8842

PROM1

prominin 1;PROM1;prominin 1

antigen AC133|hProminin|hematopoietic stem cell antigen|prominin-1|prominin-like protein 1

4p15.32

protein-coding

BACKGROUND: Hematopoietic progenitor cells (HPCs) are able to prepare the site for incoming neoplastic cells. Among different markers of HPCs, which one should be considered the most efficient was investigated. PATIENTS AND METHODS: Five hundred and seventy-nine non-metastatic lymph nodes from 49 patients affected by invasive breast cancer were submitted to an immunohistochemical comparative analysis of hematopoietic (CD34), endothelial (CD133), mesenchymal (CD117) progenitors and vascular endothelial growth factor receptor 1 (VEGFR1, also known as Flt1). The cases with an intensity-distribution score >3 were considered as high HPC expressors. Survival univariate and multivariate analyses were performed. RESULTS: Fifteen out of the 49 patients were recorded as HPC high expressors based on the immunohistochemical VEGFR1 staining. A highly significant relationship was found between high HPC immunoexpression and the development of distant metastasis as well as the occurrence of bone localization (p<0.001). By univariate analysis, CD133 showed a highly significant value regarding metastatic localizations in the bone; by multivariate analysis, CD133 emerged as the only independent prognostic variable. CONCLUSION: CD133 expression shows a potential predictive role, thus representing a helpful tool for the management of breast cancer.

BACKGROUND: Beyond its possible correlation with stemness of tumor cells, CD133/prominin1 is considered an important marker in breast cancer, since it correlates with tumor size, metastasis and clinical stage of triple-negative breast cancers (TNBC), to date the highest risk breast neoplasia. METHODS: To study the correlation between the levels of CD133 expression and the biology of breast-derived cells, CD133low and CD133high cell subpopulations isolated from triple negative MDA-MB-231 cells were compared in terms of malignant properties and protein expression. RESULTS: High expression of CD133 characterizes cells with larger adhesion area, lower proliferation rate and reduced migration speed, indicative of a less undifferentiated phenotype. Conversely, when compared with CD133low cells, CD133high cells show higher invasive capability and increased expression of proteins involved in metastasis and drug-resistance of breast tumors. Among the signalling proteins examined, PLC-beta2 expression inversely correlates with the levels of CD133 and has a role in inducing the CD133high cells to CD133low cells conversion, suggesting that, in TNBC cells, the de-regulation of this PLC isoform is responsible of the switch from an early to a mature tumoral phenotype also by reducing the expression of CD133. CONCLUSIONS: Since CD133 plays a role in determining the invasiveness of CD133high cells, it may constitute an attractive target to reduce the metastatic potential of TNBC. In addition, our data showing that the forced up-regulation of PLC-beta2 counteracts the invasiveness of CD133-positive MDA-MB-231 cells might contribute to identify unexplored key steps responsible for the TNBC high malignancy, to be considered for potential therapeutic strategies.

OBJECTIVES: To investigate whether CD133 messenger ribonucleic acid (mRNA) could provide useful information to identify metastasis or predict recurrence in patients with clear cell renal cell carcinoma (cRCC). METHODS AND MATERIALS: This study included 86 patients with cRCC and 30 healthy controls. Real-time reverse transcriptase-polymerase chain reaction was used to quantify CD133 mRNA in peripheral blood mononuclear cells before nephrectomy. RESULTS: The average CD133 mRNA in patients with metastatic cRCC (1.546 +/- 0.291) was significantly higher than that in those with localized cRCC (1.034 +/- 0.316, P = 0.022) or in controls (0.042 +/- 0.028, P = 0.001). metastasis could be identified with a sensitivity of 82.6% at specificity of 69.8% by CD133 mRNA. Among patients with localized cRCC, there was a significant difference in CD133 mRNA between the patients with recurrence (1.136 +/- 0.127) and without recurrence (1.010 +/- 0.091, P = 0.047). Recurrence could be identified with a sensitivity of 75.0% at specificity of 61.8%. Patients with a higher CD133 mRNA had a significantly higher recurrence rate than those with a low CD133 mRNA (P = 0.019). CONCLUSIONS: CD133 mRNA can be useful for identifying metastasis, predicting recurrence, and stratifying the patients into different risk groups for possible adjuvant treatment.

