N.,  Shams, K.,  Colarossi, L.,  Colarossi, C.,  Memeo, L.,  Turdo, A.,  Veschi, V.,  Franco, S.D.,  Todaro, M., & Stassi, G. (2022, December 15). CSCs is The Main Players in Drug Resistance. In Encyclopedia. https://encyclopedia.pub/entry/38817
Iacono, Melania Lo, et al. "CSCs is The Main Players in Drug Resistance." Encyclopedia. Web. 15 December, 2022.
CSCs is The Main Players in Drug Resistance
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This entry is adapted from the peer-reviewed paper 10.3390/jcm11236996

Drug resistance is doubtless the main challenge of treatment in cancer patients. It is possible to distinguish two categories of drug resistance: intrinsic resistance and acquired resistance after drug treatment. Compelling evidence highlights that intratumoral heterogeneity is one of the major hurdles involved in intrinsic drug resistance, in which the cancer stem cells (CSCs) represent the main players due to their self-renewal and differentiation abilities. 

natural products cancer stem cells drug resistance alkaloids

1. Introduction

Despite prominent advances in the field of cancer prevention and early diagnosis, it is expected that one in five people will develop cancer during their lifespan. One of the greatest challenges in translational oncology is limiting the onset of primary or acquired drug resistance, which is boosted by cancer stem cells (CSCs). CSCs represent a pluripotent heterogeneous population within tumor bulk, with self-renewal and differentiation abilities, contributing to the failure of conventional therapies and, therefore, to disease relapse and metastasis [1]. Increasing evidence points out that different natural products (NPs) can modulate the CSCs’ hallmarks and sensitize them to conventional treatment [2]. NPs show minimal side effects in comparison with chemotherapeutics, and many studies have demonstrated their emerging role as adjuvant agents in cancer treatment.

2. Cancer Stem Cells: The Main Players in Drug Resistance

Drug resistance is doubtless the main challenge of treatment in cancer patients. It is possible to distinguish two categories of drug resistance: intrinsic resistance and acquired resistance after drug treatment [3]. Compelling evidence highlights that intratumoral heterogeneity is one of the major hurdles involved in intrinsic drug resistance, in which the CSCs represent the main players due to their self-renewal and differentiation abilities [4][5]. The presence of CSCs has been characterized in different tumors, such as thyroid, colorectal, breast, prostate, and other solid tumors [6][7]. CSCs are identified and can be isolated by the expression of specific surface markers such as CD133 [8], CD44 [9], CD44v6 [10], EpCAM [11], or enzyme activity such as aldehyde dehydrogenase (ALDH) [12]. CSCs are also defined as tumor-initiating cells, as they can generate tumor xenografts in immunocompromised mice models [13]. Moreover, the failure of conventional therapies, based on the use of radiotherapy and chemotherapy to induce DNA damage in highly proliferative cells and to eradicate tumor mass, is strictly due to the presence of CSCs, which are characterized by multiple survival mechanisms [14]. In particular, the mechanisms through which CSCs escape chemotherapeutic treatments are different, such as i) drug export (the aberrant expression of ATP-binding cassette, ABC, drug pumps); ii) high survival (the inhibition of antiapoptotic processes, the high expression of proteins involved in DNA-damage repair, high telomerase activity); iii) reactive oxygen species (ROS) decrease (high ALDH activity, high expression of detoxification enzymes);and iv) the aberrant activation of pathways involved in stemness [15][16].

