Oral Squamous Cell Carcinoma (OSCC) is a form of cancer that impacts the cells covering the inside of the mouth such as the lips, tongue, gums, and inner cheeks. It is currently the most prevalent type of head and neck cancer globally, and its incidence has risen over the past  years.  The prognosis for OSCC depends on the stage at which it is detected, with earlier detection leading to better outcomes (Atia, 2019).Early detection and treatment of OSCC are challenging since healthcare resources are scarce in many parts of the country (Ali & Mirza, 2019). A group of diseases known as oral potentially malignant disorders (OPMDs) has the potential to develop into oral cancer (Warnakulasuriya et al., 2021). At the time of first diagnosis or in the future, these diseases are defined as having a probability of development of malignancy in a lesion. Oral lichen planus (OLP), oral erythroplakia (OE), oral submucous fibrosis (OSMF), proliferative verrucous leukoplakia (PVL), oral leukoplakia (OL), and actinic cheilitis (AC) are subtypes of OPMDs (Lorini et al., 2021).

The survival rate for patients with OSCC has not improved considerably in recent years, despite breakthroughs in cancer therapy. The lack of specific prognostic markers  it is difficult to predict a bad prognosis for this disease (Asio et al., 2018). Scientists have investigated several molecular and genetic markers related to OSCC to pinpoint potential signs of a dismal prognosis. The heterogeneity of oral cancer, both between patients and within tumors, presents a difficulty in the search for meaningful prognostic indicators. Genetic and epigenetic variations in cancer cells within a tumor, as well as differences in the tumor microenvironment, can lead to tumor heterogeneity.

Glycoprotein CD133 (also known as prominin-1) was initially identified in hematopoietic stem cells but has now been found to be expressed in many different types of cancers, including OSCC, colon cancer, and gliomas (Gisina et al., 2021). Cancer stem cells (CSCs) are thought to be responsible for tumor origin, progression, and recurrence (Caspa Gokulan & Devaraj, 2021). CD133 expression has been employed as a marker to identify the cells in these malignancies. The expression of CD133 has been found to increase gradually from normal mucosa to dysplasia and subsequently to OSCC, suggesting that it may play a role in the development and progression of oral cancer (Cierpikowski et al., 2021). In addition, the expression of CD133 is related to a higher risk of recurrence in OSCC patients, making it a crucial target for predicting the behavior of cancer (Hanet al., 2022).

Early diagnosis of OSCC and its premalignant forms is the key to improve the survival rate of OSCC and prevent the risk of conversion of oral potentially malignant lesions into 

The study included seventy (N=70) tissue samples consisting of 30 cases of OSCC and OPMDs each and 10 normal oral mucosa samples. The ethical approval for the study was given by the institutional review board (IRB) of Prime Foundation Pakistan (IRB Approval No: Prime/IRB/2022-509). The study was conducted from 2nd May 2022 to 30th July, 2022 and data was collected from Department of Histopathology, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan, Department of Pathology, Pathology, Peshawar Medical College (PMC) and Department of Oral Pathology, Peshawar Dental College(PDC), Peshawar, Pakistan.

The normal oral mucosa was collected  from 10 healthy persons visiting the mentioned  dental units for minor surgical procedures, such as the removal of the third molar, alveoloplasty, and implant placements.

H&E staining confirmed the diagnosis of OPMDs and OSCC in the tissue samples, while CD133 staining was evaluated by immunohistochemistry (GLUT-4 Polyclonal Antibody, Host-Rabbit, Iso type-IgG;Elabscience, USA     INCLUDE CD133 details like I have included GLUT 4 datails as an example ),using a semiquantitative scoring system.

Histopathological review of H & E stained slides

Histopathological grading of OSCC

The WHO grading system was adopted to classify  the OSCC lesions into, Well differentiated (WDSCC), moderately differentiated (MDSCC) and poorly differentiated (PDSCC) types on the basis of degree of cellular differentiation ( WHO 2017 book-El-Naggar, Chan, Grandis, Takata, &Slootweg, 2017).Bryne’s invasive tumourfront grading system was used to assess the degree of malignancy of OSCC lesions by determining the degree of keratinisation, nuclear polymorphism, number of mitoses, mode of invasion and lymphoplasmacytic infiltrate. Each histopathological features were assigned score (1-4) and were categorized into 3 grades [Grade-I (5-8 score), Grade-II (9-12 score) and grade 3 (13-20)] (Bryne et al., 1989;Dissanayake, 2017).

Histopathological grading of OPMD’s

WHO’s 2017 classification system of epithelial precursor lesions ( WHO 2017 book) was adopted for categorization of OPMDs. According to this system OPMDs were classified as mild dysplasia, moderate dysplasia, severe dysplasia.  OED was assessed from architectural and cytological alterations (El-Naggar, Chan, Grandis, Takata, &Slootweg, 2017).  Binary system of OED was adopted and cut off point of 4 architectural and 5 cytological fetures were employed to classify OED as a high risk lesion (those who have a potential for malignant transformation) and a low risk lesion (those who donot have the potential for malignant transformation) (Kujan et al., 2006).

Evaluation of  CD133 immunohistochemical staining for OSCC and OPMD’s

• The immunohistochemistry staining method allows for the identification and localization of specific proteins in tissue samples.
• Immuno Reactive Scoring System (IRS) was used for assessment of CD133 expression. It was determined by multiplication of staining intensity and percentage of positive cells. (Fedchenko, N., & Reifenrath, J. 2014 ).

Total Score (TS) = Intensity Score (IS) x Expression Score (ES)

• 1–4 =Weakly positive
• 5 – 8= Moderately positive
• 9–12 = Strongly positive

The IHC staining intensity was scored by an expert pathologist (ASK). No cytoplasmic staining or cytoplasmic staining in <10% of tumor cells was defined as score 0; faint/barely perceptible partial cytoplasmic staining in >10% of tumor cells was defined as score 1+; moderate cytoplasmic staining in >10% of tumor cells was defined as score 2+; strong cytoplasmic staining in >10% was defined as score 3+. Scores of 0 and 1+ were defined as low GLUT-4 expression while scores of 2+ and 3+ were defined as high GLUT-4 expression (Chang et al., 2017).

Statistical analysis

The data were analysed using SPSS version 20. The percentages were calculated for each categorical variable. ANOVA, chi-square test and Fisher exact tests were  applied for statistical significance, where appropriate. A probability value of less than or equal to 0.05 was considered statistically significant.

The results of the present study are summarized in the tables (Tables:1-4) given below, with essential descriptions. The average ages of the OSCC patients, OPMD patients and healthy individuals were 58.27, 61.23 and 37.10 respectively. Most of the cases of OSCC and OPMDs were older than 50 years. Among the cases of OSCC, the patients’ age ranged from 28-84 . In OSCC cases, the M: F ratio was 1:1.5, OPMDs  1:0.875, and that in healthy control was 1:1. A statistically significant relation (p=0.00003) was detected between the different age groups of the study participants (Table-1).

Table-1: Description of age, gender and tissue CD133 immunoreactivity of the study subject.

Comparing the CD 133 expression with the site of OSCC lesion (p=0.057), WHO grading system (p=0.274), ITF grading system (p=0.577) and LPI (p=0.323) showed statistically non significant relation between them (Table 2). Moderate CD133 expression was detected in the buccal mucosa, retromolar area and vestibule of the mouth of OSCC cases (N=6; 20%). Most of the lesions diagnosed as WDSCC (N=7, 23.3%) exhibited moderate CD133  immunoexpression (Table 2).

