Co-Expression of Putative Cancer Stem Cell Markers,CD133 and Nestin,in Skin Tumors

Background: Cancer stem cells (CSC) are populations of cells responsible for tumor initiation, progression andtherapeutic resistance in many cancers. In the present study, we aimed to investigate the expression pattern andclinical significance of two CSC markers, CD133 and Nestin, in a series of skin tumors. Materials and Methods:One hundred and thirteen paraffin blocks from skin cancers including 16 (14%) cases of melanoma, 37 (33%)of squamous cell cancer (SCC) and 60 (53%) of basal cell cancer (BCC) were collected and assembled in a tissuemicroarray (TMA). The samples were immunohistochemically examined for the expression of CD133 and Nestin.Expression of these markers was also correlated with clinicopathological parameters. Results: A significantdifference was observed in the expression of CD133 and Nestin in melanomas, SCC and BCC (p value=0.001).Furthermore, the level of expression was significantly higher in the melanomas compared to the SCC and BCCtumors. Expression of CD133 in the melanoma was significantly associated with increased tumor invasiveness (pvalue=0.05), a higher rate of metastasis (p value=0.04) and the presence of ulceration (p value=0.02). Increasedexpression of Nestin was observed in metastatic melanoma (p value=0.04), while no statistically significantcorrelation was found with other clinicopathological parameters including Breslow thickness, Clark level andulceration. Conclusions: Elevated expression levels of CD133 and Nestin in the melanomas are associated withadvanced disease, with more aggressive and metastatic skin tumors. Therefore, these markers could be potentialtherapeutic targets for malignant tumors of the skin.     

CD133肿瘤干细胞标志物在肺癌中的应用进展

CD133作为肿瘤干细胞标志物已被广泛应用于临床,在肺癌干细胞的分选中亦具有重要作用。全文就肿瘤干细胞概念、CD133基因和结构、CD133与肿瘤干细胞的关系、CD133的临床应用以及CD133作为肿瘤干细胞标志物的局限性作一综述。     

Clinical Significance of Cancer Stem Cell Markers CD133 and CXCR4 in Osteosarcomas

Objective: Osteosarcomas (OS) is one the most common primary bone malignancy in humans with the lungs metastasis in most cases. Metastasis and recurrence of OS is attributed to cancer stem cells (CSCs). Our study aimed to evaluate the clinical significance of CD133 and C-X-C chemokine receptor type 4 (CXCR4) as the frequently applied markers for CSCs in OS patients. Methods: In this cross-sectional, a total of 50 tissue samples from the patients with primary OS were immunohistochemically examined to detect the expression of CD133 and CXCR4. The associations of the relative expression and clinical significance of each marker were also evaluated. Results: High level expression of CD133 was detected in 26% of OS patient tissues. Of the 12 patients who showed lung metastasis, 5 cases showed high expression of CD133 with marginal trend correlation (P=0.06). No significant correlation was observed between CD133 expression and clinicopathological factors. Only 36% of cases showed CXCR4 expression which was not significantly correlated with gender, age, tumor size, necrosis, stage and metastasis (P>0.05). Clinically, patients with concomitant CD133/CXCR4 expression had significant association with lung metastasis (P=0.05). Conclusion: Our findings showed that concomitant expression of CSC markers CD133/CXCR4 might had a synergistic effect on the OS poor prognosis. These markers could be considered as potential therapeutic candidates of OS targeted therapy.     