The concept of the so-called cancer stem cell (CSC) holds that only a minority of cells within a tumor have the ability to generate a new tumor. Over the last decade, a large body of literature has implicated the protein CD133 as a marker of organ-specific adult stem cells and in some cancers as a bona fide CSC marker. In this issue of the JCI, Shmelkov et al. challenge the view that CD133 is a marker of CSCs in colon cancer (see the related article beginning on page 2111). CD133 was thought previously to have a very restricted distribution within tissues; the authors have used genetic knock-in models to demonstrate that CD133 in fact is expressed on a wide range of differentiated epithelial cells in adult mouse tissues and on spontaneous primary colon tumors in mice. In primary human colon tumors, all of the epithelial cells also expressed CD133, whereas metastatic colon cancers isolated from liver had distinct CD133+ and CD133- epithelial populations. Intriguingly, the authors demonstrate that the CD133+ and CD133- populations were equally capable of tumor initiation in xenografts. In light of these new findings, the popular notion that CD133 is a marker of colon CSCs may need to be revised.

Single cell progenies (SCPs) inherit biological properties from their isogenetic mother cells. If a single cancer cell can give rise to progenies, which can be passaged sustainably in vitro and produce tumor in xenotransplantation, the cell should be cancer initiating cell. CD133 (Prominin-1, Prom1) is the marker of human colorectal cancer (CRC) stem cells and probably a marker of metastatic cancer stem cells (CSCs). Thirty-three SCPs of CRC cell line SW480 were isolated by limited dilution methods, thirty of which are CD133 positive and three negative. All of the CD133(+) SCPs are tumorigenic, and the subcutaneous tumors expanded rapidly, while only 1 of 3 CD133(-) SCPs developed a minimal tumor in nude mice. Orthotopic transplantation experiments showed that CD133(+) SCPs possessed heterogeneity in intestinal wall invasion, lymph node and liver metastases. CD133(+) SCPs varied in cell growth, invasive ability, epithelial-mesenchymal-transition and expression of CSCs markers (CD133, CD44, and CXCR4) associated with metastatic potential. CD133(-) SCPs did not produce secondary transplanted tumor, intestinal invasion and metastasis. The results indicated CD133(+) subpopulation of SW480 SCPs bear heterogeneous invasive and metastatic ability, and CRC-CSCs might be a heterogeous subpopulation.

Although relatively good therapeutic results are achieved in non-advanced cancer, the prognosis of the advanced colon cancer still remains poor, dependent on local or distant recurrence of the disease. One of the factors responsible for recurrence is supposed to be cancer stem cells (CSCs) or tumor-initiating cells, which are a population of cancer cells with ability to perpetuate themselves through self-renewal and to generate differentiated cells, thought to be responsible for tumor recurrence. This study globally approach the possible role of tissue-derived stem cells in the initiation of colon cancer and its metastatic process in the liver. Fresh surgical specimens from colon cancer, non-tumor tissue and liver metastasis were obtained directly from the operating room, examined, and immediately processed. CSCs were selected under serum-free conditions and characterized by CD44 and CD133 expression levels. CD133(+)/CD44(+) cell populations were then investigated in paraffin-embedded tissues and circulating tumor cells isolated from peripheral blood of the same group of colon cancer patients. Our data demonstrate that metastatic properties of cell populations from blood and liver metastasis, differently from primitive tumors, seem to be strictly related to the phenotype CD133 positive and CD44 positive.

BACKGROUND: Colorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet. METHODS: Flow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The stemness and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133(+)CXCR4(+) cancer cells and patient survival. RESULTS: In human specimens, the content of CD133(+)CXCR4(+) cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133(+) cells in the HCT116 cell line, with CXCR4 expression having no impact on the stemness properties. We found that CD133(+)CXCR4(+)cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133(+)CXCR4(-) cells, CD133(+)CXCR4(+)cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133(+)CXCR4(+)cancer cells and enhance their invasive behavior, while this could not be observed in CD133(+)CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133(+)CXCR4(+)cells in human primary CRC was associated with a reduced two-year survival rate. CONCLUSIONS: Strategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.

