Umbrella Review on Cancer Stem Cell in Oral and Head and Neck Squamous Cell Carcinoma

Abstract

Cancer stem cells (CSCs) are cells in a tumor which can begin to grow, develop, and induce resistance in the tumor. Recent studies have shown that as with mesenchymal stem cells, CSCs can also regenerate themselves and be involved in tumorigenesis. Recent advances in detection of biomarkers for identifying CSCs as well as development of new techniques for evaluating the tumorigenesis and carcinogenesis roles of CSCs have been considerable. In recent years, more systematic review papers have been published about CSCs and head and neck squamous cell carcinoma (HNSCC), highlighting the need to accumulate information and draw final conclusions from these studies.

Methods: This research protocol for review followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P) checklist. The protocol for this meta-analysis was registered on PROSPERO (International Prospective Register of Systematic Reviews) and the registration number is CRD42022301720.

Results: We identified 8 review articles about CSCs in HNSCCs.

Conclusions: This umbrella review provides a comprehensive summary of the body of published systematic reviews and reviews in CSCs and HNSCCs. There is strong evidence suggesting that targeting the cancer stem cells could lead to a more definitive response, since the cancer stem cells are the putative drivers of recurrence and metastatic spread in HNSCCs.

Introduction

Oral squamous cell carcinoma (SCC) is the most common head and neck squamous cell carcinoma (HNSCC), seriously threatening the life and quality of life of patients. Current statistics show that the incidence of oral SCC has not diminished considerably, and even nonsmokers and those who do not drink alcoholic beverages are also progressively prevalence^[1].

SCC occurs at about 600,000 new cases every year worldwide, and is responsible for 1-2% of all cancer-induced mortality ^[2]. The common sites of manifestation include lips, oral and nasal cavity, larynx, and pharynx. Local tumors can often be eliminated through surgery. Nevertheless, diagnosis of many tumors that are in the advanced stage, which particularly in combination with HPV-DNA^[3], lead to poor prognosis in spite of existence of multistage therapeutic options including surgery, radio- and chemotherapy. More than 50% of patients with HNSCC would experience metastasis or recurrence in an advanced localized manner, resulting in survival rate of shorter than 1 year^[4]. Particularly in these patients, biomarkers for predicting therapeutic responses, improving treatment selection, and provision of supervision on disease of early diagnosis of tumor relapse are essential. Early diagnosis should be facilitated for improving the patient’s outcome^{[5] [6]}.

Cancer stem cells (CSCs) are cells in a tumor which can begin to grow, develop, and induce resistance in the tumor. Recent studies have shown that as with mesenchymal stem cells, CSCs can also regenerate themselves and be involved in tumorigenesis. Some cell surface markers are often used for CSC detection including CD24, CD44, and CD133^[7].

CD24 is a sialoglycoprotein which is expressed across the surface of most B lymphocytes and differentiates neuroblasts. Also, it is expressed from the myelocyte stage from neutrophils and neutrophil precursors. The coded protein is attached to the cell surface through the glycosyl phosphatidylinositol (GPI) bond. This protein assists a wide range of downstream messaging networks, and is very important for neurological development^[7].

CD44 is an hyaluronan (HA)-bound glycoprotein onto the cell surface, which is overexpressed by almost all epithelial-originated tumors, and has a key role in the initiation and metastasis of tumor. CD44 is a convincing marker for CSCs of many solid malignancies. In addition, the interaction of HA and CD44 promotes EGFR-mediated pathways, thereby leading to growth to tumor cells, migration of tumor cells, and chemotherapeutic resistance in solid tumors. CD133 is a membrane transmission glycoprotein, which alone or in collaboration with other markers, has mostly been considered for CSC detection from many solid tumors^[7].

Since CSCs are responsible for carcinogenesis and tumorigenesis, and are involved in drug and radio resistance, metastasis, tumor relapse, and its initiation, targeting CSCs is considered a potential anti-cancer therapeutic strategy. Recent advances in detection of biomarkers for identifying CSCs as well as development of new techniques for evaluating the tumorigenesis and carcinogenesis roles of CSCs have been considerable^[8].

In recent years, more systematic review papers have been published in this area, highlighting the need to accumulate information and draw final conclusions from these studies.

Umbrella reviews have been developed for overcoming such a gap of knowledge. They are previously published systematic review or meta- analyses and include replication of meta-analyses, which through a uniform approach for all factors, provides the possibility of comparing them. Since several review studies have been done on the relationship between CSCs and HNSCC, we intended to conduct an umbrella review to collate and conclude the review studies^[9].

Methods

We will compare the published data of systematic reviews and reviews of diagnostic prognosis value of the Cancer Stem Cell for SCC. This research protocol will fully follow the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA- P) checklist. The protocol for this meta-analysis was registered on PROSPERO (International Prospective Register of Systematic Reviews) and the registration number is CRD42022301720. Ethics approval and patient consent are not required as this study is an overview based on published reviews.

2.1.1. Type of studies.

We will include reviews, which must include Review and systematic review and meet the participants, index tests, and outcomes of interest criteria described as follows.

