Tumour stem cell markers CD133 and CD44 are useful prognostic factors after surgical resection of pancreatic neuroendocrine tumours
- Authors:
- Published online on: October 8, 2020 https://doi.org/10.3892/ol.2020.12204
- Article Number: 341
-
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pancreatic neuroendocrine tumours (PNETs) are rare neuroendocrine neoplasms that originate from diffuse neuroendocrine cells (1). The incidence of PNETs has been increasing rapidly in the last 50 years. The age-adjusted incidence rate increased 6.4-fold from 1973 (1.09/100 000) to 2012 (6.98/100 000), partly as a result of increased detection using endoscopic and imaging techniques (2,3). Surgery remains the mainstay of therapy for patients diagnosed with both functional and non-functional PNETs (4). Regarding biological behaviour, PNETs have traditionally been considered to be less aggressive than pancreatic adenocarcinomas; however, the pathological potential of PNETs is increasingly being recognized as highly variable (5). Outcomes after surgical resection vary widely, with recurrence rates ranging between 17 and 76% (6–8). The prominent heterogeneity of PNETs creates an urgent need for prognostic factors. Various studies have specifically investigated factors that are associated with PNET progression (1,4,8). However, the pathophysiology involved in the progression and prognosis of PNETs remains incompletely characterized.
CD44 belongs to the adhesion molecule family (9), which serves important roles in cell proliferation, apoptotic resistance, motility, metastasis and chemotherapy resistance (10–12). Studies have reported that CD44 overexpression is associated with metastasis and a poor prognosis in various types of cancer, including gastric cancer, breast cancer and hepatocellular carcinoma (13–20). Additionally, CD44 has been used as a specific marker of cancer stem cells (CSCs) in a number of human tumours (10,21,22). Furthermore, CD44 serves an important role in invasion and metastasis in a variety of human cancer types, including pancreatic adenocarcinoma (23,24).
CD133, a member of the pentaspan transmembrane glycoprotein family, is another marker of CSCs (25). CD133 was first described as a hematopoietic stem cell marker and later reported as a marker of CSCs in solid tumours (26). Previous studies have focused on CD44 and CD133 co-expression; high CD133 and CD44 expression is associated with invasion, metastasis, recurrence and decreased survival time in colon cancer, gastric cancer, oesophageal cancer, medullary thyroid carcinoma and hepatoblastoma (14,19,27–32).
CSC subpopulations are critical in cancer progression and serve as a promising therapeutic target (33). Numerous investigations have sought to identify CSC populations based on their surface markers (33–35). CSCs are also present in NETs (35), where several CSC markers have been investigated, including aldehyde dehydrogenase (ALDH), CD73 and CD24 (35–37). NET cells with high ALDHA expression exhibit CSC-like properties (35). High CD73 expression in PNET tissues is strongly associated with invasion into adjacent organs (37). CD24 expression is frequently noted in primary and metastatic midgut NETs, but is rare in PNETs (36). However, to the best of our knowledge, studies on CD44 and CD133 expression in PNETs and their prognostic value have not been performed. Therefore, the present study aimed to analyse CD44 and CD133 expression in a cohort of patients with PNETs, as well as the association between protein expression and clinicopathological characteristics, while further investigating the prognostic values of CD44 and/or CD133 in this group.
Materials and methods
Patients and samples
Patients who underwent radical surgery for a PNET between January 2,000 and December 2016 at the Department of General Surgery, Guangdong Provincial People's Hospital (Guangzhou, China) were included. Formalin-fixed paraffin-embedded primary specimens were obtained from all patients, with protocols approved by the Medical Ethics Review Committee of Guangdong General Hospital, and written informed consent was provided by all patients. The entire study was performed in accordance with the Declaration of Helsinki.
