Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer stem cells have been isolated from several solid tumors including prostate, colon, liver, breast, and ovarian cancer. Stem cells isolated from nervous system and prostate express CD133 antigen, which is widely used to isolate hematopoietic stem and progenitor cells. The aims of this study were to investigate the expression of the CD133-1 and CD133-2 epitopes in primary ovarian tumors and to biologically characterize CD133(+) ovarian cancer cells, also according to clinicopathologic parameters. Tissue specimens were obtained at primary surgery from 41 ovarian carcinomas; eight normal ovaries and five benign ovarian tumors were also collected. Flow cytometry with monoclonal antibodies against CD133-1 and CD133-2 epitopes was employed. FACS (fluorescence activated cell sorting) analysis enabled the selection of CD133(+) cells, whose epithelial origin was confirmed by immunofluorescence analysis with monoclonal anti-cytokeratin 7. CD133(+) cells gave rise to a 4.7 +/- 0.9-fold larger number of colonies than that documented in CD133(-) population (P < 0.001). Moreover, CD133(+) cells showed an enhanced proliferative potential compared to CD133(-) cells. The percentages of CD133-1- and CD133-2-expressing cells were significantly lower in normal ovaries/benign tumors with respect to those in ovarian carcinoma. Both the percentages of CD133-1- and CD133-2-expressing cells were significantly lower in omental metastases than in primary ovarian cancer (P = 0.009 and 0.007 for CD133-1- and CD133-2-expressing cells, respectively). There seems not to be any difference in the distribution of the percentage of CD133-1- and CD133-2-expressing cells according to clinicopathologic parameters and response to primary chemotherapy. CD133-1 and CD133-2 may be useful in order to select and enrich the population of CD133(+) ovarian tumor cells, which are characterized by a higher clonogenic efficiency and proliferative potential.
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PMID:Expression of CD133-1 and CD133-2 in ovarian cancer. 1786 44

Human colorectal cancer is one of the best, if not the best, understood tumour diseases. These tumours develop stepwise via an adenoma-carcinoma sequence. The steps in this process can easily be discriminated with light microscopy. The breakthrough in understanding carcinogenesis was the finding that mutations in tumour suppressor genes and oncogenes accumulate in parallel with these steps. This accumulation is the cause for the malignant progression of colorectal cancers, leading to highly invasive and migrating tumour cells. This concept is known as the multistep carcinogenesis model and has become the paradigm of tumour progression in general. But this model does not explain the complex, heterogeneous histology of colorectal tumours or the good differentiation of metastases, which are expected to have lost their differentiation because of the accumulation of mutations. Here, we present the model of migrating tumour stem cells, which explains these contradictions in the context of the histology of colorectal tumours. Thus colorectal tumours consist of tumour stem cells, which have recently been defined as a small CD133-positive population of tumour cells. These cells trans-differentiate into epithelial cells, which represent the main mass of the colorectal tumours. Moreover, the tumour stem cells are the active component of migration and invasion, thus conferring the malignant phenotype. Taken together, mutations confer to the tumour cells the capability to live outside of their stem cell niche and intestinal compartment. In addition, the trans-differentiation potential of the tumour cell confers plasticity to the tumour and thus contributes to the heterogeneity of colorectal cancers.
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PMID:The migrating cancer stem cells model--a conceptual explanation of malignant tumour progression. 1793 98

Anti-angiogenic drugs, alone or in combination with chemotherapeutics, are increasingly used by medical oncologists. In many cases, however, their mechanism of action and the tailoring of optimal dosage/schedule are still elusive. Circulating endothelial cell (CEC) and progenitor (CEP) number and viability are modulated in a large series of diseases including cancer, and look promising as surrogate biomarkers for the definition of the optimal biological dose of anti-angiogenic drugs and for patients' stratification. Along with CECs and CEPs, potential EC- and CEP-related surrogate molecular markers such as VE-Cadherin and CD133 are currently under preclinical and clinical investigation.
Cancer Metastasis Rev 2008 Mar
PMID:Chemotherapy and the tumor microenvironment: the contribution of circulating endothelial cells. 1806 48

Through a whole-cell panning approach, we previously identified a panel of antibodies that bound to prostate cancer cell surface antigens. One such antigen, CUB domain-containing protein 1 (CDCP1), was recognized by monoclonal antibody 25A11 and is a single transmembrane molecule highly expressed in several metastatic cancers as well as on CD34(+)CD133(+) myeloid leukemic blast cells. We show CDCP1 expression on prostate cancer cell lines by real-time quantitative PCR (RT-qPCR), flow cytometry, and immunohistochemistry and on prostate cancer patient samples by RT-qPCR and immunohistochemical staining. In cell-based assays, antibody 25A11 inhibited prostate cancer cell migration and invasion in vitro. Further characterization showed that CDCP1 is internalized on antibody binding. When 25A11 was coupled to the cytotoxin saporin either directly or via a secondary antibody, both resulted in prostate cancer cell killing in vitro. In vivo targeting studies with an anti-CDCP1 immunotoxin showed significant inhibition of primary tumor growth as well as metastasis in a mouse xenograft model. These data provide support for continued evaluation of anti-CDCP1 therapy for potential use in cancer in primary and metastatic disease.
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PMID:Targeting CUB domain-containing protein 1 with a monoclonal antibody inhibits metastasis in a prostate cancer model. 1848 59