Table- 2: CD133 Immunoreactivityandclinico-pathological parameters of OSCC

CD 133 tissue immunoexpression  and clinical presentation of the OPMDs (p=0.40), site of OPMDs (p=0.885), binary grading system (p=0.217) , subepithelial inflammatory changes (p=0.49) and grades of subepithelial inflammatory infiltrate (p=0.866) were not significantly related (Table-3). Buccal mucosa, retromolar area and vestibule of the mouth, showed moderate CD133 expression (N=8; 26.7%). Moderate and severe dysplasia showed  moderate CD133immuno expression. Statistically significant relationship was observed between CD 133 tissue immunoexpression and WHO grading system for OED ( p=0.007) [Table-3].

Table 3:CD133 Immunoreactivity and clinico-pathological parameters among OPMD’s

Among the cases (OSCC & OPMDs), moderate level of CD133 immuno-expression of  was detected in 60% (N=18/30) of the tumor samples and 56.67% (N=17/30) in oral preneoplastic samples. Absence of CD 133 immuno-expression was noted in all (N=10) the samples of Normal oral mucosa. Statistical comparison made between CD133 immunoexpression among the study participants revealed significant difference thus rejecting the null hypothesis in favour of alternate hypothesis (Table-4).

Table-4: CD133 tissue immunoreactivity among the study participants

There is a need for trustworthy biomarkers that can assist in the early detection and prognosis of oral cancer, as current diagnostic methods and prognostic indicators have limitations. The expression of CD133 has been proposed as a prognostic factor in  OSCC and has emerged as a possible CSC marker in numerous human cancers. Therefore, to evaluate its potential clinical significance as a biomarker and therapeutic target, this study was conducted to examine the immunohistochemical expression of CD133 in OSCC, OPMDs, and normal oral mucosa.

(Hasegawa et al., 2015).

The present study revealed a greater incidence of oral OSCC and OPMDs in males compared to females. This points to a gender-based discrepancy, with OPMDs and OSCC being more prevalent among males in our study population. The high occurrence of these conditions in males can be attributed to the increased frequency of harmful habits among this demographic. The literature presents conflicting views on the prevalence of OPMDs in both genders.(Yardimci, Kutlubay, Engin, & Tuzun, 2014)  A study conducted in India also reported a higher occurrence of OPMDs in males.(Srivastava, Sharma, Pradhan, Jyoti, & Singh, 2020)

In our study most of OPMD and OSCC cases occurred in the age group 41 – 60 years. The findings from a previous study indicate that, traditionally, the average age of individuals diagnosed with potentially malignant disorders of the oral cavity (OPMDs) is typically within the range of 50 to 69 years. This age range has been considered as the primary demographic for the occurrence of these disorders. However, recent research indicates that approximately 5% of cases involving OPMDs have been documented in individuals who are under the age of 30 years(Ray, 2017).

Our findings show that the most prevalent site among the OSCC cases was the buccal mucosa, comprising 40% of the total cohort, followed by the tongue at 18.33%. The results of this study differ from previous research conducted in Pakistan, where the tongue was identified as the site most frequently affected by OSCCs, accounting for 37.1% of cases, followed closely by the buccal mucosa at 30.3%. Another study conducted in Mexico by Hernandez-Guerrero et al.(Hernández-Guerrero et al., 2013)also supported the tongue as the predominant site of involvement, reporting a frequency of 44.7%. However, contrasting findings were reported by Bhurgri in South Karachi, where the buccal mucosa took precedence, being the most frequently involved site in oral malignancies at 55.9%, followed by the tongue at 28.4%(Bhurgri, 2005). These variations in site preference are not unique to a specific region but can be observed globally. For instance, in Iraq, the lip is identified as the preferential site for individuals exposed to ultraviolet radiation(Nemes, Redl, Boda, Kiss, & Márton, 2008), while in Hungary, the floor of the mouth is reported as the most frequently affected site in OSCC patients (Nemes et al, 2008). In another study, the higher prevalence of OSCC on the alveolar ridge was attributed to the practice of snuff (Sahaf et al., 2017). This habit, combined with periodontitis, contributes to the formation of soft tissue craters. These craters create an environment conducive to the accumulation of snuff deposits over an extended duration, thereby increasing the risk of developing OSCC on the alveolar ridge. This highlights the localized impact of specific risk factors on the anatomical distribution of OSCC, emphasizing the importance of considering regional practices and habits in understanding the patterns of oral cancer incidence.

The results of a previous study have provided valuable insights into the distribution and nature of OPMDs. According to this study, the most frequently affected site for OPMDs was identified as the buccal mucosa. This finding suggests that the buccal mucosa, which is the inner lining of the cheek, is particularly prone to the development of these potentially precancerous conditions. The significance of pinpointing the most common site for OPMDs lies in enhancing targeted surveillance and early detection efforts, especially in clinical examinations focusing on the buccal mucosa(Saboor, Khan, Afsar, & Khan, 2023). Furthermore, the study identified Leukoplakia as the most prevalent premalignant lesion within the OPMD category which appearsas whitish, thickened patches on the oral mucosa. This information is crucial for clinicians and researchers in prioritizing monitoring and intervention strategies for individuals exhibiting these leukoplakic patches(Dissemond, 2004).

We concluded that there was a strong CD133 expression in OSCC as compared to OPMDs. The normal oral mucosa was negative for CD133 expression.

Previous studies showed a significant association between CD133+CSCs and OSCCs, particularly those of more advanced stages. This suggests the potential involvement of CD133+ CSCs in the transformative process of premalignant oral lesions, as indicated by studies conducted by Ravindran and Devaraj in 2012(Ravindran & Devaraj, 2012), and Liu et al. in 2013(Liu et al., 2013). Moreover, there is notable evidence pointing to the presence of CSCs expressing CD133 in the majority of oral epithelial dysplasias (OEDs) that have progressed to malignant transformation and developed into OSCCs, as highlighted by Liu et al. in 2013(Liu et al., 2013). This underscores the role of CD133 as a valuable predictor, serving to identify oral premalignant lesions that carry a heightened risk of progressing into oral cancer. The presence of CD133+ CSCs in both OSCCs and premalignant lesions suggests its potential utility as a biomarker for assessing the risk and prognosis of oral cancer development.

Despite extensive literature research, we could not find any comparable study on CD133 expression among various grades of OSCC. However, in our study, most of the MDSCC and PDSCC showed moderate to strong CD133 expression as compared to WDSCC. This finding though not statistically significant can help us in predicting the behaviour of the tumor.

The immunohistochemical expression of CD133 in OSCC and OPMDs. CD133 has been identified as a putative CSC marker in several human malignancies, including OSCC. Its expression has been suggested as a prognostic factor in OSCC, with several studies reporting a significant association between CD133 expression and poor survival outcomes. Furthermore, CD133 has been proposed as a therapeutic target for OSCC, with several studies demonstrating the potential efficacy of CD133-targeted therapies in preclinical models. In addition to its potential clinical implications in OSCC, detecting CD133 expression in OPMDs may help identify high-risk lesions with potential for malignant transformation. CD133 expression has been reported in both oral leukoplakia and oral erythroplakia, two common types of OPMDs, and its detection may aid in the early diagnosis and treatment of these lesions. The expression of CD133 in normal oral mucosa also suggests that it may play a role in normal tissue homeostasis. However, the significance of CD133 expression in normal oral mucosa is not fully understood and requires further investigation.