肿瘤干细胞标记物CD133和EpCAM在子宫内膜癌中的表达及意义

  目的   研究肿瘤干细胞标记物CD133和EpCAM在正常子宫内膜及子宫内膜癌组织中的表达及其临床病理意义。   方法   应用免疫组化法检测CD133和EpCAM在65例子宫内膜癌和30例正常增生期子宫内膜组织中的表达情况,并分析其与子宫内膜癌病理分级、临床分期、浸润深度及淋巴结转移等临床病理指标之间的关系。   结果   CD133和EpCAM在子宫内膜癌组织中的表达显著高于正常子宫内膜组织（P=0.02,P=0.007）,在子宫内膜癌组织中,CD133和EpCAM的表达与肿瘤大小（P=0.006,P= 0.007）、组织学分级（P=0.008,P=0.013）、浸润深度（P < 0.001,P=0.008）、淋巴结转移（P=0.002,P=0.024）、FIGO分期（P=0.004,P= 0.010）均呈显著正相关关系。CD133和EpCAM在子宫内膜癌中的表达呈正相关（r=0.84,P < 0.010）。   结论   肿瘤干细胞标记物CD133和EpCAM与肿瘤的发生及进展有关,检测其在子宫内膜癌组织中的表达情况有助于预测肿瘤的生物学行为。      

Cancer Stem Cells and Stemness Markers in Oral Squamous Cell Carcinomas

Head and neck squamous cell carcinoma (HNSCC) is one of the world top ten most common cancers withits highest occurrence in the Indian subcontinent and different aggressive and etiological behavioural patterns.The scenario is only getting worst with the 5 year survival rates dropping to 50%, persistent treatment failuresand frequent cases of relapse/recurrence. One of the major reasons for these failures is the presence of cancerstem cells (CSCs), a small population of cancer cells that are highly tumourigenic, capable of self-renewal andhave the ability to differentiate into cells that constitute the bulk of tumours. Notably, recent evidence suggeststhat cancer stem cells are especially resistant to conventional therapy and are the “drivers” of local recurrenceand metastatic spread. Specific markers for this population have been investigated in HNSCC in the hope ofdeveloping a deeper understanding of their role in oral cancer pathogenesis, elucidating novel biomarkers forearly diagnosis and newer therapeutic strategies. This review covers the fundamental relevance of almost all theCSC biomarkers established to date with a special emphasis on their impact in the process of oral tumourigenesisand their potential role in improving the diagnosis, prognosis and treatment of OSCC patients.     

Prognostic Value of Cancer Stem Cell Markers CD44 and ALDH1/2 in Gastric Cancer Cases

Purpose: To determine expression levels of CD44 and ALDH1/2, known cancer stem cell (CSC) markers, in stomach adenocarcinomas and assess relationships with clinicopathologic parameters and prognosis. Methods: Eighty patients diagnosed with gastric cancer between the years 2011-2015 were included in this study of clinicopathologic characteristics, postoperative prognostic indexes and stem cell marker CD44 and ALDH1/2 expression in paraffin-embedded tumour sections analyzed immunohistochemically. Clinicopathologic parameters were evaluated using the chi-square test and t-test. Survival analyses were conducted using Kaplan-Meier statistics. Results: We observed positive CD44 and ALDH1/2 staining in 45.0 % and 67.5% of tumour tissues, respectively, but not in normal gastric mucosa. Recurrence-free survival (RFS) was found to be shorter in cases with high levels of CD44 expression (p=0.004). Similarly, short RFS was observed in patients with high levels of CD44 and ALDH1/2 co-expression (p=0.004). Furthermore, tumour invasion depth was found to correlate with high CD44 and ALDH1/2 co-expression (p=0.028). Conclusion: The cancer stem cell markers CD44 and ALDH1/2 may indicate poor patient prognosis and play a role in tumour development and invasion.     

ALDH1 in Combination with CD44 as Putative Cancer Stem Cell Markers are Correlated with Poor Prognosis in Urothelial Carcinoma of the Urinary Bladder