The histological types and grades of all samples were determined by experienced pathologists. The clinical stage of patients with PNETs was evaluated based on the TNM classification system (American Joint Committee on Cancer, TNM Staging System for Pancreatic Neuroendocrine Tumours, 7th edition, 2010) (38). Histological grades of the tumours were assessed according to the World Health Organization (WHO) 2010 classification (39). Routine pathology staining was used for Ki-67 and to calculate percentage as Ki-67 index, the detail is the same as percentage of CD44/CD133 in the immunohistochemistry method. Mitotic count and Ki-67 index were assessed independently by two pathologists who evaluated ≥10 high-power fields for each section. The results of Ki-67 index and mitotic count were further verified by a senior chief pathologist.
The inclusion criteria for patients were as follows: i) Initial treatment, including radical resection; ii) pathological confirmation of PNET by postoperative histopathological diagnosis; iii) no adjuvant therapy prior to surgery; iv) tumour lacking involvement of the celiac axis or the superior mesenteric artery, or without exhibiting distal metastasis; and v) no history of other malignancies. In total, 5 patients were excluded based on these criteria. Additionally, a single patient succumbed to a massive abdominal haemorrhage during the perioperative period and was excluded. Finally, a total of 71 eligible patients were identified.
Information regarding clinicopathological characteristics was collected for each patient. Follow-up information on prognosis was collected through clinic visits in outpatient departments, telephone calls and questionnaires. Disease-free survival (DFS) was calculated from the date of diagnosis to local recurrence or distal metastasis. Overall survival (OS) was measured from the date of diagnosis to death due to any cause, in addition to perioperative death caused by surgical complications.
Immunohistochemistry
Slides (4-µm thick, two serial sections for each sample) of formalin-fixed (37–40% for 24 h) at room temperature, paraffin-embedded specimens with the highest tumour content were used for immunohistochemical staining. Briefly, immunochemistry for CD44 (rabbit monoclonal antibody; 1:100; cat. no. ab51037; Abcam) and CD133 (rabbit polyclonal antibody; 1:200; cat. no. orb99113; Biorbyt, Ltd.) and Ki-67 (rat polyclonal antibody; 1:2,000; MIB-1; Gene Tech Co., Ltd.) was performed using commercially available antibodies. Sections were heated at 60°C for 1 h and de-paraffinized in xylene and rehydrated in a graded ethanol series. Subsequently, antigen retrieval was performed using a microwave at 110°C for 3 min. Endogenous peroxidase activity was blocked using 3% hydrogen peroxide. Non-specific binding was blocked using 3% bovine serum albumin (cat. no. G5001; Servicebio, http://www.servicebio.cn/search-result?search=G5001) in PBS at room temperature for 30 min. The aforementioned primary antibodies were added overnight at 4°C. After sufficient PBS washes at room temperature for 5 min (three times), sections were stained at room temperature for 1 h with horseradish peroxidase-labelled goat anti-rabbit antibodies (1:200; cat. no. K5007; Dako; Agilent Technologies, Inc.). The sections were subsequently stained with 3,3′-diaminobenzidine. Slides were observed under a light microscope (XSP-C204; CIC, magnification, ×100).
CD44 and CD133 immunostaining were blindly scored by two independent pathologists using a semi-quantitative method that included staining intensity (scored from 0 to 3) and the percentage of positively stained tumour cells (scored from 0 to 100). Briefly, staining intensities were scored as follows: 0, no staining; 1, weak staining; 2, moderate staining; or 3, intense and strong staining. The percentage of positively stained tumour cells was determined by counting the number of positive staining cells and the number of all tumour cells in ≥10 random-selected high-power fields (HPFs), and calculated by the formula: Percentage (range, 0–100)=Number of stained cells/Total number of cells ×100. A total score was calculated for each sample using the following formula: Total score (range, 0–300)=Staining intensity scores (range, 0–3)xPercentage of positively stained cells (range, 0–100).