Overall, the potential clinical implications of CD133 expression in OSCC, OPMDs, and normal oral mucosa may serve as a valuable biomarker for the early detection and treatment of oral cancer. Furthermore, CD133-targeted therapies may hold promise as a novel treatment approach for OSCC and other cancers. However, the limitations to using CD133 as a biomarker and therapeutic target need to be considered, such as the potential lack of specificity to CSCs and the heterogeneity of CSC populations. Further research is required to fully understand the biological and clinical significance of CD133 expression and its potential limitations as a biomarker and therapeutic target.

Limitations

It was a time-bound study. The study included a relatively small sample size of 70 patients, which might limit the generalizability of the findings. With a small sample, the results may not accurately represent the entire population, and there is an increased risk of chance associations. The study did not include comprehensive information on potential risk factors associated with OSCC and OPMDs, such as smoking habits, alcohol consumption, or HPV infection. The absence of these variables limits the ability to explore potential risk factors for these conditions. The study provided cross-sectional data, which does not allow for assessing changes or developments over time. Longitudinal data would provide a more comprehensive understanding of disease progression and treatment outcomes. As the study relies on data from patients attending specific medical and dental centers, there might be selection bias, as patients attending these centers may have different characteristics than the general population.

Strength of the study

The relationship of CD133 expression and Bryne’s ITF grading system of OSCC ,  Binary grading system of OPMDs, subepithelial inflammatory infiltrate and its grades,  were assessed for the first time in the international literature according to our knowledge.

Based on our findings, it can be concluded that, All the OSCC, and OPMD cases were positive for CD133 expression as compared to normal oral mucosa . OSCC cases showed a higher percentage of moderate and strong CD133 expression than OPMDs.Among various grades of OSCC, MDSCC and PDSCC showed more intense CD133 expression as compared to WDSCC.CD133 can be used as a predictor for invasiveness in OSCC and OPMDs.

Recommendations and future directions

A large-scale study with a diverse population from multiple centers should be conducted to enhance the generalizability of the findings. A more extensive sample size will provide more robust statistical power to detect associations accurately. To further substantiate the possible role of CD133 in OSCC and OPMDs,follow-up of patients is recommended. To develop new approaches to the treatment. Incorporate molecular studies to examine genetic and epigenetic changes associated with OSCC and OPMDs. Molecular markers can enhance diagnostic accuracy and improve understanding of disease mechanisms. Conduct validation studies on CD133 as a biomarker for OSCC and OPMDs using independent datasets. Validation will confirm the reliability and clinical utility of CD133 as a potential prognostic and diagnostic marker.Based on the findings of risk factors, develop effective prevention strategies, public health campaigns, and educational programs to reduce the incidence of OSCC and OPMDs. Encourage collaboration between clinicians, pathologists, molecular biologist, and researchers to foster interdisciplinary research in oral cancer and potentially malignant disorders. Such collaboration can lead to more comprehensive and innovative diagnosis, treatment, and prevention approaches. Promote public awareness about the early signs and symptoms of OSCC and OPMDs and the importance of regular oral health check-ups .Further research is required to find the relation of CD133 expression in serum and saliva besides samples of OSCC and OPMDs.