Background: The aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is one of the promising markersfor identifying cancer stem cells in many cancer types, along with other markers including CD44. The aim ofthe present study was to evaluate the expression and clinical significance of putative cancer stem cell markers,CD44 and ALDH1A1, in a series of urothelial carcinomas of urinary bladder (UCUB) by tissue microarray(TMA). Materials and Methods: A total of 159 Urothelial Carcinomas (UC) including 96 (60%) low gradeand 63 (40%) high grade carcinomas were immunohistochemically examined for the expression of CD44 andALDH1A1. Correlations of the relative expression of these markers with clinicopathological parameters werealso assessed. Results: High level expression of ALDH1A1 was found in 16% (25/159) of bladder UC which wassignificantly correlated with increased tumor size (p value=0.002), high grade (p value<0.001), pathologic stage(T1, p value=0.007 and T2, p value<0.001) and increased rate of recurrence (p value=0.013). A high level of CD44expression was found in 43% (68/159) of cases, being positively correlated with histologic grade (p value=0.032)and recurrence (p value=0.039). Conclusions: Taken together, our results showed that ALDH1 was concurrentlyexpressed in a fraction of CD44+ tumors and its expression correlated with poor prognosis in UCs. ALDH1A1could be an ideal marker for targeted therapy of UCs in combination with conventional therapies, particularlyin patients with high grade carcinomas. These findings indicate that cells expressing ALDH1A1 along with CD44can be a potential therapeutic target in bladder carcinomas.     

Stem Cell Genes in Androgen-independent Prostate Cancer

Despite recent advances in the detection and treatment of early stage prostate cancer, there remains little effective therapy for patients with locally advanced and/or metastatic disease. Although the majority of patients with advanced disease respond initially to androgen ablation therapy, most go on to develop androgen-independent tumors that are inevitably fatal. Therefore, understanding the mechanisms by which a hormone-sensitive tumor escapes hormonal control is critical to the development of effective therapeutic modalities. The study of the differentiation pathways of normal and abnormal prostate growth has led to the development of a stem cell model for prostate cancer [1–3]. Recent work discussed in this commentary suggests that prostate tumors resist apoptosis and proliferate by adopting features of normal prostatic stem/progenitor cells. Basal cells, the putative stem/progenitor cells of the prostate, possess the phenotype of androgen-independence as do most advanced prostate cancers. Therefore, the study of basal cells may prove critical to understanding prostate carcinogenesis and to the development of novel strategies for preventing and managing prostate cancer.     

Liposarcoma Cells with Aldefluor and CD133 Activity have a Cancer Stem Cell Potential

ABSTRACT: Aldehyde dehydrogenase (ALDH) has recently been shown to be a marker of cancer stem-like cells (CSCs) across tumour types. The primary goals of this study were to investigate whether ALDH is expressed in liposarcomas, and whether CSCs can be identified in the ALDHhigh subpopulation. We have demonstrated that ALDH is indeed expressed in 10 out of 10 liposarcoma patient samples. Using a liposarcoma xenograft model, we have identified a small population of cells with an inducible stem cell potential, expressing both ALDH and CD133 following culturing in stem cell medium. This potential CSC population, which makes up for 0,1-1,7 % of the cells, displayed increased self-renewing abilities and increased tumourigenicity, giving tumours in vivo from as few as 100 injected cells.     

乳腺癌肿瘤干细胞标记物CD44+ESA+CD24-Λlow在非小细胞肺癌组织中的表达及其意义

背景与目的:人体各种组织都存在干细胞,肿瘤组织也存在肿瘤干细胞(tumor stem cell,TSC).乳腺癌TSC已经被分离出来,其标记物也已被确定,但肺癌的TSC仍未被分离出来.本研究旨在探讨乳腺癌肿瘤干细胞标记物(CD44 ESA CD24/low)在非小细胞肺癌(NSCLC)组织中的表达及其意义.方法:应用免疫组织化学法检测77例NSCLC组织中CD44、ESA与CD24的表达.分析其与患者吸烟、肿瘤的大小、癌的组织学类型、组织分化程度、淋巴结转移和预后的关系.结果:77例NSCLC组织中CD44、ESA与CD24的阳性率分别为63.6%、66.2%和7.8%.低分化及未分化组CD44的阳性率明显高于高分化组,高分化组ESA的阳性率明显高于中度分化组和低分化及未分化组;腺癌组ESA的阳性率明显高于鳞癌组(p<0.05).(CD44 ESA CD24/low标记的阳性率为36.4%,与患者吸烟、肿瘤的大小、癌的组织学类型、组织分化程度、淋巴结转移和预后无关(P>0.05).结论:乳腺癌肿瘤干细胞标记物((CD44 ESA CD24/low)表达与NSCLC肿瘤的大小、癌的组织学类型、组织分化程度、淋巴结转移和预后等临床病理学指标无关.     