2.1.2. Participants.

Study participants who diagnosed with SCC according to pathologic histology examination will be included. There are no limitations in age, race, nation, sex, and nationality of participates, as well as treatment plan and stage of cancer.

2.1.3. Index tests and 2.1.4. Outcome measures.

Any type of single stem cell marker or combined stem cell marker aimed at evaluating the diagnostic and prognostic value of cancer stem cells in oral and head and neck cancer is considered eligible.

2.1.5. Exclusion criteria.

The exclusion criteria were as follows: publications without complete data; protocols, conference abstracts, guidelines, consensus, documents or expert position papers, summaries, comments, letters, brief reports, and proceeding studies; and duplicated articles.

2.1.6. Inclusion criteria.

Review and systematic review In English language about cancer stem cell and oral and head and neck cancer. Data extraction would include the Author’s name, Country of origin, year of publication, number of reviewed studies and type and value of cancer stem cell in oral and head and neck cancer.

2.2. Search methods for identification of studies

The search for relevant review studies were conducted by authors. A systematic search was performed using PubMed, Embase, Web of Science, and Cochrane Library to identify relevant articles from inception to 2022. There were no limitations on the year of publication. The references of relevant articles were searched to identify additional potential studies.

2.3. Selection of studies

We managed all retrieved titles and abstracts with the reference manager software EndNote (Version X7, Thomson Reuters). Two authors independently screened the titles and the abstracts. If a title or abstract appeared to meet the eligibility criteria for inclusion in the review, or we could not determine eligibility, a full-text version of the article was obtained and assessed by 2 authors (MSM and MB) to determine whether it met the inclusion criteria. We resolved discordant evaluations by discussion to reach consensus.

2.4. Data extraction and management

A draft data extraction sheet will be developed using Microsoft Excel 2013 (Microsoft Corp, Redmond, WA, www.microsoft. com). Two reviewers will independently extract study characteristics from the included reviews including: author name, number of authors, publication year, journal name, country of the journal, and types of included studies, number of included studies, and number of participants, name of stem cell, results of statistical analysis including sensitivity, specificity, likelihood ratio, predictive value, DOR, and area under curve. If we find that multiple reviews are identified for the same research question but share the same primary study, the repeated and identical data that overlaps the original study will only be included once. For the updated original study, the most recent study will be selected for data extraction, and the old version will be used as supplemental information if needed. If diagnostic performance indices in each original study were not found, we will use the number of TP, FP, TN, FN to calculate sensitivity, specificity, and DOR. For missing or unclear data, we will contact the research author for access. The difference will be resolved by consensus. If there remains any discrepancy, the one auditor will make a consensus decision.

Results

We identified 8 review articles about CSCs in head ana neck SCCs. The characteristics of these studies are shown in Table 1.

Table 1. Table 1.

Main Results	Cancer Stem Cells	Type of Article	Journal	Site of SCC	Year of Publication	First Author	Title
Types of CSC markers in head and neck cancers include, Cell surface markers, Metabolic marker, Pluripotency markers, and Self-renewal pathways	CD44, CD133, CD10, ABCB5, ALDH1, BMI1, SOX2, OCT4, NANOG, SHH, NOTCH, EGFR, WNT	Review	Frontiers in Oral Health	HNC	2021	Shahoumi LA [15]	Oral Cancer Stem Cells: Therapeutic Implications and Challenges	1
CSCs are one of the promising therapeutic options to increase the effectiveness of tumor treatment. One of the most important markers in the initiation and progression of cancer are CSCs, and they are related to various properties of cancer, including metastasis, tumorigenesis, and recurrence. CSCs are known as the origin of cancer.	CD44, CD133, ALDH, CD10, CD29, ZsGreen-cODC	Review	Cancer Cell Inter-national	HNSCC	2020	Baniebrahimi GH [16]	Cancer stem cells and oral cancer: insights into molecular mechanisms and therapeutic Approaches	2
Potential targeting of CSCs can be realized in targeting of the CSC-related molecules, interfering with the environment helping CSC functions or preventing molecular pathways critical for the CSC survival	CD44, CD133 , CD98, CD10, side population (SP), ALDH, ZsGreen- Codc , CD166, CD271, integrins, c- Met	Review	Cancers	HNSCC	2019	Peitzsch C [6]	Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications	3
CSCs have been isolated in ESCC for over a decade; however, effective therapies targeting these cells are absent. Further studies are required in order to identify novel and effective therapeutics for ESCC	CD133, CD318, CD38, CD34, CD44 CD90, CD338, CD326, SP marker	Review	Oncology letters	Esophageal	2019	WU Q [17]	Cancer stem cells in esophageal squamous cell cancer	4
Targeting the CSC population has become an effective method of cancer treatment. Many of studies were based on in vitro data and none have gone through the early clinical stages.	CD44, CD133, CD38, CD34 ,ALDH, C-Met, OCT-4, CD24	Review	Precision Clinical Medicine	HNSCC	2019	Chen D [18]	Targeting cancer stem cells in squamous cell carcinoma	5
Most studies pertaining to HNSCC remain limited and are based on cancers from other organs/tissues. More studies relating to HNSCC CSCs should be undertaken which will help in treatment of HNSCC.	CD44, CD133, SP marker, C-Met, AIDH, OCT-4, NANOG ,Nestin	Review	The Scientific World Journal	Head and Neck	2014	Shah A [19]	The Evolving Concepts of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma	6
Slow growing cancer stem cells evade conventional therapies, and, reactivated and regenerate tumors locally or at distant sites. This might help to explain the relatively high recurrence rates in patients with HNSCC	CD133, CD44, ALDH, EMT	Review	Asian Pacific Journal of Cancer Prevention	HNSCC	2013	Satpute PS [20]	Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma	7
The CSC theory offers an interesting insight into why now available therapies for head and neck cancer so often fail. An understanding of CSCs has the probable to identify novel markers for therapy	CD44, CD133, ALDH, , OCT-4,NANOG ,Nestin , Bmi, CD26, CD29	Review	Journal of Oncology	HNSCC	2010	Monroe MM [21]	Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma	8

