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An Emerging Cancer Stem Cell Target Domrachev B, Singh S, Li D, Rudloff U. Mini-Review: PDPK1 (3-phosphoinositide dependent protein kinase-1), An Emerging Cancer Stem Cell Target. J Cancer Treatment Diagn.(2021);5(1):30-35 Journal of Cancer Treatment and Diagnosis Mini Review Open Access Mini-Review: PDPK1 (3-phosphoinositide dependent protein kinase-1), An Emerging Cancer Stem Cell Target Bogdan Domrachev1, Sitanshu Singh1, Dandan Li2, Udo Rudloff1,2* 1Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 2Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA Article Info ABSTRACT Article Notes Cancer stem cells (CSCs) are subpopulations of tumor cells that possess Received: February 24, 2021 abilities for self-renewal, differentiation, and tumor initiation. These rare Accepted: April 12, 2021 but therapy-recalcitrant cells are assumed to repopulate tumors following *Correspondence: administration of systemic chemotherapy driving therapy failure, tumor *Correspondence to: Dr. Udo Rudloff, MD PhD, Investigator, recurrence, and disease progression. In early clinical trials, anti-CSC therapies Rare Tumor Initiative Pediatric Oncology Branch, NCI Hatfield have found limited success to-date possibly due to the inherent heterogeneity Center, Center for Cancer Research – 2B-34D, 10 Center Drive, and plasticity of CSCs and the incomplete characterization of essential CSC Bethesda, MD 20892-0001, USA; Telephone No: 240-760-6238; targets. Here, we review the role of 3-phosphoinositide dependent protein E-mail: [email protected]. kinase-1 (PDPK1) as an emerging CSC target. While most previous studies have © 2021 Rudloff U. This article is distributed under the terms of relied on CSC models which are based on lineage and tissue-specific marker the Creative Commons Attribution 4.0 International License. profiles to define the relationships between putative target and CSC traits, this review discusses PDPK1 and its role in CSC biology with an emphasis on CSC systems which are based on proposed function like label-retaining cancer cells (LRCCs). Keywords: Cancer Stem Cells 3-Phosphoinositide Dependent Protein Kinase-1 The cancer stem cell (CSC) hypothesis Label Retaining Cancer Cells Drug Resistance The near universal development of resistance to systemic Chemotherapy cytotoxic chemotherapy has been a stubbornly incalcitrant problem in oncology for decades. Commonly, after an initial period of tumor cancers experience disease progression, detoriation of their quality ofregression life, and succumband disease to their control illness patients1. Thus, theafflicted introduction by advanced of the CSC hypothesis, which provided a fundamentally novel explanation for the commonly observed treatment failures and raised prospects to overcome therapy resistance via novel therapy approaches, was greeted with great interest2. within hematological malignancies at the Princess Margaret CancerThree Centre decades in Toronto,ago, the Canadaidentification3,4, and of from tumor-initiating breast cancer cells by Clark and colleagues thereafter5, suggested a hierarchical model of carcinogenesis6. Contrary to the clonal evolution model which suggests stochastic cancer cell divisions resulting in biologically equivalent cancer cells in each daughter cell generation, the CSC theory holds that (1) cancer arises from cells with dysregulated heterogeneous mass of cells which include a small fraction of self-renewal mechanisms, and (2) cancer is comprised of a these cells are functionally distinct from the bulk, differentiated cancerstem-like cells progenitor2,7,8. While cellsthe exactthat driveorigin tumor of the progression,CSC remains anddebated that with experimental research supporting both CSCs arising via malignant transformation from normal stem cells as well as via Page 30 of 35 Domrachev B, Singh S, Li D, Rudloff U. Mini-Review: PDPK1 (3-phosphoinositide dependent protein kinase-1), An Emerging Cancer Stem Cell Target. J Cancer Treatment Journal of Cancer Treatment and Diagnosis Diagn.(2021);5(1):30-35 9,10, the concept of CSCs adapting their phenotype under chemotherapy pressure is does explain the inherent heterogeneity of tumors and the intriguingly also discussed in the origin and initial emerge commonlyde-differentiation observed of cancerresistance cells to chemoradiotherapy2,11 of CSCs20 is drug resistant. Recent duefindings to the show induction that therapeutic of EMT factors pressure and chemotherapyFailure to eradicate treatment thesewith newself-renewing, cancer cells fromresistant this can induce in non-CSCs a transient, stem-like state which poolcells ofleads cells andto repopulationis cause for tumor of residual recurrence tumors (Fig. 1A)post-12. revert to their original phenotype upon