Statistical analysis
Statistical analysis was performed using SPSS software v24.0 (IBM Corp.). The presentation of data adopt mean ± SD. Frequency distributions and categorical variables were compared using the χ2 test or ordinal regression, and continuous variables were compared using one-way ANOVA, differences among groups were compared using one-way ANOVA followed by LSD post hoc test. The Kaplan-Meier survival method with the log-rank test was used to assess survival time. P<0.05 (two-tailed) was considered to indicate a statistically significant difference.
Results
Patient characteristics
The present study included a total of 71 patients, of whom 42 were men (59.2%). The mean age was 45.2 years (range, 10–78 years). A total of 31 (43.7%) patients had functional PNETs, while 40 (56.3%) patients had non-functional PNETs. All patients underwent an intended curative resection. A total of 40 (56.3%) of these patients underwent a pancreaticoduodenectomy or distal pancreatectomy, 7 patients (9.9%) had a segmental pancreatectomy, 16 patients (22.5%) had an enucleation, 7 patients (9.9%) had a local resection and 1 patient (1.4%) had a duodenum-preserving resection of the pancreatic head,. Only 1 patient exhibited an R1 surgical margin, where the tumour was adjacent to the adrenal gland. A total of 31 (43.6%) patients were categorized as G1 grade and 30 (42.3%) patients were categorized as G2 grade and 10 (14.1%) patients were categorized as G3 grade, according to the 2010 WHO classification of tumours of the digestive system. A total of 15 patients (21.1%) experienced recurrence, with a median time to recurrence of 2.5 years (range, 0.5–8.0 years; data not shown).
CD44 and CD133 expression in PNETs
Both CD44 and CD133 expression were observed in PNET tissues. CD44 and CD133 were primarily detected in the cytoplasm and cytomembrane of cells. CD44 exhibited two staining patterns: Diffuse staining and scattered staining (Fig. 1A and B). The same staining patterns were also noted for CD133 (Fig. 1C and D).
The expression levels of CD44 and CD133 were evaluated in serial sections. The obtained staining scores ranged from 0 (no staining) to 264 for CD44 staining and from 0 to 243 for CD133 staining. For further analysis, CD44/133 expression was divided into 4 levels: Level 0, no staining; level 1, score 1–100; level 2, score 101–200; and level 3, score 201–300. Representative images of staining levels are presented in Fig. 2. The number of cases in each level is presented in Table I. Overall, CD44 staining was stronger than CD133 staining (Table I; Fig. 3), and a significant association was observed between CD44 and CD133 expression (P<0.001; Table I).
CD44/CD133 expression and clinicopathological parameters in PNETs
Patients were stratified according to the total score of IHC staining, and the association between CD44/CD133 expression, and clinical characteristics of the enrolled patients were compared. The associations between CD44 or CD133 expression and the clinicopathological characteristics of patients with PNET are presented in Tables II and III, respectively. Increased CD44 expression was associated with poor tumour differentiation (P=0.007), high Ki-67 index (P=0.001), added mitotic count (P=0.003), high histological grade (P=0.001) and advanced stage (P=0.025) (Table II). Increased CD133 expression was also associated with high Ki-67 index (P=0.014), age (P=0.028) and added mitotic count (P=0.012), but not with tumour differentiation (P=0.118), tumour histologic grade (P=0.126) and stage (P=0.203) (Table III). No significant associations were observed between CD44/133 expression and other clinical parameters, such as sex, tumour location, tumour size, TNM stage and functionality (Tables II and III).