1. EI-Naggar AK. WHO classification of head and neck tumours. International Agency; 2017.
2. Bryne M, Koppang HS, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high 
   1. Adnan, Y., Ali, S. M. A., Farooqui, H. A., Kayani, H. A., Idrees, R., & Awan, M. S. (2022). High CD44 Immunoexpression Correlates with Poor Overall Survival: Assessing the Role of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma Patients from the High-Risk Population of Pakistan. International journal of surgical oncology, 2022, 9990489. doi.org/10.1155/2022/9990489
   2. Aghajani, M., Mansoori, B., Mohammadi, A., Asadzadeh, Z., & Baradaran, B. (2019). New emerging roles of CD133 in cancer stem cell: Signaling pathway and miRNA regulation. Journal of cellular physiology, 234(12), 21642-21661.
   3. Ahmadian, E., Dizaj, S. M., Sharifi, S., Shahi, S., Khalilov, R., Eftekhari, A., & Hasanzadeh, M. (2019). The potential of nanomaterials in theranostics of oral squamous cell carcinoma: Recent progress. TrAC Trends in Analytical Chemistry, 116, 167-176.
   4. Ahmed, E. M., Bandopadhyay, G., Coyle, B., & Grabowska, A. (2018). A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells. Cellular oncology, 41,319-328.
   5. Akbari, M., Shomali, N., Faraji, A., Shanehbandi, D., Asadi, M., Mokhtarzadeh, A., ... & Baradaran, B. (2020). CD133: An emerging prognostic factor and therapeutic target in colorectal cancer. Cell biology international, 44(2), 368-380.
   6. Ali, S. A., Awan, M. S., Atif, S., Ali, N., & Mirza, Y. (2018). Correlation of human papillomavirus infection and clinical parameters with five-year survival in oral squamous cell carcinoma. The Journal of Laryngology & Otology, 132(7), 628-635.
   7. Ali, S. M. A., & Mirza, Y. (2019). Overexpression of EGFR, COX2 and p53 in oral squamous cell carcinoma patients of Pakistan and correlation with prognosis. Annals of Oncology, 30, vii21-vii22.
   8. Anitha, J. (2019). Expression of Cancer Stem Cell Marker CD44 in Oral Squamous Cell Carcinoma of Tongue (Doctoral dissertation, Ragas Dental College and Hospital, Chennai)./10791/1/240602319
   9. Anwar, N., Pervez, S., Chundriger, Q., Awan, S., Moatter, T., & Ali, T. S. (2020). Oral cancer: Clinicopathological features and associated risk factors in a high risk population presenting to a major tertiary care center in Pakistan. Plos one, 15(8), e0236359.
   10. Ariyawardana, A. (2020). Malignant Transformation of Oral Potentially Malignant Disorders. Textbook of Oral Cancer: Prevention, Diagnosis and Management, 159-177.
   11. Artells, R., Moreno, I., Diaz, T., Martinez, F., Gel, B., Navarro, A.,& Monzo, M. (2010). Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patientEuropean journal of cancer, 46(3), 642-649.
   12. Asio, J., Kamulegeya, A., & Banura, C. (2018). Survival and associated factors among patients with oral squamous cell carcinoma (OSCC) in Mulago hospital, Kampala, Uganda. Cancers of the Head & Neck, 3, 1-10.
   13. Atia, H. M. H. (2019). Epidemiology of Oral Cancer in Khartoum Dental Teaching Hospital, Khartoum State, Sudan (2018) (Doctoral dissertation, University of Gezira).
   14. Baba, O., Hasegawa, S., Nagai, H., Uchida, F., Yamatoji, M., Kanno, N. I,& Bukawa, H. (2016). Micro RNA‐155‐5p is associated with oral squamous cell carcinoma metastasis and poor prognosis. Journal of oral pathology & medicine, 45(4), 248-255.
   15. Barillari, G., Melaiu, O., Gargari, M., Pomella, S., Bei, R., & Campanella, V. (2022). The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview. International Journal of Molecular Sciences, 23(15), 8336.
   16. Barzegar Behrooz, A., Syahir, A., & Ahmad, S. (2019). CD133: beyond a cancer stem cell biomarker. Journal of drug targeting, 27(3), 257-269.
   17. Bauer, M., Jasinski-Bergner, S., Mandelboim, O., Wickenhauser, C., & Seliger, B. (2021). Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies. Cancers, 13(20), 5189.
   18. Baykul, T., Yilmaz, H. H., Aydin, Ü., Aydin, M. A., Aksoy, M. C., & Yildirim, D. (2010). Early diagnosis of oral cancer. Journal of International Medical Research, 38(3), 737-749.
   19. Behlfelt, K., Linder-Aronson, S., McWilliam, J., Neander, P., & Laage-Hellman, J. (1989).
   20. Dentition in children with enlarged tonsils compared to control children. Eur J
   21. Orthod 11(4), 416-429.
   22. Bhurgri, Y. (2005). Cancer of the oral cavity-trends in Karachi South (1995-2002). Asian Pac J Cancer Prev, 6(1), 22-26.
   23. Bourguignon LY. 2008 Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. InSeminars in cancer biology; 18(4): 251-9
   24. Brouha, X. D., Tromp, D. M., Hordijk, G. J., Winnubst, J. A., & de Leeuw, J. R. (2004). Oral and pharyngeal cancer: analysis of patient delay at different tumor stages. Head & Neck, 26(9), 731-736.
   25. Bueno, C., Velasco-Hernandez, T., Gutiérrez-Agüera, F., Zanetti, S. R., Baroni, M. L., Sánchez-Martínez, D., ... & Menéndez, P. (2019). CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity. Leukemia, 33(8), 2090-2125.
   26. Cantile, M., Collina, F., D'Aiuto, M., Rinaldo, M., Pirozzi, G., Borsellino, C., ... & Di Bonito, M. (2013). Nuclear localization of cancer stem cell marker CD133 in triple-negative breast cancer: a case report. Tumori Journal, 99(5), e245-e250.
   27. Caspa Gokulan, R., & Devaraj, H. (2021). Stem cell markers CXCR-4 and CD133 predict aggressive phenotype and their double positivity indicates poor prognosis of oral squamous cell carcinoma. Cancers, 13(23), 5895.
   28. Chaitra, L. P., Prashant, A., Gowthami, C. S., Hajira, B., Suma, M. N., Mahesh, S. S., ... &
   29. Sheeladevi, C. S. (2019). Detection of cancer stem cell-related markers in
   30. different stages of colorectal carcinoma patients of Indian origin by
   31. Journal of cancer research and therapeutics, 15(1), 75-81.
   32. Chakraborty, D., Natarajan, C., & Mukherjee, A. (2019). Advances in oral cancer detection. Advances in clinical chemistry, 91, 181-200.
   33. Chen, H., Lin, J., Shan, Y., & Zhengmao, L. (2019). The promotion of nanoparticle delivery to two populations of gastric cancer stem cells by CD133 and CD44 antibodies. Biomedicine & Pharmacotherapy, 115, 108857.
   34. Chen, K., Li, Z., Jiang, P., Zhang, X., Zhang, Y., Jiang, Y., ... & Li, X. (2014). Co-expression of CD133, CD44v6 and human tissue factor is associated with metastasis and poor prognosis in pancreatic carcinoma. Oncology reports, 32(2), 755-763.