2.1. Drug Export in CSCs

It is common knowledge that the high expression of ABC proteins contributes to chemotherapy resistance and that CSCs overexpress different drug-transporter pumps, including ABCB1, ABCG2, and ABCC1 [15][17]. The Hoechst 33342 side population assay is a useful method to identify and isolate the CSC subpopulation in solid and hematopoietic tumors [18]. Yin et al. reported that CD133+ EPCAM+ liver CSCs express high levels of ABCG2 and ABCB1 and are highly resistant to doxorubicin treatment. The use of specific ABC inhibitors increases doxorubicin intracellular efflux, decreasing the sphere-forming capacity and viability of CSCs [19]. Other ABC transporters, including multidrug resistance protein 1 (MRP1, ABCC1), breast cancer resistance protein (BCRP), and MRP5/ABCC5, are reported as multidrug resistance transporters in solid and hematopoietic tumors [20][21][22]. Moreover, CD133+ melanoma CSCs expressed higher levels of ABCB5 compared to CD113− cells and are resistant to the antiapoptotic activity of the natural compound caffeic acid phenethyl ester [23]. In the lung, the high expression levels of ABCB1 in CSCs mediated the resistance to PHA-665752 and crizotinib, a MET inhibitor [24]. Although the targeting of ABC transporters could be an effective strategy to target CSCs, the use of specific inhibitors causes many side effects, due to the expression of the same targets in normal cells, as well [24].

2.2. Enhanced Survival Ability in CSCs

CSCs can also circumvent the toxic effects induced by chemotherapeutic treatment activating DNA damage response (DDR) by the ATM(ataxia-telangiectasia-mutated)- and ATR (ATM- and RAD3-related)-dependent phosphorylation of targets such as Check-1, Check-2, or H2A.X (known as γH2A.X when phosphorylated) [25]. Manic and co-workers demonstrated that in colorectal CSCs the treatment with chemotherapeutic agents induces the activation of the DDR players, such as PARP1, RAD51, and/or MRE11, resulting in higher DNA damage repair machinery [26]. In breast cancer, both BRCA1wt and BRCA1mut CSCs were highly resistant to PARP inhibitors, due to the high expression of Rad51 and Sam68, and the inhibition of this critical signaling axis hampered CSC viability [27][28]. In addition, CD133+ glioma CSCs displayed resistance to radiotherapy treatment by the activation of DNA-damage repair mechanisms, where Check-1 and Check-2 are the main players. The inhibition of these two effectors reverted the radioresistance in glioma-CSCs, suggesting that targeting DNA damage could be a promising therapeutic approach for brain cancer treatment [29].
The deregulation of apoptotic pathways is another mechanism underlying CSC-mediated chemoresistance. A weak expression of death receptors, such as TRAIL and FAS, and the overexpression of inhibitor apoptosis proteins (IAPs) have been described in CSCs compared to differentiated tumor cells [6][30]. In CSCs, IAPs are often overexpressed and impair the activation of the apoptosis cascade by mediating pro-apoptotic protein degradation [31]. CD133+ colorectal CSCs highly resistant to 5-fluorouracil (5-FU) treatment expressed high levels of SURVIVIN, and the use of a specific aptamer-SURVIVIN siRNA enhanced the in vitro and in vivo 5-FU efficacy [32][33]. Moreover, in nasopharyngeal CSCs, XIAPs increased the stability of SOX2, and the use of an inhibitor of the IAP family in combination with 5-FU impaired tumor growth [34]. It has been reported that an aberrant expression of BCL-2 family members in CSCs contributes to drug resistance [20][35]. BCL-2 is overexpressed in leukemia stem cells and the use of a specific inhibitor of BCL-2, venetoclax, combined with azacitidine, resulted in disease remission in acute myeloid leukemia by CSC targeting [36][37]. In gastro-esophageal cancers, the use of the small molecule AT-101, which inhibits the BCL-2 family, decreased the expression of CSC markers (YAP1/SOX9) [38] (NCT00561197).
One of the effects of radiotherapy is the induction of DNA damage through the production of ROS and water-derived radicals. In CSCs, the presence of ROS is dramatically reduced due to the increase in ROS scavengers, limiting apoptosis induction and DDR mechanism activation [39]. The CSCs can also escape from anticancer therapies by increasing aldehyde dehydrogenase (ALDH) activity, which acts by reducing intracellular ROS levels. In turn, ROS generated from radio- and chemotherapy enhance the cytosolic expression of aldehydes, such as ALDH1A and 3A1 [40]. High levels of drug-metabolizing enzymes, such as ALDH1a1 and bleomycin hydrolase (BLMH1), have been characterized in the secretome of colorectal CSCs, increasing chemoresistance [41]. Moreover, several studies have pointed out that CSCs isolated from different tumor types display high ALDH expression levels and activity, which boost their chemoresistance [12][42]. Therefore, the upregulation of ROS levels could be an efficient strategy to counteract CSC features and sensitize CSCs to treatments.