Table II.Association between CD44 expression and clinicopathological characteristics in patients with pancreatic neuroendocrine tumours (n=71). |
Table III.Association between CD133 expression and clinicopathological characteristics in patients with pancreatic neuroendocrine tumours (n=71). |
Survival analysis
The median follow-up time for this cohort was 57 months (range, 12–182 months). The single patient with an R1 surgical margin was excluded from the survival analysis to maintain sample homogeneity. Kaplan-Meier survival curves for DFS and OS stratified by Ki-67 index or histological grade are presented in Fig. 4. Consistent with the aforementioned immunohistochemistry observations, increased Ki-67 proliferative index and high histological grade were associated with a poor prognosis in patients with PNET. Additionally, Kaplan-Meier survival curves revealed that patients with PNET with low or no CD44 expression had significantly improved OS and DFS rates (Fig. 5A and B). Increased CD133 expression was associated with a poor OS rate (Fig. 5C); however, this association was not significant (P=0.0741). However, CD133 expression was a significant prognostic factor for DFS (P=0.0008; Fig. 5D).
To further evaluate the combined effect of CD44 and CD133 co-expression on the prognosis in patients with PNET, the CD44 expression levels were combined with the CD133 expression levels for each sample, obtaining combined scores ranging from 0 to 6. Kaplan-Meier analysis revealed that patients with high combined scores exhibited significantly decreased OS and DFS rates (Fig. 5E and F). Among the patients with a combined score ≤1, none of the patients developed recurrence during the follow-up period. Two G1 grade patients with a Ki-67 index ≤1% experienced recurrence during the follow-up period, suggesting that a total combined score ≤1 (indicating no CD44 and CD133 expression, or that one of them is not expressed and the other is expressed at a low level) may be a more effective predictor of a favourable prognosis in patients with PNETs than low histological grade or low Ki-67 index.
Discussion
Surgical resection remains the primary curative modality in the management of PNETs (4). However, heterogeneous behaviour and unpredictable pathology are a challenge to optimal treatment decision-making. The use of CD44 and CD133 as markers for CSCs, which may promote tumourigenesis and regeneration, has been actively investigated in various types of solid tumour, such as gastric cancer, breast cancer and colon cancer (14,40,41). Additionally, the presence of CSCs has been confirmed in NETs (35). However, no evidence is available on the expression levels of the CSC markers CD44 and CD133 in PNETs and their effect on the prognosis in patients with PNET.
In the present study, data from 71 patients with PNET were obtained to examine the significance of CD44 and CD133 as prognostic markers for survival. Immunohistochemical analysis revealed that both CD44 and CD133 were expressed in most PNET tissues and revealed a tendency toward co-expression. Overall, CD44 exhibited a higher positive rate and stronger staining intensity compared with CD133. Survival analysis demonstrated that CD133 and/or CD44 upregulation may predict an unfavourable prognosis in patients with PNETs.
CSC populations are primarily responsible for tumour initiation, growth and metastasis (42). To date, studies on CSCs in NETs have been rare. Gaur et al (35) identified and characterized neuroendocrine CSCs from a midgut carcinoid cell line (CNDT2.5) using ALDH as a surface marker, revealing that CSCs are present in NETs. However, tumour biological characteristics and stem cell markers may differ between midgut NETs and PNETs. For example, CD24 is a CSC marker, and its expression is frequently noted in primary and metastatic midgut NETs, but is rarely observed in pancreatic and duodenal NETs (36). In midgut NET cells, Gaur et al (35) observed that nearly all CNDT2.5 cells bind to CD44, whereas cells were not labelled with CD133. In the present immunohistochemical assessment of PNET tissues, CD44 and CD133 were co-expressed in PNETs. The significant associations between CD44 and/or CD133 and the prognosis in patients with PNETs suggest that these proteins are important tumour promoters and potential CSC markers in PNETs.