   35. Chen, S., Song, X., Chen, Z., Li, X., Li, M., Liu, H., & Li, J. (2013). CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PloS one, 8(2), e56380.
   36. Cierpikowski, P., Lis-Nawara, A., & Bar, J. (2021). SHH Expression Is Significantly Associated With Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma. Anticancer Research, 41(11), 5405-5413.
   37. Davis, M., Gassner, K., Rodriguez-Barrueco, R., & Llobet-Navas, D. (2018). Stem Cells andCancer. Stem Cell Genetics for Biomedical Research: Past, Present, and Future, 271-309.
   38. de Bree, R., Takes, R. P., Shah, J. P., Hamoir, M., Kowalski, L. P., Robbins, K. T., ... & Ferlito, A. (2019). Elective neck dissection in oral squamous cell carcinoma: Past, present and future. Oral oncology, 90, 87-93.
   39. Deng, Y., Su, Q., Mo, J., Fu, X., Zhang, Y., & Lin, E. H. (2013). Celecoxib downregulates CD133 expression through inhibition of the Wnt signaling pathway in colon cancer cells. Cancer investigation, 31(2), 97-102.
   40. Desiderio, V., Papagerakis, P., Tirino, V., Zheng, L., Matossian, M., Prince, M. E., ... & Papagerakis, S. (2015). Increased fucosylation has a pivotal role in invasive and metastatic properties of head and neck cancer stem cells. Oncotarget, 6(1), 71.
   41. Dhumal, S. N., Choudhari, S. K., Patankar, S., Ghule, S. S., Jadhav, Y. B., & Masne, S. (2022). Cancer stem cell markers, cd44 and aldh1, for assessment of cancer risk in opmds and lymph node metastasis in oral squamous cell carcinoma. Head and Neck Pathology, 16(2), 453-465.
   42. Dissemond, J. (2004). Oral lichen planus: an overview Journal of dermatological treatment, 15(3), 136-140.
   43. Elbasateeny, S. S., Salem, A. A., Abdelsalam, W. A., & Salem, R. A. (2016). Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer..Pathology-Research and Practice, 212(1), 10-16.
   44. El, H., & Palomo, J. M. (2011). Airway volume for different dentofacial skeletal patterns. Am
   45. J Orthod Dentofacial Orthop, 139(6), e511-e521.
   46. Fan, X., Khaki, L., Zhu, T. S., Soules, M. E., Talsma, C. E., Gul, N., ... & Eberhart, C. G. (2010). NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem cells, 28(1), 5-16.
   47. Farah, C. S., Pollaers, K., & Frydrych, A. (2019). Management of premalignant disease of the oral mucosa. Premalignant conditions of the oral cavity, 229-276.
   48. Fedchenko, N., & Reifenrath, J. (2014). Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue - a review. Diagnostic pathology, 9, 221. https://doi.org/10.1186/s13000-014-0221-9
   49. Feng, Y., Spezia, M., Huang, S., Yuan, C., Zeng, Z., Zhang, L., ... & Ren, G. (2018). Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes & diseases, 5(2), 77-106.
   50. Ford, P. J., & Rich, A. M. (2021). Tobacco use and oral health. Addiction, 116(12), 3531-3540.
   51. Fostok, S., El-Sibai, M., Bazzoun, D., Lelièvre, S., & Talhouk, R. (2019). Connexin 43 loss triggers cell cycle entry and invasion in non-neoplastic breast epithelium: a role for noncanonical Wnt signaling. Cancers, 11(3), 339.
   52. Fujii, K., Kumagai, K., Hamada, Y., & Suzuki, R. (2015). Clinicopathological significance and prognostic value of CD133 expression in oral squamous cell carcinoma. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 27(2), 176-182.
   53. G Lee, D., Lee, J. H., K Choi, B., Kim, M. J., Kim, S. M., S Kim, K., ... & S Kwon, B. (2011). H+-myo-inositol transporter SLC2A13 as a potential marker for cancer stem cells in an oral squamous cell carcinoma. Current cancer drug targets, 11(8), 966-975.
   54. Georgaki, M., Theofilou, V. I., Pettas, E., Stoufi, E., Younis, R. H., Kolokotronis, A., ... & Nikitakis, N. G. (2021). Understanding the complex pathogenesis of oral cancer: A comprehensive review.Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 132(5), 566-579.
   55. Gisina, A., Novikova, S., Kim, Y., Sidorov, D., Bykasov, S., Volchenko, N., ... & Lupatov, A. (2021). CEACAM5 overexpression is a reliable characteristic of CD133-positive colorectal cancer stem cells. Cancer Biomarkers, 32(1), 85-98.
   56. Glumac, P. M., & LeBeau, A. M. (2018). The role of CD133 in cancer: a concise review. Clinical and translational medicine, 7, 1-14.
   57. Glumac, P. M., Gallant, J. P., Shapovalova, M., Li, Y., Murugan, P., Gupta, S., ... & LeBeau, A. M. (2020). Exploitation of CD133 for the targeted imaging of lethal prostate cancer. Clinical Cancer Research, 26(5), 1054-1064.
   58. González-Moles, M. Á., Keim-del Pino, C., & Ramos-García, P. (2022). Hallmarks of Cancer Expression in Oral Lichen Planus: A Scoping Review of Systematic Reviews and Meta-Analyses. International Journal of Molecular Sciences, 23(21), 13099.
   59. González-Moles, M. Á., Warnakulasuriya, S., Gonzalez-Ruiz, I., Gonzalez-Ruiz, L., Ayen, A., Lenouvel, D., & Ramos-Garcia, P. (2020). Clinicopathological and prognostic characteristics of oral squamous cell carcinomas arising in patients with oral lichen planus: A systematic review and a comprehensive meta-analysis. Oral Oncology, 106, 104688..
   60. Grosse-‐Gehling, P., Fargeas, C. A., Dittfeld, C., Garbe, Y., Alison, M. R., Corbeil, D., & Kunz--Schughart, L. A. (2013). CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. The Journal of pathology, 229(3), 355-378.
   61. Guo, M., Luo, B., Pan, M., Li, M., Xu, H., Zhao, F., & Dou, J. (2020). Colorectal cancer stem cell vaccine with high expression of MUC1 serves as a novel prophylactic vaccine for colorectal cancer. International Immunopharmacology, 88, 106850.
   62. Habu, N., Imanishi, Y., Kameyama, K., Shimoda, M., Tokumaru, Y., Sakamoto, K., ... & Ogawa, K. (2015). Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma. BMC cancer, 15(1), 1-14.
   63. Han, Y. K., Park, H. Y., Park, S. G., Hwang, J. J., Park, H. R., & Yi, J. M. (2022). Promoter Methylation of Cancer Stem Cell Surface Markers as an Epigenetic Biomarker for Prognosis of Oral Squamous Cell Carcinoma. International Journal of Molecular Sciences, 23(23), 14624.
   64. Hernández-Guerrero, J. C., Jacinto-Alemán, L. F., Jiménez-Farfán, M. D., Macario-Hernández, A., Hernández-Flores, F., & Alcántara-Vázquez, A. (2013). Prevalence trends of oral squamous cell carcinoma. Mexico City’s General Hospital experience. Medicina oral, patología oral y cirugía bucal, 18(2), e306.