2.3. Stemness Induction in CSCs by Different Signaling Pathways

Several signaling pathways, among which are Notch, Sonic-Hedgehog (SHH), Wnt/β-catenin, PI3K/Akt/mTOR (mTORC1 and mTORC2), TGF-β, JACK/STAT, and Hippo-YAP/TAZ, are aberrantly activated or deregulated in CSCs compared to normal stem cells [43].
The Wnt signaling pathway plays a key role during embryogenesis, and in many cancers, such as breast, colorectal, thyroid, and esophageal cancers, its activation promotes CSC growth and chemoresistance [43][44]. It has been demonstrated that the Wnt pathway is crucial for the maintenance of intestinal crypt homeostasis, and the APC mutation in transgenic mice increased the presence of LGR5+ stem cells at the bottom of crypts, boosting the transformation in microadenoma [45]. Vermeulen et al. demonstrated that the Wnt pathway is highly activated in CD133+ colorectal CSCs and can be influenced by extrinsic factors secreted by TME cells [46]. In hepatocellular carcinoma, the activation of the Wnt signaling pathway, induced by protein tyrosine kinase-2 (PTK2), boosted CSC tumorigenic potential and contributed to sorafenib resistance [47]. In endometrial CSCs, Lu and co-workers showed that SPARC-related modular calcium binding 2 (SMOC-2) interacts with Fzd6 and LRP6 (LDL-receptor-related protein 6) receptors and activates the Wnt/β-catenin pathway, increasing cisplatin and placlitaxel resistance [48].
The SHH signaling pathway is involved in normal embryogenesis development and plays a key role in the promotion of tumor growth and in drug resistance, upregulating the genes involved in CSC maintenance, such as CD44, CCND2, c-MYC, NANOG, OCT4, and ALDH1 [49][50]. The SHH signaling pathway is involved in chemoresistance mechanisms by the modulation of the ABCG2 transporter and ALDH activity [51][52].
The dual TGF-β role in tumor progression has been extensively studied [53]. In fact, TGF-β is a key regulator of stemness, promoting EMT and radio-/chemoresistance [54][55]. Moreover, it has been shown that the cooperation of TGF-β with other signaling pathways increases CSC features. TGF-β and tumor necrosis factor alpha (TNF-α) induced a mesenchymal phenotype in breast CSCs by decreasing CLDN3-4-7 gene expression and, in turn, increasing in vivo tumorigenesis and resistance to oxaliplatin, etoposide, and paclitaxel [56]. In leukemia stem cells, TGF-β regulated the activation of AKT and induced FOXO3a nuclear localization, boosting sphere-forming ability and tumor growth [57].
In addition to the mechanisms described above, other intrinsic and extrinsic factors contribute to drug resistance in CSCs. Increasing evidence sheds new light on the role of epigenetic alterations in increasing intratumoral heterogeneity and in the failure of standard therapies [58]. Several molecular mechanisms, such as DNA methylation, chromatin remodeling, regulation by non-coding RNAs, and the modification of histone proteins, contribute to the aberrant expression of ABC transporters in solid and hematological tumors [1][59]. Furthermore, numerous studies point out that the crosstalk between CSCs and the tumor microenvironment (TME) influences the plasticity of CSCs, promoting drug resistance [6][60].
To overcome this challenge in cancer treatment, many researchers have focused on the development of therapeutic approaches targeting CSCs and the different mechanisms involved in drug resistance. In this regard, NPs could be considered eligible candidates.

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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Melania Lo Iacono
,
Miriam Gaggianesi
,
Paola Bianca
,
Ornella Roberta Brancato
,
Giampaolo Muratore
,
Chiara Modica
,
Narges Roozafzay
,
Kimiya Shams
,
Lorenzo Colarossi
,
Cristina Colarossi
,
Lorenzo Memeo
,
Alice Turdo
,
Veronica Veschi
,
Simone Di Franco
,
Matilde Todaro
,
Giorgio Stassi
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Revisions: 4 times (View History)
Update Date: 22 Dec 2022
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