Surgical resection remains the curative treatment for patients with PNET. Most studies on prognostic factors for outcomes after resection of PNET include patients with distal metastases at resection, stage III patients with tumours involving the celiac axis or the superior mesenteric artery, R1 resections or patients with familial syndromes (43–46). In the present study, a selective group of patients with stage I–II PNETs with R0 resection was included, and risk factors for prognosis were analysed. In the present cohort, recurrences were noted in patients with Ki-67 index ≤1 and in G1 patients. However, patients with a CD44/CD133 total combined score ≤1 exhibited no risk of recurrence. By contrast, patients with an increased total score exhibited a significantly increased risk of recurrence. Therefore, the type of follow-up visit may be selected based on different recurrence risks to be more cost-effective. To the best of our knowledge, there is no evidence that evaluates the effects of adjuvant therapy after radical surgical resection of PNETs. In current clinical practice, the decision regarding adjuvant therapy after surgery remains at the discretion of the attending physician. The present findings may help to avoid unnecessary adjuvant treatments in patients with a very low risk of recurrence and to optimize patient selection to investigate the role of adjuvant therapy based on recurrence risk in further clinical research.
There are several limitations to the present study. First, due to the low incidence of PNETs, the sample size of a PNET cohort in a single centre is typically small, as in the current study. Given that a large cohort is required to meet the requirements of Cox regression analysis, it was not possible to perform this analysis. Second, the aforementioned conclusions are limited by the nature of single-centre data; an external validation cohort is required to investigate whether the prognostic value of CD44/CD133 is significant in other populations. Third, there was an extended inclusion period in the present study. During this period, follow-up strategies, surgical resection techniques and systemic treatments have changed, which may have altered patient outcomes. However, these limitations are difficult to overcome given the low incidence and long course of PNETs. Further prospective and multi-centre trials are warranted to discover prognostic factors for PNETs and to reveal the underlying mechanisms involved in the development of this type of tumour.
In conclusion, the present study revealed that CD44/CD133 expression may be a useful biomarker to predict prognosis after surgical resection of PNETs, and it may have a pivotal role in the progression of PNETs. The current study was limited by the nature of a retrospective design, and further prospective studies and laboratory research are required to confirm the present results and provide additional evidence for the role of CD44/CD133 in PNETs.
Acknowledgements
Not applicable.
Funding
The present study was supported by a grant from the Special Fund for Science and Technology Development of Guangdong Province (grant no. 2016A030313769).
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
BH conceived the present study. ZS and DL drafted the initial manuscript. HW performed the immunohistochemical examination of the sections. ZS was a major contributor to drafting the final version of the manuscript. ZS, DL and BH analysed and interpreted the patient data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Formalin-fixed, paraffin-embedded primary specimens were obtained from all patients with protocols approved by the Medical Ethics Review Committee of Guangdong Provincial People's Hospital (Guangzhou, China; approval no. KY2020-169-01), and written informed consent was provided by all patients. All the work was performed in accordance with the Declaration of Helsinki.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