    

   65. Hasegawa, T., Tanakura, M., Takeda, D., Sakakibara, A., Akashi, M., Minamikawa, T., & Komori, T. (2015). Risk factors associated with distant metastasis in patients with oral squamous cell carcinoma. Otolaryngology--Head and Neck Surgery, 152(6), 1053-1060.
   66. Hass, R., von der Ohe, J., & Ungefroren, H. (2020). Impact of the tumor microenvironment on tumor heterogeneity and consequences for cancer cell plasticity and stemness. Cancers, 12(12), 3716.
   67. Hsiao, J. R., Chang, C. C., Lee, W. T., Huang, C. C., Ou, C. Y., Tsai, S. T., ... & Chang, J. S. (2018). The interplay between oral microbiome, lifestyle factors and genetic polymorphisms in the risk of oral squamous cell carcinoma. Carcinogenesis, 39(6), 778-787.
   68. Hsieh, J. L., Lu, C. S., Huang, C. L., Shieh, G. S., Su, B. H., Su, Y. C., ... & Shiau, A. L. (2012). Acquisition of an enhanced aggressive phenotype in human lung cancer cells selected by suboptimal doses of cisplatin following cell deattachment and reattachment. Cancer letters, 321(1), 36-44.
   69. Huang, X., Huang, J., Leng, D., Yang, S., Yao, Q., Sun, J., & Hu, J. (2017). Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells. World Journal of Surgical Oncology, 15(1), 1-10.
   70. Ilango, S., Paital, B., Jayachandran, P., Padma, P. R., & Nirmaladevi, R. (2020). Epigenetic alterations in cancer. Frontiers in Bioscience-Landmark, 25(6), 1058-1109.
   71. Ilyas, S. (2022). Immunohistochemistry examination to reveal the pathogenesis of Oral Squamous Cell Carcinoma. International Journal of Ecophysiology, 4(1), 5-25.
   72. Jafarian, A. H., Mostaan, L. V., Roshan, N. M., Khazaeni, K., Parsazad, S., & Gilan, H. (2015). Relationship between the expression of matrix metalloproteinase and clinicopathologic features in oral squamous cell carcinoma. Iranian Journal of Otorhinolaryngology, 27(80), 219.
   73. Jamal, M., Rath, B. H., Tsang, P. S., Camphausen, K., & Tofilon, P. J. (2012). The brain microenvironment preferentially enhances the radioresistance of CD133+ glioblastoma stem-like cells. Neoplasia, 14(2), 150-158.
   74. Ji, J., Judkowski, V. A., Liu, G., Wang, H., Bunying, A., Li, Z., ... & Yu, J. S. (2014). Identification of novel human leukocyte antigen-A* 0201-restricted, cytotoxic T lymphocyte epitopes on CD133 for cancer stem cell immunotherapy. Stem Cells Translational Medicine, 3(3), 356-364.
   75. Jiajia, Q., Yan, S., Changqing, Y., Wenjing, J., Han, Z., Yuanpan, C., & Qiuyan, L. (2017). Clinical significance of CD44 and CD133 expression in oral potentially malignant disorder and oral squamous cell carcinoma. Hua xi kou Qiang yi xue za zhi= Huaxi Kouqiang Yixue Zazhi= West China Journal of Stomatology, 35(3), 311-316.
   76. Johnson, N. W., Warnakulasuriya, S., Gupta, P. C., Dimba, E., Chindia, M., Otoh, E. C., ... & Kowalski, L. (2011). Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions. Advances in dental research, 23(2), 237-246.
   77. Jorge, E. P., Santos-Pinto, A. d., Gandini Júnior, L. G., Guariza Filho, O., & Castro, A. B. B.
       1. (2011). Evaluation of the effect of rapid maxillary expansion on the upper
   78. airway using nasofibroscopy: Case report and description of the technique. Dent
   79. Press J Orthod, 16(1), 81-89.
   80. Jung, K., Wang, P., Gupta, N., Gopal, K., Wu, F., Ye, X., ... & Lai, R. (2014). Profiling gene promoter occupancy of Sox2 in two phenotypically distinct breast cancer cell subsets using chromatin immunoprecipitation and genome-wide promoter microarrays. Breast Cancer Research, 16(6), 1-13.
   81. Kakabadze, M. Z., Paresishvili, T., Karalashvili, L., Chakhunashvili, D., & Kakabadze, Z. (2020). Oral microbiota and oral cancer. Oncology Reviews, 14(2).
   82. Kang, Y., Chen, J., Li, X., Luo, M., Chen, H., Cui, B., ... & Zhang, P. (2021). Salivary KLK5 and uPA are potential biomarkers for malignant transformation of OLK and OLP. Cancer Biomarkers, 31(4), 317-328.
   83. Karim, S., Gururaj, N., & Sujatha, G. P. (2019). Oral lichen planus and oral lichenoid lesions: An analysis of 64 cases in Indian population. Journal of Oral and Maxillofacial Pathology, 23(3), 442-448. doi: 10.4103/jomfp.JOMFP_236_18.
   84. Ke, C. C., Liu, R. S., Yang, A. H., Liu, C. S., Chi, C. W., Tseng, L. M., ... & Lee, O. K. (2013). CD133-expressing thyroid cancer cells are undifferentiated, radioresistant and survive radioiodide therapy. European journal of nuclear medicine and molecular imaging, 40, 61-71.
   85. Ketchen, S. E. (2019). Targeting the actin polymerisation pathway for improved treatment of glioblastoma (Doctoral dissertation, University of Leeds).
   86. Keum, N., & Giovannucci, E. (2019). Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nature reviews Gastroenterology & hepatology, 16(12), 713-732.
   87. Kohga, K., Tatsumi, T., Takehara, T., Tsunematsu, H., Shimizu, S., Yamamoto, M., ... & Hayashi, N. (2010). Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. Journal of hepatology, 52(6), 872-879.
   88. Kumar, S. (2016). Oral submucous fibrosis: A demographic study. Journal of Indian Academy of Oral Medicine and Radiology, 28(2), 124.
   89. Kumari, P., Debta, P., & Dixit, A. (2022). Oral potentially malignant disorders: etiology, pathogenesis, and transformation into oral cancer. Frontiers in Pharmacology, 13.
   90. La Rosa, G. R. M., Gattuso, G., PEduLLà, E., Rapisarda, E., Nicolosi, D., & Salmeri, M. (2020). Association of oral dysbiosis with oral cancer development. Oncology letters, 19(4), 3045-3058.
   91. Lan, H., Lu, H., Wang, X., & Jin, H. (2015). MicroRNAs as potential biomarkers in cancer: opportunities and challenges. BioMed research international, 2015.doi.org/10.1155/2015/125094
   92. Lan, X., Wu, Y. Z., Wang, Y., Wu, F. R., Zang, C. B., Tang, C., ... & Li, S. L. (2013). CD133 silencing inhibits stemness properties and enhances chemoradiosensitivity in CD133-positive liver cancer stem cells. International journal of molecular medicine, 31(2), 315-324.
   93. Li, J. I., Zhong, X. Y., Li, Z. Y., Cai, J. F., Zou, L., Li, J. M., ... & Liu, W. (2013). CD133 expression in osteosarcoma and derivation of CD133+ cells. Molecular medicine reports, 7(2), 577-584.
   94. Lingen, M. W., Kalmar, J. R., & Karrison, T. (2017). Oral cancer: Diagnosis, management, and rehabilitation. Thieme Medical Publishers./dp/1588903095,.
   95. Liu, S., Liu, L., Ye, W., Ye, D., Wang, T., Guo, W., ... & Zhang, Z. (2016). High vimentin expression associated with lymph node metastasis and predicated a poor prognosis in oral squamous cell carcinoma. Scientific reports, 6(1), 38834.
   96. Liu, W., Wu, L., Shen, X. M., Shi, L. J., Zhang, C. P., Xu, L. Q., & Zhou, Z. T. (2013). Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia. International journal of cancer, 132(4), 868-874.
   97. Liu, X., Si, W., Liu, X., He, L., Ren, J., Yang, Z., ... & Sun, L. (2017). JMJD6 promotes melanoma carcinogenesis through regulation of the alternative splicing of PAK1, a key MAPK signaling component. Molecular cancer, 16, 1-18.
   98. Lompardía, S. L., Díaz, M., Papademetrio, D. L., Mascaró, M., Pibuel, M., Álvarez, E., & Hajos, S. E. (2016). Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib. Glycobiology, 26(4), 343-352.
   99. Lorini, L., Bescós Atín, C., Thavaraj, S., Müller-Richter, U., Alberola Ferranti, M., Pamias Romero, J., ... & Simonetti, S. (2021). Overview of oral potentially malignant disorders: from risk factors to specific therapies. Cancers, 13(15), 3696.