INTRODUCTION: Colorectal cancer (CRC) stem cells or tumor-initiating cells (Co-TIC) are implicated in both cancer recurrence and extranodal metastasis. CD133 and CXCR4 are specific cell surface markers that are indicators of Co-TIC. The presence of lymph node (LN) metastases is one of the strongest negative prognostic factors for CRC patients. We examined the relationship between the Co-TIC markers CD133 and CXCR4 and LN involvement in CRC. METHODS: CRC cells were isolated via enzymatic digestion. CD133(+), CXCR4(+), and double-positive CRC cells were detected by fluorescence-activated cell sorting analysis. The percentages of CD133(+), CXCR4(+), and double-positive cells were identified and correlated to the number and percentage of positive LN on staging. RESULTS: Twenty-seven samples underwent fluorescence-activated cell sorting analysis. The mean percentage of CD133(+) cells was 3.94% (range 0.15%-19.06%). The mean percentage of CXCR4(+) cells was 6.15% (range 0%-27.11%). The mean percentage of CD133(+)CXCR4(+) cells was 0.45% (range 0%-2.08%). Thirteen patients had LN metastasis: 8 N1 disease and 5 N2 disease. The correlation coefficients between the percentage of Co-TIC marker-positive cells and percentage of positive LN were r = 0.58 (P = 0.0016) for CD133(+) cells, r = 0.36 (P = 0.5868) for CXCR4(+) cells, and r = 0.56 (P = 0.0022) for double-positive cells. DISCUSSION: Our results show CD133(+) and CD133(+)CXCR4(+) cancer cells correlate with the presence of LN metastasis in CRC. Further studies will examine whether these markers can give consistent prognostic information and may help to develop novel diagnostic and therapeutic options.

cancer stem-like cells are enriched in CD133-positive (CD133(+)) colorectal cancer (CRC) cells. To date, the biological significance of CD133 expression in cancer stem-like cells is still unknown. B7-H3, a costimulatory molecule, plays a pivotal role in tumor immune escape by inhibiting the functions of T cells. To identify a new marker to predict the tumor grade of CRC, we analyzed the expression of B7-H3 and CD133 in colorectal tumor samples, and their clinical significance was determined. By using a series of techniques including pathologic tissue microarray technology, immunohistochemistry, and immunofluorescent staining, we found B7-H3 was expressed in 56.73% of the CRC cases (59/104) sampled; CD133 was detected in 26.92% of the CRC cases (28/104) sampled. Further analysis indicated that 22 of these CD133(+) samples expressed B7-H3. We also found coexpression of CD133 and B7-H3 in tumor tissue samples (r = 0.321, P < 0.01). Moreover, in contrast to individual CD133 or B7-H3 expression, the coexpression of B7-H3 and CD133 was evidently associated with the depth of tumor invasion, lymphatic metastasis, distant metastasis, and Dukes stage, suggesting it is a valuable biomarker for the progression of CRC. Indeed, the patients with coexpression of B7-H3 and CD133 had a poorer survival than the other patients (P < 0.05). In summary, our results reveal that B7-H3 was aberrantly expressed in CD133(+) CRC cells, and the expression level was closely associated with tumor progression.

The tumour-specific 'pre-metastatic niche' has emerged as a potential driving force for tumour metastasis and has been confirmed using mouse models of cancer metastasis. Vascular endothelial growth factor receptor-1(+) hematopoietic progenitor cells (HPCs) have been shown to play an important role in metastasis, forming a 'pre-metastatic niche' at designated sites for distant tumour progression. Here, CD133+ human umbilical hematopoietic progenitor cells (HUHPCs) were purified from human umbilical cord blood and expanded in vitro. We studied the effects of CD133+ HUHPCs on the growth and metastasis of four colorectal cancer (CRC) cell lines by using cell-to-cell co-culture. Our results revealed that CD133+ HUHPCs promoted the proliferation and invasion of CRC cells in vitro and enhanced tumour growth and metastasis in vivo. Moreover, CD133+ HUHPCs were observed in the pre-metastatic liver tissue using immunohistochemical analysis after co-injection of SW480/EGFP(+) cells and HUHPCs. Further experiments were therefore conducted to uncover the molecular mechanisms by which CD133+ HUHPCs influenced colon carcinogenesis and cancer progression. Extracted proteins were separated using the two-dimensional difference in gel electrophoresis technology. Among the differentially expressed proteins, mitogen-activated protein 4 kinase 4, stromal cell-derived factor-1, matrix metallopeptidase 9, calumenin, peripherin, leucine zipper, putative tumour suppressor 1 and guanidinoacetate methyltransferase attracted our attention. Western blot analysis further confirmed the differential expression of these proteins. Altogether, these results suggest that CD133+ HUHPCs may induce proliferation or metastasis of CRC cells and impact their derived proteins by providing a pre-metastatic microenvironment.