PNETs |
pancreatic neuroendocrine tumours |
CSC |
cancer stem cell |
ALDH |
aldehyde dehydrogenase |
OS |
overall survival |
DFS |
disease-free survival |
References
Vinik A, Casellini C, Perry RR, Feliberti E and Vingan H: Diagnosis and management of pancreatic neuroendocrine tumors (PNETS). De Groot LJ, Chrousos G and Dungan K: Endotext, MDText.com, Inc. (South Dartmouth, MA). 2000. | |
Simard EP, Ward EM, Siegel R and Jemal A: Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin. 62:118–128. 2012. View Article : Google Scholar : PubMed/NCBI | |
Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T and Yao JC: Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3:1335–1342. 2017. View Article : Google Scholar : PubMed/NCBI | |
Chiruvella A and Kooby DA: Surgical management of pancreatic neuroendocrine tumors. Surg Oncol Clin N Am. 25:401–421. 2016. View Article : Google Scholar : PubMed/NCBI | |
Kidd M, Modlin I and Oberg K: Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat Rev Clin Oncol. 13:691–705. 2016. View Article : Google Scholar : PubMed/NCBI | |
Haynes AB, Deshpande V, Ingkakul T, Vagefi PA, Szymonifka J, Thayer SP, Ferrone CR, Wargo JA, Warshaw AL and Fernández-del Castillo C: Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: Short-term and long-term patient outcomes. Ach Surg. 146:534–538. 2011. | |
Solorzano CC, Lee JE, Pisters PW, Vauthey JN, Ayers GD, Jean ME, Gagel RF, Ajani JA, Wolff RA and Evans DB: Nonfunctioning islet cell carcinoma of the pancreas: Survival results in a contemporary series of 163 patients. Surgery. 130:1078–1085. 2001. View Article : Google Scholar : PubMed/NCBI | |
Wei IH, Harmon CM, Arcerito M, Cheng DF, Minter RM and Simeone DM: Tumor-associated macrophages are a useful biomarker to predict recurrence after surgical resection of nonfunctional pancreatic neuroendocrine tumors. Ann Surg. 260:1088–1094. 2014. View Article : Google Scholar : PubMed/NCBI | |
Bajorath J: Molecular organization, structural features, and ligand binding characteristics of CD44, a highly variable cell surface glycoprotein with multiple functions. Proteins. 39:103–111. 2000. View Article : Google Scholar : PubMed/NCBI | |
Thapa R and Wilson GD: The importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int. 2016:20872042016. View Article : Google Scholar : PubMed/NCBI | |
Naor D, Wallach-Dayan SB, Zahalka MA and Sionov RV: Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol. 18:260–267. 2008. View Article : Google Scholar : PubMed/NCBI | |
Ponta H, Sherman L and Herrlich PA: CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 4:33–45. 2003. View Article : Google Scholar : PubMed/NCBI | |
Naor D, Nedvetzki S, Golan I, Melnik L and Faitelson Y: CD44 in cancer. Crit Rev Clin Lab Sci. 39:527–579. 2002. View Article : Google Scholar : PubMed/NCBI | |
Lu L, Wu M, Sun L, Li W, Fu W, Zhang X and Liu T: Clinicopathological and prognostic significance of cancer stem cell markers CD44 and CD133 in patients with gastric cancer: A comprehensive meta-analysis with 4729 patients involved. Medicine. 95:e51632016. View Article : Google Scholar : PubMed/NCBI | |
Wang SJ and Bourguignon LY: Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance. Am J Pathol. 178:956–963. 2011. View Article : Google Scholar : PubMed/NCBI | |
Chang SJ, Ou-Yang F, Tu HP, Lin CH, Huang SH, Kostoro J, Hou MF, Chai CY and Kwan AL: Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24−/low) indicate poor prognosis in triple-negative breast cancer. Hum Pathol. 48:48–55. 2016. View Article : Google Scholar : PubMed/NCBI | |