withdrawal of However, accepting an exclusively hierarchical model to chemotherapyother CSC traits. underscoring These therapy-induced the dynamic natureCSC-like of theircells capture cancer pathogenesis is at odds with several clinical adaptive mechanisms in response to cancer therapy. burden reduction due to the assumed chemosensitivity of Intratumoral CSC heterogeneity findings: for most cancers, the concept of effective tumor CSC heterogeneity is, in large, also the result of the the clinic as tumor, in particular solid organ malignancies, complex dynamic interplay and interdependence between notthe bulkuncommonly non-CSC tumordo not cell regress population at all is uponnot observed treatment in CSCs and surrounding stromal milieu forming the CSC with systemic chemotherapy1 niche. One of the best investigated CSC niche–CSC interface are adaptations of CSCs residing in hypoxic areas21. tumor cell progeny does not apply. The when concept tumor of recurrencetreatment- Hypoxic, poorly perfused areas of solid organ cancers are occursescaping very CSCs, rapidly, self-renewal or when and cancer repopulating treatment proliferating accelerates most heavily populated with CSCs. Within these hypoxic tumor growth. The hierarchical model works best in clinical scenarios which initially see a reduction in tumor like tumor associated macrophages, suppressing dendritic burden and then, after a latency period, tumors recur. andniches cytotoxic CSCs create T acell unique function, environment upregulate by attracting inhibitory M2- 21,22. CSC Mechanisms of cancer stem cell therapy resistance – inherent versus acquired? immune checkpoints or pro-angiogenic signals ratesresiding and in shapeperi-vascular vascularization regions onand the ECM other formation hand find23. patients’ tumoral biopsies support that CSCs are inherently, CSCsa nutrient-rich within the invasiveenvironment, front ofhave tumors higher have proliferativeupregulated a prioriA plethora, resistant of into vitro,chemoradiotherapy in vivo as well8,14 .as Inherent findings CSC in migratory and invasive capabilities, and the overlap with characteristics mediating resistance to chemoradiotherapy include upregulation of DNA damage repair mechanism programs essential for metastasis like21 e.g. the CXCR4/ on multiple levels including upregulation of G1/M and in the metastatic spread of cancers . Overall, while the CXLX12 axis suggests these cells to be causally involved G2 dynamic interplay of CSCs with nearly all stromal elements /S checkpoints, efficient scavenging of reactive oxygen ECM‘niche components,concept’ is a simplificationit provides functionalof the very rationalecomplex andfor species (ROS), increased drug efflux via upregulation of the phenotypic differences and heterogeneity observed ATP-binding cassettes and8 other drug transporters, or L . Conventional chemotherapies areupregulation most effective of pro-survival, in rapidly anti-apoptosisproliferating cellsregulators going they become major educators of their microenvironment. frequentlylike Bcl-2 throughor Bcl-X S phase. CSCs on the other hand are Reciprocally,among CSCs. Asthese CSCs educated need to stromal find their cells niches, signal vice back versa, and known to be quiescent cells which have left the cell cycle and thus escape the genotoxic effect of many currently therapy resistance21. employed chemotherapy agents15,16. Additionally, CSCs impact CSC traits like CSC quiescence, self-renewal, or It is also likely that cancer stem cells are coming in can effectively sense chemotherapy agents as xenobiotics and out of the CSC pools increasing heterogeneity and and through activation of ALDH1A1 or ALDH3A1 enzymes pleiotropism of CSC traits within tumors further9. In which effectively can metabolize chemotherapy agents17. this regard, targeting rare, infrequent CSC populations However, CSCs are also able to acquire under therapy pressure novel therapy resistance traits18. Following on such markers to capture CSC populations mediating short courses of chemotherapy the fraction of CSCs to chemotherapydefined by CSC resistance surface markersmight have and led an to overreliance the largely 14 dramatically 7 non-CSC tumoral bulk cells has been shown to change far . Thus, there has been a renewed refocus on preclinical CSCdisappointing models with early improved clinical recapitulationresults of anti-CSC of tumoral therapy stem so acquired a more. Comparing aggressive CSCs phenotype between chemotherapy-manifested by naïve versus chemotherapy-resistant conditions, CSCs cell biology, like LRCCs, which are less biased by culture conditions, cell lineage markers, or results derived from immune compromised mouse models9. theseupregulation stemness of regulatorsthe
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