干细胞标记物CK19、Notch3、CD133、P75NTR、STRO-1及ABCG2在肺鳞癌中的表达及意义

背景与目的 已有研究表明在肿瘤中存在着能够自我更新与多向分化的肿瘤干细胞,它们与正常人体内的干细胞有着相似的特征.本研究选取了被认为可作为干细胞标记物的部分抗体,以观察它们在肺鳞癌中的表达及意义.方法 采用S-P免疫组织化学方法,对54例手术切除肺鳞癌标本进行了CK19、Notch3、CD133、P75NTR、STRO-1及ABCG2的检测,另外选取了10例正常肺组织标本进行对照.结果 54例肺鳞癌标本中,除发现STRO-1及P75NTR在所有病例均为阴性表达外,其余标记均存在不同程度的阳性表达,但是阳性细胞的分布无规律性.其中,CK19阳性率为66.67%(36/54),Notch3为87.04%(47/54),CD133为50%(27/54),ABCG2为61.11%(33/54),并且Notch3、CD133和ABCG2在中低分化肺鳞癌中的表达高于高分化鳞癌(P＜0.05),而CK19、CD133和ABCG2在有淋巴结转移的肺鳞癌中的表达高于无淋巴结转移(P＜0.05),在连续切片中4种标记同时阳性的细胞数均少于总细胞数目的2%,3种及4种抗体共同阳性细胞所占百分比与鳞癌的分化程度和是否有淋巴结转移无统计学相关.结论 肺鳞癌中存在着某些干细胞标记物的表达,其表达程度与肺鳞癌的分化程度及淋巴结转移相关,但是阳性细胞在组织学的分布上无规律性,同时表达多种干细胞标记的肿瘤细胞数少于2%,可能为肿瘤干细胞.     

Expression of CD133 Cancer Stem Cell Marker in IDH-Mutant and IDH-wildtype (Isocitrate Dehydrogenase) Astrocytoma

Objective: This study evaluated the differences between IDH1-R132H and CD133 expression in different categories of  astrocytoma. Material and methods: This study used a cross-sectional design.  Sixty-seven paraffin embedded block of Diffuse Astrocytoma (DA), Anaplastic Astrocytoma (AA) and Glioblastoma (GB) were assessed using using the monoclonal antibody IDH1-R132H and Rabbit polyclonal antibody CD133. Results: It was found that there was a significant relationship between the expression of IDH1-R132H and CD133 in DA, AA and GB (p<0.001). Astrocytoma with IDH-mutant molecular status will express more markers of cancer stem cell CD133 than IDH-wildtype. Conclusion: The IDH1-R132H and CD133 can provide predictive value on treatment success, disease prognosis, recurrence and can be considered as target combination therapy with chemotherapy.     

胰腺癌干细胞表面标志物的研究进展

胰腺癌预后极差。近年来,肿瘤干细胞理论引起人们的关注。对胰腺癌干细胞自我更新和耐药机制的深入研究可能会发现对胰腺癌更有效的治疗措施。目前许多实体瘤肿瘤干细胞的分离鉴定还相当困难,主要是因为缺乏特异的肿瘤干细胞分子标志。现对胰腺癌干细胞表面标志物的研究现状作一综述。     

Clinicopathological Significance of CD133 and ALDH1 Cancer Stem Cell Marker Expression in Invasive Ductal Breast Carcinoma