BACKGROUND: To study on expressions and clinical significances of CD133 protein and CD133 mRNA in primary lesion of gastric adenocarcinoma (GC). METHODS: expressions of CD133 protein by immunostaining (99 cases) and CD133 mRNA by semi-quantitative RT-PCR (31 cases) were detected in primary lesion and in noncancerous gastric mucosa tissue (NCGT). Correlations of CD133 protein expression with clinicopathological parameters and post-operative survival were analyzed. Relations of CD133 mRNA level with Ki-67 labeling index (LI), and lymphatic metastasis were assessed too. RESULTS: Brown particles indicating CD133 protein positivity occurred in some parts of tumor cells and epithelium. Expressive percentage of CD133 protein positivity was significantly higher in subgroups with >5 cm diameter (P = 0.041), later TNM stage (P = 0.044), severer lymph node metastasis (P = 0.017), occurrences of lymphatic invasion (P = 0.000) and vascular invasion (P = 0.000) respectively. Severer invasion depth (P = 0.011), lymph node metastasis occurrence (P = 0.043) and later TNM stage (P = 0.049) were the independent risk factors for CD133 protein expression. Average brightness scale value (BSV) of CD133 mRNA was significantly higher in subgroups with >5 cm diameter (P = 0.041), lymph node metastasis occurrence (P = 0.004) and in lower Ki-67 LI (P = 0.02). Relative analysis revealed that BSV of CD133 mRNA related positively to metastatic lymphatic nodes ratio (P = 0.008) and metastatic lymph node number (P = 0.009), but negatively to Ki-67 LI (P = 0.009). Survival of positive subgroup of CD 133 protein was significantly poorer (P = 0.047). Lymph node metastasis occurrence (P = 0.042), later TNM stage (P = 0.046) and CD 133 protein positive expression (P = 0.046) were respectively the independent risk factors to survival. CONCLUSION: Higher expressive level of CD133 mRNA is associated to lower Ki-67 LI and severer lymphatic metastasis. Therefore, the expressive level of CD133 mRNA can play an appropriate role to reflect the status of lymph node metastasis and proliferation of GC. CD133 protein expression is closely related with larger tumor, later TNM stage, lymphtic metastasis and survival of GC.

BACKGROUND AND AIM: CD133 is one of the most important cancer-initiating (stem) cell markers and was confirmed to be expressed in solid cancers such as colon cancer. However, no one has investigated the role of CD133 in intrahepatic cholangiocarcinoma (IHCC). The aim of this study was to clarify the clinical role of CD133 expression in IHCC. PATIENTS AND METHODS: Twenty-nine patients with IHCC who underwent hepatic resection at our institution were enrolled in this study. expression of CD133 was examined using anti-CD133 antibody. Staining was observed in the cytoplasm of cancer cells and CD133-positive cells distributed in the whole tumor. The patients were divided into two groups: the CD133-positive group (n = 14) and CD133-negative group (n = 15), in which no staining of CD133 was observed. Clinicopathological factors including hypoxia-inducible factor-1alpha expression were compared between the two groups. The prognostic factors were investigated by multivariate analysis using Cox's proportional hazard model. RESULTS: The 5-year survival rate in the CD133-positive group (8.0%) was worse than that in the CD133-negative group (57.0%). In the CD133-positive group, the incidence of intrahepatic metastasis and positive expression of hypoxia-inducible factor-1alpha tended to be higher than that in the CD133 negative group. The multivariate analysis revealed CD133 expression was an independent prognostic indicator in IHCC. CONCLUSIONS: CD133 expression tended to be related to higher incidences of intrahepatic metastasis and positive expression of hypoxia-inducible factor-1alpha; furthermore, it was independently related to worse prognosis. Therefore, the CD133 expression is a potential prognostic indicator in IHCC.