   100. Loro, L. L., Laskin, D. M., & Giglio, J. A. (2018). Oral cavity and oropharyngeal cancer. Seminars in Roentgenology, 53(2), 75-81. doi: 10.1053/j.ro.2017.11.001.
   101. Louis, A. R. (2019). Immunohistochemical Evaluation of Stromal Myofibroblasts by Alpha Smooth Muscle Actin in Potentially Malignant and Malignant Lesions of the Oral Cavity: A Retrospective study (Doctoral dissertation, Best Dental Science College, Madurai).tnmgrmu.ac.in/10776.
   102. Lu, Y., Li, L., Chen, H., Jing, X., Wang, M., Ge, L., ... & Tang, X. (2021). Peroxiredoxin1 knockdown inhibits oral carcinogenesis via inducing cell senescence dependent on mitophagy. OncoTargets and therapy, 14, 239.
   103. Luna, E. C. M., Bezerra, T. M. M., de Barros Silva, P. G., Cavalcante, R. B., Costa, F. W. G., Alves, A. P. N. N., ... & Pereira, K. M. A. (2020). CD133 role in oral carcinogenesis. Asian Pacific Journal of Cancer Prevention: APJCP, 21(9), 2501.
   104. Lv, Y., & Zhang, Y. (2019). SPECT/CT imaging of targeting CD44+/CD133+ prostate cancer stem cells in nude mice using 99mTc-labeled hyaluronan.
   105. Ma, L., Liu, T., Jin, Y., Wei, J., Yang, Y., & Zhang, H. (2016). ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells. Tumor Biology, 37, 12889-12896.
   106. Manzano-Figueroa, S. (2021). Papel de C3G en la diseminación, tumorigénesis y señalización celular del glioblastoma./b1232ba1-8a71-4939-adb0-38f63a0fa205
   107. Mărgăritescu, C., Pirici, D., Simionescu, C., & Stepan, A. (2011). The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Rom J Morphol Embryol, 52(3 Suppl), 985-993.
   108. Martin TA, Harrison G, Mansel RE, Jiang WG. 2003 The role of the CD44/ezrin complex in cancer metastasis. Critical reviews in oncology/hematology; 46(2): 165-86
   109. Martínez-‐Ramos, C., & Lebourg, M. (2015). Three‐dimensional constructs using hyaluronan cell carrier as a tool for the study of cancer stem cells. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 103(6), 1249-1257.
   110. McDonald B, Kubes P. Interactions between CD44 and hyaluronan in leukocyte trafficking. Frontiers in immunology 2015; 6(68): 1-6
   111. Meng, X., Lou, Q. Y., Yang, W. Y., Wang, Y. R., Chen, R., Wang, L.,& Zhang, L. (2021). The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential. Cancer Communications, 41(10), 981-1006.
   112. Mishra, A., Meherotra, R., & Bhola, S. (2015). An overview of oral cancer in Indian subcontinent and recommendations to decrease its incidence. Ecancermedicalscience, 9, 526.
   113. Müller, S. (2018). Oral epithelial dysplasia, atypical verrucous lesions and oral potentially malignant disorders: focus on histopathology. Oral surgery, oral medicine, oral pathology and oral radiology, 125(6), 591-602.
   114. Nadal, R., Ortega, F. G., Salido, M., Lorente, J. A., RodríguezRivera, M., Delgado Rodríguez, M., ... & Serrano, M. J. (2013). CD133 expression in circulating tumor cells from breast cancer patients: potential role in resistance to chemotherapy. International journal of cancer, 133(10), 2398-2407.
   115. Nagao, T., & Kerr, A. R. (2023). Noninvasive Diagnostic. Oral Submucous Fibrosis: A Guide to Diagnosis and Management, 13, 197.
   116. National Comprehensive Cancer Network. (2022). NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf.
   117. Nemes, J. A., Redl, P., Boda, R., Kiss, C., & Márton, I. J. (2008). Oral cancer report from Northeastern Hungary. Pathology & Oncology Research, 14, 85-92.
   118. Neville, B. W., Damm, D. D., Allen, C. M., & Chi, A. C. (2019). Oral and maxillofacial pathology. Elsevier. 5th edition..,. 9780323789820
   119. Nikitakis, N. G., Pentenero, M., Georgaki, M., Poh, C. F., Peterson, D. E., Edwards, P., ... & Sauk, J. J. (2018). Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications. Oral surgery, oral medicine, oral pathology and oral radiology, 125(6), 650-669.
   120. Niklander, S., Bordagaray, M. J., Fernández, A., & Hernández, M. (2021). Vascular endothelial growth factor: A translational view in oral non-communicable diseases. Biomolecules, 11(1), 85.
   121. Pai, S., Bamodu, O. A., Lin, Y. K., Lin, C. S., Chu, P. Y., Chien, M. H., ... & Tsai, J. T. (2019). CD47-SIRPα signaling induces epithelial-mesenchymal transition and cancer stemness and links to a poor prognosis in patients with oral squamous cell carcinoma. Cells, 8(12), 1658.
   122. Panta, P., & Andreadis, D. (2019). Introduction to oral cancer. Oral Cancer Detection: Novel Strategies and Clinical Impact, 1-27.
   123. Piao, L. S., Hur, W., Kim, T. K., Hong, S. W., Kim, S. W., Choi, J. E., ... & Yoon, S. K. (2012). CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer letters, 315(2), 129-137.
   124. Rana, M., Kanwar, R., & Yadav, S. (2021). Epidemiology of oral cavity cancer in India. Journal of Family Medicine and Primary Care, 10(2), 568-574. doi: 10.4103/jfmpc.jfmpc_1176_20.
   125. Ranganathan, K., & Kavitha, L. (2019). Oral epithelial dysplasia: Classifications and clinical relevance in risk assessment of oral potentially malignant disorders. Journal of oral and maxillofacial pathology: JOMFP, 23(1), 19.
   126. Ranganathan, K., & Loganathan, K. (2023). Biomarkers in Oral Submucous Fibrosis.In Oral Submucous Fibrosis: A Guide to Diagnosis and Management (pp. 227-260). Cham: Springer International Publishing.10.1007/978-3-031-12855-4
   127. Rao, R. S., Raju K, L., Augustine, D., & Patil, S. (2020). Prognostic significance of ALDH1, Bmi1, and OCT4 expression in oral epithelial dysplasia and oral squamous cell carcinoma. Cancer Control, 27(1), 1073274820904959.
   128. Rao, U. K. M., Thavarajah, R., Joshua, E., & Ranganathan, K. (2018). Loss of heterozygosity as a marker to predict progression of oral epithelial dysplasia to oral squamous cell carcinoma. Journal of Oral and Maxillofacial Pathology: JOMFP, 22(2), 155.
   129. Rassouli, F. B., Matin, M. M., & Saeinasab, M. (2016). Cancer stem cells in human digestive tract malignancies. Tumor Biology, 37, 7-21.
   130. Ravindran, G., & Devaraj, H. (2012). Aberrant expression of CD133 and musashi‐1 in preneoplastic and neoplastic human oral squamous epithelium and their correlation with clinicopathological factors. Head & neck, 34(8), 1129-1135
   131. Ray, J. G. (2017). Oral potentially malignant disorders: Revisited. Journal of oral and maxillofacial pathology: JOMFP, 21(3), 326.
   132. Ren, F., Sheng, W. Q., & Du, X. (2013). CD133: a cancer stem cells marker, is used in colorectal cancers. World journal of gastroenterology, 19(17), 2603-2611.
   133. Romeo, U., Palaia, G., Tenore, G., Del Vecchio, A., Botti, R., Nammour, S., ... & Polimeni, A. (2020). Preoperative intra-oral ultrasound in the evaluation of early oral squamous cell carcinoma: prospective study. Head & Face Medicine, 16(1), 1-9. https://doi.org/10.1186/s13005-020-00239-8
   134. Saboor, A., Khan, M. M., Afsar, B., & Khan, A. S. (2023). Serum E-Cadherin level in various clinical variants of oral potentially pre-malignant disorders. Khyber Medical University Journal, 15(3), 167-170.
   135. Saghravanian, N., Anvari, K., Ghazi, N., Memar, B., Shahsavari, M., & Aghaee, M. A. (2017). Expression of p63 and CD44 in oral squamous cell carcinoma and correlation with clinicopathological parameters. Archives of oral biology, 82, 160-165.
   136. Saluja, T. S., Ali, M., Mishra, P., Kumar, V., & Singh, S. K. (2019). Prognostic value of cancer stem cell markers in potentially malignant disorders of oral mucosa: a meta-analysis. Cancer Epidemiology, Biomarkers & Prevention, 28(1), 144-153.