Background: Biomarkers in breast neoplasms provide invaluable information regarding prognosis and help determining the optimal treatment. We investigated the possible correlation between cancer stem cell (CSC) markers (CD133, and ALDH1) in invasive ductal breast carcinomas with some clinicopathological parameters. Aim: To assess the correlation between expression of cancer stem cell (CSC) markers (CD133, and ALDH1) and clinicopathological parameters of invasive ductal breast carcinomas. Materials and Methods: Immunohistochemical analysis of CD133 and ALDH1 was performed on a series of 120 modified radical mastectomy (MRM) specimens diagnosed as invasive ductal breast carcinoma. Results: Expression of both CD133 and ALDH1 was significantly changed and related to tumor size, tumor stage (TNM), and lymph node metastasis. A negative correlation between CD133 and ALDH1 was found. Conclusions: Detecting the expression of CD133 and ALDH1 in invasive ductal breast carcinomas may be of help in more accurately predicting the aggressive properties and determining the optimal treatment.     

Discrimination of Cancer Stem Cell Markers ALDH1A1, BCL11B,BMI-1, and CD44 in Different Tissues of HNSCC Patients

Cancer stem cells (CSCs) are accountable for the progress of head and neck squamous cell carcinoma (HNSCC). This exploratory study evaluated the expression of molecular CSC markers in different tissues of HNSCC patients. Tissue specimens of primary tumor, lymph node metastases and macroscopically healthy mucosa of 12 consecutive HNSCC patients, that were treated with surgery and adjuvant radio(chemo)therapy upon indication, were collected. Samples were assessed for the expression of p16 as a surrogate for HPV-related disease and different molecular stem cell markers (ALDH1A1, BCL11B, BMI-1, and CD44). In the cohort, seven patients had HPV-related HNSCC; six thereof were oropharyngeal squamous cell carcinoma. While expression of BMI-1 and BCL11B was significantly lower in healthy mucosa than both tumor and lymph node metastasis, there were no differences between tumor and lymph node metastasis. In the HPV-positive sub-cohort, these differences remained significant for BMI-1. However, no significant differences in these three tissues were found for ALDH1A1 and CD44. In conclusion, this exploratory study shows that CSC markers BMI-1 and BCL11B discriminate between healthy and cancerous tissue, whereas ALDH1A1 and CD44 were expressed to a comparable extent in healthy mucosa and cancerous tissues.     

CD44、CD133耦连miR-425装载纳米脂质体对结直肠癌干细胞PDL-1表达的下调作用

目的 探究CD44、CD133耦连miR-425装载纳米脂质体对结直肠癌干细胞PDL-1表达的下调作用.方法选择结直肠癌细胞系HCT116分选出CD44、CD133/1+细胞,进行miR-425装载纳米脂质体转染,分为对照组(转染con-trol载体)、实验组(转染miR-425慢病毒载体),空白组以纳米脂质体代替,测定干细胞生长状态,检测PDL-1表达水平.结果分选的CD 133/1+细胞呈圆形,12 h后开始贴壁生长,状态良好.qRT-PCR检测显示实验组的miR-425的相对表达水平为(182.44±22.19),对照组与空白组分别为(1.84±1.11)和(1.67±0.98),实验组明显高于对照组与空白组(P<0.05).MTT检测结果表明,与空白组(0.78±0.22)、对照组(0.81±0.17)比较,实验组(0.24±0.15)的HCT116细胞生长速度明显减慢(P<0.05).空白组与对照组的细胞增殖率分别为(0.48±0.14)与(0.51±0.18),都明显高于实验组的(0.30±0.11).Western blot检测分析显示实验组、对照组、空白组的PDL-1相对表达量分别为(0.33±0.13)、(0.76±0.21)和(0.82±0.15),实验组明显低于对照组与空白组(P<0.05).结论CD44、CD133耦连miR-425装载纳米脂质体能抑制结直肠癌干细胞PDL-1的表达,从而显著抑制干细胞的生长、增殖能力.     