Hepatocellular carcinoma (HCC) is a prevalent disease worldwide, and the majority of HCC-related deaths occur due to local invasion and distant metastasis. cancer stem cells (CSCs) are a small subpopulation of cancer cells that have been hypothesized to be responsible for metastatic disease. Recently, we and others have identified a CSC population from human HCC cell lines and xenograft tumors characterized by their expression of CD133. However, the precise molecular mechanisms by which CD133(+) cancer stem-like cells mediate HCC metastasis have not been sufficiently analyzed. Here, we have sorted HCC cells using CD133 as a cancer stem cell (CSC) marker by magnetic-activated cell sorting (MACS) and demonstrated that the CD133(+) HCC cells not only possess greater migratory and invasive capacity in vitro but are also endowed with enhanced metastatic capacity in vivo and in human HCC specimens when compared to CD133(-) HCC cells. Gene expression analysis of the CD133(+) and CD133(-) cells of the HCC line SMMC-7721 revealed that G protein-coupled receptor 87 (GPR87) is highly expressed in CD133(+) HCC cells. In this study, we explored the role of GPR87 in the regulation of CD133 expression. We demonstrated that the overexpression of GPR87 up-regulated CD133 expression, promoted CSC-associated migratory and invasive properties in vitro, and increased tumor initiation in vivo. Conversely, silencing of GPR87 expression reduced the levels of CD133 expression. CONCLUSION: GPR87 promotes the growth and metastasis of CD133(+) cancer stem-like cells, and our findings may reveal new targets for HCC prevention or therapy.

Lung cancer is the most preventable cancer worldwide but has a poor prognosis. Recent advances in the study of lung cancer stem cell (CSC) populations has led to a growing recognition of the central importance of cells with stem cell-like properties in lung tumorigenesis. High number of CD133+ cells is associated with the maintenance, metastasis and drug-resistance of lung cancer. CD133 serves as a stemness biomarker for CD133+ CSCs, which have been found in lung cancer tissues. This article reviews the major studies supporting the existence and importance of CD133+ CSCs in the maintenance, metastasis and drug resistance of lung cancer. Continued research in the field of CD133+ CSCs biology is vital, as ongoing efforts promise to yield new prognostic and therapeutic targets.

Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapy. In present study, we identified a subpopulation of cells isolated from the A549 cell line with marker CD133. In vivo results showed that A549 CD133+ cells displayed high liver metastatic potential. Severe liver cell damage with tumor cell invasion revealed by pathological examination and these changes were consistent with the results of serological tests where the plasma GPT and GOT level are significantly higher than that of the control group. Compared with A549 cells, A549 CD133+ cells expressed high levels of VEGF and exhibited high migration and invasion capability. In conclusion, we first reported that A549 CD133+ cells exhibited characteristic of high liver metastatic potential which makes it be a suitable model for further study of liver metastasis of lung adenocarcinoma and provide a potential platform for anti-metastatic drug discovery or evaluation.

CD133 (Prominin-1) is considered the most important cancer stem cell (CSC)-associated marker identified so far, with increased expression in the CSC fraction of a large variety of human malignancies, including melanoma. Here we investigated the effects of CD133 downregulation in vitro and in vivo in human metastatic melanoma. The average number of CD133 molecules on the cell surface of FEMX-I melanoma cells was decreased by 8.7-fold and 1.8-fold using two different short hairpin RNAs. Downregulation of CD133, confirmed by immunocytochemistry, Western blotting, microarray analysis, and reverse transcription-polymerase chain reaction, resulted in slower cell growth, reduced cell motility, and decreased capacity to form spheroids under stem cell-like growth conditions. Clonal analysis revealed that the reduction in growth rate was proportional to the extent of CD133 downregulation. Monoclonal antibodies directed against two different epitopes of the CD133 protein induced a specific, dose-dependent cytotoxic effect in FEMX-I cells. The downregulation of CD133 severely reduced the capacity of the cells to metastasize, particularly to the spinal cord. In the CD133 downregulated cells, microarray analysis revealed expression changes for only 143 annotated genes (76 up- and 67 downregulated). Ten of the 76 upregulated genes coded for Wnt inhibitors, suggesting an interaction between CD133 and the canonical Wnt pathway. We conclude that CD133, in addition to its role as a CSC marker, is an important therapeutic target for metastatic melanoma and, potentially, for other CD133-expressing cancer types.

cancer stem cells expressing CD133 exist in a wide array of tumors and their identification in malignant melanoma may help refine classification, diagnosis and treatment. To study the correlation between CD133 expression in childhood melanoma and lymph node and/or visceral metastasis, we evaluated 12 cases of malignant melanoma and 12 control cases of Spitz nevus occurring in children. Double immunostaining with CD133 and Ki-67 was performed in the cases showing CD133 positivity. Three melanoma patients had lymph node metastasis and only one had multivisceral metastases; CD133 was positive only in these four patients. The Ki-67 index was lower in the CD133(+) cells in comparison with the CD133(-) melanoma cells in three cases. We found no positivity for CD133 in all the Spitz nevi. CD133(+) cancer stem cell expression in childhood malignant melanoma might correlate with lymph node and/or visceral metastasis and may have a low proliferative Ki-67 index that might explain their chemoresistance.