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.
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PMID:The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. 1880 32

Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen(+) (ESA) CD44(hi) CD24(lo), CD44(hi) CD133(+), and CD133(+) CD24(lo)] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEM(Res) MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEM(Sens) MCF7. The levels of Numb, and Numb-L-[P]-Ser(265) were similar in GEM(Res) and GEM(Sens) MCF7 cells. Only the levels of Numb-L (long)-Ser(295) decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEM(Res) MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112-2120) and Numb-1 (87-95) eliminated NICD(positive), CD24(hi) CD24(lo) MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.
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PMID:Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells. 1904 52

Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem-like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)-deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of gamma34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of alpha47. Infection with oHSV G47Delta (ICP6(-), gamma34.5(-), alpha47(-)) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Delta significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis.
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PMID:Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. 1935 38

Evidence suggests that multiple tumors, including pancreatic adenocarcinoma, display heterogeneity in parameters that are critical for tumor formation, progression and metastasis. Understanding heterogeneity in solid tumors is increasingly providing a plethora of new diagnostic and therapeutic approaches. In this study, a particular focus was put on identifying a subpopulation of stem cell-like, slow cycling tumor cells in a pancreas adenocarcinoma cell lines. Using a label retention technique a subpopulation of slow cycling cells (DiI+/SCC) was identified and further evaluated in the BxPC-3 and Panc03.27 cell lines. These slowly cycling cells managed to retain the lipophilic labeling dye DiI, while the bulk of the cells (>94%) did not. The DiI+/SCC population, showed only a partial overlap with the CSC markers CD24(+)/CD44(+), CD133(+) and ALDH but they survived chemotherapeutic treatment, and were able to recreate the initial heterogeneous tumor cell population. DiI+/SCCs exhibited an increased invasive potential as compared with their non-label retaining, faster cycling cells (DiI-/FCC). They also had increased tumorigenic potential and morphological changes resembling cells that have undergone an epithelial to mesenchymal transition (EMT). Analysis of DiI+/SCC cells by real time PCR revealed a selective up-regulation of tell tale components of the Hedgehog/TGFbeta pathways, as well as a down-regulation of EGFR, combined with a shift in crucial components implied in EMT. The presented findings offer an expanded mechanistic understanding that associates tumor initiating potential with cycling speed and EMT in pancreatic cancer cell lines.
Clin Exp Metastasis 2009
PMID:Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. 1942 80

In over 70% of the cases, patients with curative surgery and adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC) develop recurrent tumors. The cancer stem cell (CSC) hypothesis suggests that CSCs are chemoresistant and enriched in recurrent tumors. This study analyzes tumorbiology, expression of the metastasis-promoting CXCR4 and actinin-4, and of the CSC marker CD133 in primary and recurrent PDAC. Twenty-six patients underwent resection for primary and recurrent PDAC and most developed tumor recurrence within 2 years. In 81% the histologic tumor grade was unchanged. Immunohistochemistry could be performed with 15 pairs of primary and recurrent PDAC. The mean Ki-67 proliferation index increased (P = 0.06). About 30% of tumor cells were positive for CXCR4 and almost all tumor cells expressed actinin-4, but there were neither significant changes in the expression levels in recurrent PDAC, nor specifically enhanced levels in metastases. The prominent CD133 pattern was an apical membrane staining of inflammatorily altered, non-neoplastic ductal structures equally observed in primary and recurrent PDAC. The membrane CD133 positivity was consistently absent in neoplastic PDAC cells. Cytoplasmic CD133 positivity was extremely rare (0.85 and 0.34 cells/cm(2) in primary and recurrent PDAC, respectively; P = 0.07). Tumor grade is mainly unchanged and the expression of CXCR4, actinin-4 and CD133 are not enhanced in recurrent PDAC. The apical membrane CD133 positivity of normal and inflammatorily altered ductal structures and its lack in tumor cells bring the role of CD133 as a specific CSC marker in PDAC into question.
Clin Exp Metastasis 2009
PMID:Comparative analysis of tumorbiology and CD133 positivity in primary and recurrent pancreatic ductal adenocarcinoma. 1948 31

Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies.
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PMID:The effects of telomerase inhibition on prostate tumor-initiating cells. 1990 30


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