Suitability of CD133 as a Marker for Cancer Stem Cells in Melanoma

Objectives: CD133 is considered a cancer stem cell (CSC) marker in various malignancies; however, its role as a biomarker of malignant melanoma remains controversial. The present study was conducted to evaluate the suitability of CD133 surface antigen as a CSC marker in melanoma. Methods: Human melanoma cells were fractionally separated by magnetic cell separation depending on the CD133 phenotype and transplanted into immunodeficient mice to evaluate their tumorigenic capacity. Furthermore, the time until the development of a palpable tumor and the growth rate were measured, and the final tumor volume was assessed after 8 weeks. The immunohistochemical expression of CD133 in the induced neoplasia was then compared using histomorphometry. Results: Notably, neoplasms were induced in all the groups (n = 48), including in the CD133-negative group. Tumors induced by unsorted cells had the largest volume (p = 0.014) but were detected significantly later in this group (p ≤ 0.001). Interestingly, all explanted tumors expressed CD133, with no significant differences among groups. Conclusions: In contrast to the results obtained in prior studies, the suitability of CD133 as a CSC marker could not be demonstrated. The current encouraging progress in targeted therapy for malignant melanoma highlights the need to identify more effective targets.     

CD44+鼻咽癌细胞的干细胞生物学特性

目的从人鼻咽癌SUNE-1 5-8F细胞株中分离出CD44⁺细胞并探讨其生物学特性。方法常规培养SUNE-1 5-8F细胞,采用流式细胞学技术检测SUNE-1 5-8F细胞中CD44⁺的表达并用流式细胞仪分选CD44⁺细胞;采用四甲基偶氮唑蓝（MTT）法、克隆形成实验等检测并比较CD44⁺、CD44^-细胞在体外增殖、分化等方面的差异;并用反转录聚合酶链反应（RT-PCR）检测干细胞基因Oct4、Bmi-1的表达。结果CD44⁺细胞在鼻咽癌细胞中SUNE-1株所占的比率约为52.5%;新分选的CD44+细胞在无血清培养液和完全培养液中较CD44^-及未分选细胞均显示出较强增殖能力;RT-PCR示Bmi-1和Oct4 mRNA在CD44+细胞中的表达水平明显高于CD44^-细胞。CD44⁺和CD44-细胞在接受2Gy放射处理后,其平均克隆生成效率分别为(23.44±1.90)%和(7.78±1.17)%（P＜0.001）;CD44⁺细胞较CD44^-细胞在相同顺铂和多西他赛药物浓度下显示出更高的细胞存活率。结论CD44⁺细胞具有类肿瘤干细胞特性,可能是鼻咽癌的重要肿瘤干细胞标志之一。     

CD133和CD44在骨肉瘤中的表达及其临床意义

 目的
探讨CD133和CD44在骨肉瘤中的表达情况及其与骨肉瘤患者预后的关系。方法应用免疫组织化学方法检测CD133和CD44在79例骨肉瘤
患者石蜡切片标本中的表达情况,应用卡方检验比较CD133、CD44表达与患者临床病理资料的相互关系,Kaplan-Meier法计算患者生存
率,Log rank检验比较CD133、CD44阴性低表达组与高表达组患者之间的生存差异,并以性别、年龄、肿瘤部位、肿瘤大小、
Ennecking 分期、CD133和CD44表达水平、局部复发及肺转移为变量指标,应用Cox回归模型进行多因素分析,研究这些因素与骨肉瘤
患者生存率之间的关系。结果CD133和CD44的表达水平与患者性别、年龄、肿瘤部位、肿瘤大小、Ennecking分期及局部复发无关,发
生肺转移的骨肉瘤患者其CD133和CD44的表达明显高于未发生转移的骨肉瘤患者,差异有统计学意义(P值分别为0.00014和0.0008)。
经单因素生存分析表明,影响骨肉瘤患者预后的因素有：肿瘤大小,局部复发,肺转移,CD44和CD133表达水平。多因素分析显示CD133
和CD44表达水平及肿瘤大小是影响患者预后的独立影响因素。结论CD133和CD44表达水平与骨肉瘤肺转移密切相关,检测CD133和CD44
的表达可以作为骨肉瘤患者肺转移及预后预测的指标。