PURPOSE: We examined whether RNA expression of CD133, a surface molecule expressed on progenitors from hematopoietic and endothelial lineages, and CD146, a pan-endothelial marker, are increased in the blood of cancer patients and whether these factors correlate with patient characteristics and are predictive factors of survival. EXPERIMENTAL DESIGN: We developed a real-time quantification method (nuclear acid sequence-based amplification) to determine expression of CD146 and CD133 mRNA in the peripheral blood mononuclear cells of 131 progressive cancer patients, 37 healthy volunteers, and 5 patients who received granulocyte colony-stimulating factor. Overall survival and other clinicopathologic variables were obtained. Cox proportional hazards studies were done. RESULTS: We show that patients with metastatic disease have a significant increase in CD133 mRNA (P = 0.03), specifically patients with bone metastasis (P < 0.001). cancer patients with high CD133 mRNA expression, using a defined cutoff value, show a decreased survival compared with patients with low or undetectable CD133 expression (21% versus 45% cumulative survival, respectively, after 20 months; P = 0.01). Among patients with metastasis to the bone, cumulative survival was 22%, compared with 61% for patients with high or low CD133 levels (P = 0.004). Multivariate analysis showed that CD133 expression is an independent predictor for overall survival in patients with bone metastases. CD146 mRNA was not increased in patients with cancer, nor did it correlate with clinical variables or survival. CONCLUSION: CD133, but not CD146, mRNA expression is increased in cancer patients with metastatic disease, specifically with bone metastasis. In addition, CD133 mRNA expression seems to be an independent prognostic factor for overall survival.

OBJECTIVE: To investigate the expression of tumor stem cell marker CD133 and endothelin-converting enzymes (ECE) in non-small cell lung carcinoma (NSCLC) and their association with NSCLC lymphoid metastasis. METHODS: CD133 and ECE expressions was detected immunohistochemically in the specimens from 77 patients with NSCLC, and the association of CD133 and ECE expressions with the tumor size, histological type, differentiation, lymphoid metastasis, and prognosis of NSCLC was analyzed. RESULTS: The positive expression rate of CD133 and ECE was 51.9% (40/77) and 45.5% (35/77) in these specimens, respectively. Both CD133 and ECE expressions were associated positively with lymphoid metastasis (r=0.246 and 0.339, P<0.05), and inversely with the survival time of the patients (P<0.05). CD133 and ECE expressions were not related to tumor size, histological type, and differentiation of the tumor (P>0.05). CD133 expression was associated positively with ECE expression in NSCLC (r=0.249, P<0.05). CONCLUSION: CD133 and ECE expressions are associated with lymphoid metastasis and prognosis of NSCLC, and their overexpression often suggests unfavorable prognosis of NSCLC.

BACKGROUND: Pancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network. METHODS: A highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC. RESULTS: We found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N-cadherin expression. CONCLUSIONS: These results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis.

The metastasis-related molecules CD133, CD44v6 and human tissue factor (TF) have been shown to be associated with tumor invasion and metastasis. This study aimed to determine whether co-expression of these three molecules was associated with metastasis and overall prognosis in pancreatic carcinoma. We analyzed the expression profiles of these three molecules by immunohistochemistry and evaluated the relationship of their expression profiles with metastasis and prognosis in 109 pancreatic carcinomas. The results showed that the expression levels of CD133, CD44v6 and TF were increased in pancreatic carcinoma. Co-expression of CD133, CD44v6 and TF (tri-expression) was also detected in pancreatic carcinoma. Clinical analysis showed that individual expression of CD133, CD44v6 or TF was associated with vessel invasion, lymph node metastasis and liver metastasis, while tri-expression was associated with lymph node metastasis. Survival analysis showed that patients with co-expression of CD133 and TF or tri-expression had lower and the lowest overall survival rates, respectively. Univariate analysis showed that T-factor, lymph node metastasis, TNM stage, and individual levels or tri-expression of CD133, CD44v6 and TF were survival risk factors. Multivariate analysis showed that tri-expression of CD133, CD44v6 and TF was an independent predictor of survival. These results suggest that overexpression of CD133, CD44v6 and TF is associated with pancreatic carcinoma metastasis. Tri-expression of these three molecules may be a useful predictor for pancreatic carcinoma prognosis.