   137. Samman, N., Mohammadi, H., & Xia, J. (2003). Cephalometric norms for the upper airway in a healthy Hong Kong Chinese population. Hong Kong Med J.
   138. Sana, J., Zambo, I., Skoda, J., Neradil, J., Chlapek, P., Hermanova, M., ... & Veselska, R. (2011). CD133 expression and identification of CD133/nestin positive cells in rhabdomyosarcomas and rhabdomyosarcoma cell lines. Analytical Cellular Pathology, 34(6), 303-318.
   139. Sankaranarayanan, R., Ramadas, K., Amarasinghe, H., Subramanian, S., & Johnson, N. (2015). Oral Cancer: Prevention, Early Detection, and Treatment. In Cancer: Disease Control Priorities, Third Edition (Volume 3).pubmed.ncbi.nlm.nih.gov/26913350.
   140. Scully, C. (2011). Oral cancer aetiopathogenesis; past, present and future aspects. Med Oral Patol Oral Cir Bucal, 16(3), e306-11.
   141. Seiichi, Y., & Toshiro, K. (2011). Expression of CD133 and Extracellular Matrix Molecules in Malignant Brain Tumors. Neuroscience & Medicine, 2011.
   142. Shahzad, R., Anjum, T., & Shahid, A. B. (2024). Cutaneous metastasis in hypopharyngeal carcinoma: a case report. Asian biomedicine : research, reviews and news, 18(1), 30–34. https://doi.org/10.2478/abm-2024-0006
   143. Shaw, R. J., Lowe, D., Woolgar, J. A., Brown, J. S., Vaughan, E. D., Evans, C., ... & Rogers, S. N. (2010). Extracapsular spread in oral squamous cell carcinoma. Head & Neck: Journal for the Sciences and Specialties of the Head and Neck, 32(6), 714-722.
   144. Singh, A., Srivastava, A. N., Akhtar, S., Siddiqui, M. H., Singh, P., & Kumar, V. (2018). Correlation of CD133 and Oct-4 expression with clinicopathological and demographic parameters in oral squamous cell carcinoma patients. Nat J Maxillofac surg, 9(1), 8.
   145. Sridharan, G., Shankar, A. A., & Toluidine, B. (2016). Blue staining for oral cancer detection: A review of literature. Journal of International Society of Preventive and Community Dentistry, 6(2), 106-113. doi: 10.4103/2231-0762.175413.
   146. Sun, L., Feng, J., Ma, L., Liu, W., & Zhou, Z. (2013). CD133 expression in oral lichen planus correlated with the risk for progression to oral squamous cell carcinoma. Annals of Diagnostic Pathology, 17(6), 486-489.
   147. Syrjänen, S., & Syrjänen, K. (2019). HPV in head and neck carcinomas: Different HPV profiles in oropharyngeal carcinomas–Why?. Acta cytologica, 63(2), 124-142.
   148. Sahaf, R., Naseem, N., Anjum, R., Nagi, A. H., & Path, F. (2017). A study of 89 cases of oral squamous cell carcinoma presenting at Teaching Hospitals of Lahore, Pakistan. J Pak Dent Assoc, 26(01), 27-31.
   149. Srivastava, R., Sharma, L., Pradhan, D., Jyoti, B., & Singh, O. (2020). Prevalence of oral premalignant lesions and conditions among the population of Kanpur City, India: A cross-sectional study. J Fam Med Primary Care, 9(2), 1080-1085.
   150. Tan, Y., Chen, B. O., Xu, W. E. I., Zhao, W., & Wu, J. (2014). Clinicopathological significance of CD133 in lung cancer: A metaanalysis. Molecular and clinical oncology, 2(1), 111-115.
   151. Tanaka, S., Nakada, M., Yamada, D., Nakano, I., Todo, T., Ino, Y., ... & Hirao, A. (2015). Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells. Journal of neuro-oncology, 121, 239-250.
   152. Thakkar, S., Sharma, D., Kalia, K., & Tekade, R. K. (2020). Tumor microenvironment targeted nanotherapeutics for cancer therapy and diagnosis: A review. Acta biomaterialia, 101, 43-68.
   153. Tseng, J. Y., Yang, C. Y., Yang, S. H., Lin, J. K., Lin, C. H., & Jiang, J. K. (2015). Circulating CD133+/ESA+ cells in colorectal cancer patients. journal of surgical research, 199(2), 362-370.
   154. Vora, P., Venugopal, C., Salim, S. K., Tatari, N., Bakhshinyan, D., Singh, M., ... & Singh, S. (2020). The rational development of CD133-targeting immunotherapies for glioblastoma. Cell Stem Cell, 26(6), 832-844.
   155. Vora, P., Venugopal, C., Salim, S. K., Tatari, N., Bakhshinyan, D., Singh, M., ... & Singh, S. (2020). The rational development of CD133-targeting immunotherapies for glioblastoma. Cell Stem Cell, 26(6), 832-844.
   156. Wakamatsu, Y., Sakamoto, N., Oo, H. Z., Naito, Y., Uraoka, N., Anami, K., ... & Yasui, W. (2012). Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathology international, 62(2), 112-119.
   157. Wang SJ, Bourguignon LY. 2011 Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. The American journal of pathology; 178(3): 956-63
   158. Wang, C., Wang, J., Chen, Z., Gao, Y., & He, J. (2017). Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review. Chinese journal of cancer, 36(1), 1-17.
   159. Wang, S., Xu, Z. Y., Wang, L. F., & Su, W. (2013). CD133+ cancer stem cells in lung cancer. Frontiers in Bioscience-Landmark, 18(2), 447-453.
   160. Warnakulasuriya, S. (2009). Global epidemiology of oral and oropharyngeal cancer. Oral Oncology, 45(4-5), 309-316. doi: 10.1016/j.oraloncology.2008.06.002.
   161. Warnakulasuriya, S., Kujan, O., Aguirre‐Urizar, J. M., Bagan, J. V., González‐Moles, M. Á., Kerr, A. R., ... & Johnson, N. W. (2021). Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer. Oral diseases, 27(8), 1862-1880.
   162. Wen, L., Chen, X. Z., Yang, K., Chen, Z. X., Zhang, B., Chen, J. P., ... & Hu, J. K. (2013). Prognostic value of cancer stem cell marker CD133 expression in gastric cancer: a systematic review. PloS one, 8(3), e59154.
   163. Wu, K. X., Yeo, N. J. Y., Ng, C. Y., Chioh, F. W. J., Fan, Q., Tian, X., ... & Cheung, C. (2022). Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy. BMC biology, 20(1), 1-21.
   164. Yanamoto, S., Yamada, S. I., Takahashi, H., Naruse, T., Matsushita, Y., Ikeda, H., ... & Umeda, M. (2014). Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: Effect of neoadjuvant chemotherapy on local recurrence. International Journal of Oncology, 44(4), 1153-1162.
   165. Yang, C. C., Hung, P. S., Wang, P. W., Liu, C. J., Chu, T. H., Cheng, H. W., & Lin, S. C. (2011). miR 181 as a putative biomarker for lymph‐node metastasis of oral squamous cell carcinoma. Journal of oral pathology & medicine, 40(5), 397-404.
   166. Yardimci, G., Kutlubay, Z., Engin, B., & Tuzun, Y. (2014). Precancerous lesions of oral mucosa. World J Clin Cases, 2(12), 866.
   167. Yasser, F., Mushtaq, S., Ahmad, A., Tauseef, A., & Yasser, R. (2020). Examine the Prevalence of Risk Factors and Causes of Oral Squamous Cell Carcinoma. National Editorial Advisory Board, 31(8), 97.
   168. Zhang, J., Luo, N., Luo, Y., Peng, Z., Zhang, T., & Li, S. (2012). microRNA-150 inhibits human CD133-positive liver cancer stem cells through negative regulation of the transcription factor c-Myb. International journal of oncology, 40(3), 747-756.
   169. Zhang, Q., Shi, S., Yen, Y., Brown, J., Ta, J. Q., & Le, A. D. (2010). A subpopulation of CD133+ cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer letters, 289(2), 151-160.
   170. Zhang, X., Peng, Y., & Zou, K. (2018). Germline stem cells: a useful tool for therapeutic cloning. Current stem cell research & therapy, 13(4), 236-242.
   171. Zhou, J., Chen, Q., Zou, Y., Zheng, S., & Chen, Y. (2019). Stem cells and cellular origins of the mammary gland: updates in rationale, controversies, and cancer relevance. Stem Cells International. https://doi.org/10.1155/2019/7512702.
   prognostic value. J Pathol. 1992;166(4):375-381. doi: 10.1002/path.1711660409.,