Jian-Hui C, Er-Tao Z, Si-Le C, Hui W, Kai-Ming W, Xin-Hua Z, Chaung-Qi C, Shi-Rong C and Yu-Long H: CD44, Sonic Hedgehog, and Gli1 expression are prognostic biomarkers in gastric cancer patients after radical resection. Gastroenterol Res Pract. 2016:10130452016. View Article : Google Scholar : PubMed/NCBI | |
Zhao Q, Zhou H, Liu Q, Cao Y, Wang G, Hu A, Ruan L, Wang S, Bo Q, Chen W, et al: Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models. Oncotarget. 7:47431–47443. 2016. View Article : Google Scholar : PubMed/NCBI | |
Durko L, Wlodarski W, Stasikowska-Kanicka O, Wagrowska-Danilewicz M, Danielewicz M, Hogendorf P, Strzelczyk J and Malecka-Panas E: Expression and clinical significance of cancer stem cell markers CD24, CD44, and CD133 in pancreatic ductal adenocarcinoma and chronic pancreatitis. Dis Markers. 2017:32768062017. View Article : Google Scholar : PubMed/NCBI | |
Iseki Y, Shibutani M, Maeda K, Nagahara H, Ikeya T and Hirakawa K: Significance of E-cadherin and CD44 expression in patients with unresectable metastatic colorectal cancer. Oncol Lett. 14:1025–1034. 2017. View Article : Google Scholar : PubMed/NCBI | |
Chanmee T, Ontong P, Kimata K and Itano N: Key roles of hyaluronan and its CD44 receptor in the stemness and survival of cancer stem cells. Front Oncol. 5:1802015. View Article : Google Scholar : PubMed/NCBI | |
Bourguignon LYW, Earle C and Shiina M: Activation of matrix hyaluronan-mediated CD44 signaling, epigenetic regulation and chemoresistance in head and neck cancer stem cells. Int J Mol Sci. 18:18492017. View Article : Google Scholar | |
Ohara Y, Oda T, Sugano M, Hashimoto S, Enomoto T, Yamada K, Akashi Y, Miyamoto R, Kobayashi A, Fukunaga K, et al: Histological and prognostic importance of CD44(+)/CD24(+)/EpCAM(+) expression in clinical pancreatic cancer. Cancer Sci. 104:1127–1134. 2013. View Article : Google Scholar : PubMed/NCBI | |
Li XP, Zhang XW, Zheng LZ and Guo WJ: Expression of CD44 in pancreatic cancer and its significance. Int J Clin Exp Pathol. 8:6724–6731. 2015.PubMed/NCBI | |
Grosse-Gehling P, Fargeas CA, Dittfeld C, Garbe Y, Alison MR and Corbeil D Kunz-Schughart LA: CD133 as a biomarker for putative cancer stem cells in solid tumours: Limitations, problems and challenges. J Pathol. 229:355–378. 2013. View Article : Google Scholar : PubMed/NCBI | |
Bauer N, Fonseca AV, Florek M, Freund D, Jaszai J, Bornhauser M, Fergeas CA and Corbeil D: New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133). Cells Tissues Organs. 188:127–138. 2008. View Article : Google Scholar : PubMed/NCBI | |
Bellizzi A, Sebastian S, Ceglia P, Centonze M, Divella R, Manzillo EF, Azzariti A, Silvestris N, Montemurro S, Caliandro C, et al: Co-expression of CD133(+)/CD44(+) in human colon cancer and liver metastasis. J Cell Physiol. 228:408–415. 2013. View Article : Google Scholar : PubMed/NCBI | |
Mokrowiecka A, Veits L, Falkeis C, Musial J, Kordek R, Lochowski M, Kozak J, Wierzchniewska-Lawska A, Vieth M and Malecka-Panas E: Expression profiles of cancer stem cell markers: CD133, CD44, Musashi-1 and EpCAM in the cardiac mucosa-Barrett's esophagus-early esophageal adenocarcinoma-advanced esophageal adenocarcinoma sequence. Pathol Res Pract. 213:205–209. 2017. View Article : Google Scholar : PubMed/NCBI | |
Wang J, Wu Y, Gao W, Li F, Bo Y, Zhu M, Fu R, Liu Q, Wen S and Wang B: Identification and characterization of CD133+CD44+ cancer stem cells from human laryngeal squamous cell carcinoma cell lines. J Cancer. 8:497–506. 2017. View Article : Google Scholar : PubMed/NCBI | |