Discussion

From among cancer stem cells (CSCs) which are also called tumor- initiating cells (TICs), positively marked CSCs for CD133, CD44, CD166, aldehyde dehydrogenase (ALDH), and epithelial cells adhesion molecule (EpCAM) show 100-fold capacity for initiating cancer. In a heterogenous tumor mass, only about 0.05-3% of cells are suspected to be CSC and they can proliferate under hypoxia. CSCs, cancer cells, and normal stem cells share many cytochemical properties such as inhibiting the oxidation-reduction system for generation of reactive oxygen species (ROS) and high expression of drug resistance vectors. Nevertheless, when compared with normal stem cells, CSCs develop a unique metabolic flexibility, including shifting between oxidative phosphorylation (OXPHOS) and glycolysis as their main source of energy. Considering the similarities between CSCs and other cancer cells as well as normal stem cells, limited bioimaging and chemotherapeutic agents have been developed for CSCs^[10].

According to Table 1, in oral SCCs, the major CSCs that have been studied and found in oral cavity cancers were CD44, followed by CD133 and ALDH with an equal ratio. Further, the order of CSCs studied in the esophagus region has been as follows: CD44, CD133, and CD90 in terms of prevalence. Finally, the CSCs examined in other regions of the head and neck have been CD44 and ALDH with the highest prevalence, followed by CD133, OCT-4, C-met, CD166, SP (Side Papulation), CD38, CD32, CD24, NANOG, and Nestin ^[11].

It has been shown that several forms of CD44 have been verified empirically, which are directly involved in many malignant tumors and some of them are associated with metastatic progression. Recent evidence has reinforced the potential role of CD44 in CSCs and their impact on disease progression as well as treatment outcome. As an important component of the extracellular matrix, HA is heavily involved in many cellular processes, such as cell adhesion, cell migration, innate immunity, wound healing, and cancer progression^[12]. Accumulating evidence suggests that the HA-CD44 interaction in the extracellular area promotes various signaling pathways, which have a key role in progression of tumor cells in different solid tumor malignancies. In addition, the HA-CD44 interaction also stimulates metabolic and multidrug vectors, which are heavily associated with treatment resistance^[13]. Eventually, the HACD44 interaction causes development of cell skeleton changes which reinforce mobility and aggression of tumor cells. Most current evidence shows that different types of CD44 are linked to these interactions^[11].

Acquisition of genetic variations, the clonal evolution as well as the tumor microenvironment cause progression of cancer, metastasis, and treatment resistance. These events are in line with development of heterogeneity and giant phenotypical flexibility of cancer cells, which help support tumor progression and disease resistance. Targeting resistant cells is a major challenge in oncology. Nevertheless, the essential processes have still remained poorly understood. Although current treatments can reduce the tumor size and enhance the life expectancy, relapse and multidrug resistance (MDR) have eventually remained as the second cause of mortality in developed countries. Recent evident notes the stem phenotypes in cancer cells, promoted by CSCs, and been known as the main culprit of cancer recurrence, resistance (radiotherapy, hormone therapy, or chemotherapy) and metastasis. Various mechanisms have been proposed for resistance to CSCs, such as drug outflow through ABC transmitters, hyperactivation of DNA damage response (DDR), evading apoptosis, activation of prosurvival pathways, promotion of cell cycle and cell metabolic changes. Nevertheless, targeted therapy for these special mechanisms of CSCs is only to some extent effective in preventing or resolving resistance, thus suggesting other reasons for CSCs flexibility. The aim of this paper has been presenting an integrated image of MDR mechanisms functioning in the behavior of CSCs, as well as suggesting a new model of tumor evolution along the course of chemotherapy. Targeting the pathways mentioned here may be promising and show new strategies for the future clinical therapeutic approaches^[14].

Conclusion

Based on the conclusions presented in this paper, there are many areas for applying CSCs in prognosis and diagnosis of HNSCC. This umbrella review provides a comprehensive summary of the body of published systematic reviews and reviews in CSCs and HNSCCs. There is a strong evidence suggesting that targeting the cancer stem cells could lead to a more definitive response, since the cancer stem cells are the putative drivers of recurrence and metastatic spread in HNSCCs.

Conflict of interests

None.