Han SA, Jang JH, Won KY, Lim SJ and Song JY: Prognostic value of putative cancer stem cell markers (CD24, CD44, CD133, and ALDH1) in human papillary thyroid carcinoma. Pathol Res Prac. 213:956–963. 2017. View Article : Google Scholar | |
Zhou JY, Chen M, Ma L, Wang X, Chen YG and Liu SL: Role of CD44(high)/CD133(high) HCT-116 cells in the tumorigenesis of colon cancer. Oncotarget. 7:7657–7666. 2016. View Article : Google Scholar : PubMed/NCBI | |
Bahnassy AA, Fawzy M, El-Wakil M, Zekri AR, Abdel-Sayed A and Sheta M: Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data. Transl Res. 165:396–406. 2015. View Article : Google Scholar : PubMed/NCBI | |
Putzer BM, Solanki M and Herchenroder O: Advances in cancer stem cell targeting: How to strike the evil at its root. Adv Drug Deliv Rev. 120:89–107. 2017. View Article : Google Scholar : PubMed/NCBI | |
Leon G, MacDonagh L, Finn SP, Cuffe S and Barr MP: Cancer stem cells in drug resistant lung cancer: Targeting cell surface markers and signaling pathways. Pharmacol Ther. 158:71–90. 2016. View Article : Google Scholar : PubMed/NCBI | |
Gaur P, Sceusi EL, Samuel S, Xia L, Fan F, Zhou Y, Lu J Tozzi F, Lopez-Berestein G, Vivas-Mejia P, et al: Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors. Gastroenterology. 141:1728–1737. 2011. View Article : Google Scholar : PubMed/NCBI | |
Salaria S, Means A, Revetta F, Idrees K, Liu E and Shi C: Expression of CD24, a stem cell marker, in pancreatic and small intestinal neuroendocrine tumors. Am J Clin Pathol. 144:642–648. 2015. View Article : Google Scholar : PubMed/NCBI | |
Katsuta E, Tanaka S, Mogushi K, Shimada S, Akiyama Y, Aihara A, Matsumura S, Mitsunori Y, Ban D, Ochiai T, et al: CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. Int J Oncol. 48:657–669. 2016. View Article : Google Scholar : PubMed/NCBI | |
American Joint Committee on Cancer, TNM Staging System for Pancreatic Neuroendocrine Tumours, . (7th). 2010. | |
World Health Organization Classification of Tumours Pathology and Genetics of Pancreas Tumours, . 2010. | |
Hirata A, Hatano Y, Niwa M, Hara A and Tomita H: Heterogeneity of Colon Cancer Stem Cells. Adv Exp Med Biol. 1139:115–126. 2019. View Article : Google Scholar : PubMed/NCBI | |
Das PK, Rakib MA, Khanam JA, Pillai S and Islam F: Novel therapeutics against breast cancer stem cells by targeting surface markers and signaling pathways. Curr Stem Cell Res Ther. 14:669–682, 2×x. 2019. View Article : Google Scholar : PubMed/NCBI | |
Clevers H: The cancer stem cell: Premises, promises and challenges. Nat Med. 17:313–319. 2011. View Article : Google Scholar : PubMed/NCBI | |
Zagar TM, White RR, Willett CG, Tyler DS, Papavassiliou P, Papalezova KT, Guy CD, Broadwater G, Clough RW and Czito BG: Resected pancreatic neuroendocrine tumors: Patterns of failure and disease-related outcomes with or without radiotherapy. Int J Radiat Oncol Biol Phys. 83:1126–1131. 2012. View Article : Google Scholar : PubMed/NCBI | |
Mehta S, de Reuver PR, Gill P, Andrici J, D'Urso L, Mittal A, Pavlakis N, Clarke S, Samra JS and Gill AJ: Somatostatin receptor SSTR-2a expression is a stronger predictor for survival than Ki-67 in pancreatic neuroendocrine tumors. Medicine. 94:e12812015. View Article : Google Scholar : PubMed/NCBI | |
Boninsegna L, Panzuto F, Partelli S, Capelli P, Fave GD, Bettini R, Pederzoli P, Scarpa A and Falconi M: Malignant pancreatic neuroendocrine tumour: Lymph node ratio and Ki67 are predictors of recurrence after curative resections. Eur J Cancer. 48:1608–1615. 2012. View Article : Google Scholar : PubMed/NCBI | |
Oh TG, Chung MJ, Park JY, Bang SM, Park SW, Chung JB and Song SY: Prognostic factors and characteristics of pancreatic neuroendocrine tumors: Single center experience. Yonsei Med J. 53:944–951. 2012. View Article : Google Scholar : PubMed/NCBI |