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At least 289 records · Page 16Linked to original sources

PubMed2005

Preparation and characterization of monoclonal antibodies against nucleostemin, a protein that controls cell proliferation in stem cells and cancer cells.

Nucleostemin (NS) is a novel protein that promotes the proliferation of stem cells and cancer cells. The aim of this study is to prepare specific monoclonal antibodies against nucleostemin as a tool in nucleostemin research. To generate the antibodies, the cDNA coding nucleostemin was cloned from human gastric cancer cell line NCI-N87 with reverse transcriptase-polymerase chain reaction (RT-PCR). The partial cDNA fragment was inserted into prokaryotic expression vector pGEX-4T1 to make glutathione S-transferase (GST) fusion protein in Escherichia coli, and the whole-length cDNA fragment was cloned into vector pcDNA3 for expression in mammalian cells. The spleen cells, from the BALB/c mouse immunized with the GST-nucleostemin fusion protein, were used to prepare the monoclonal antibody with hybridoma technique. After screening with enzyme-linked immunosorbent assay (ELISA) and subcloning, six specific monoclonal antibodies against nucleostemin were obtained. Moreover, they also worked well in Western blotting, immunoprecipitation, and immunohistochemistry. These antibodies will be helpful in elucidating biological functions and the molecular mechanism of nucleostemin.

Animals↗

PubMed2006

The neurobiology of neurooncology.

The histological classification of brain tumors currently is based on the morphological appearance and protein expression patterns that reflect specific cell types within the central nervous system. Recent studies have suggested that the cells of origin for brain tumors may persist in the fully formed tumors, and that these "cancer stem cells" might represent the relevant cellular targets for anticancer therapy. In this regard, insights into the developmental neurobiology of brain tumors has significant impact on our understanding of the molecular and cellular pathogenesis of these devastating cancers, as well as the development of new strategies for treating brain tumors.

Astrocytoma↗

PubMed1999

bcl-2 protein expression is associated with a prognostically favourable phenotype in breast cancer irrespective of p53 immunostaining.

AIM: A role for altered programmed cell death in cancer stems from the description of alterations on tumour-associated genes involved in the regulation of apoptosis such as p53 and bcl-2. The balance between the latter may have significant implications for the pathobiology of breast cancer. This study was therefore undertaken to evaluate the expression of these two gene products with opposite functions. METHODS AND RESULTS: A total of 142 paraffin-embedded tumour blocks were evaluated for nuclear p53 (a marker of p53 inactivation) and cytoplasmic bcl-2 immunohistochemistry. The results were semiquantitated. The bcl-2 protein was found within the infiltrating neoplastic cells of 97 (68%) specimens but it was also detectable in tumours' in situ compartments and in benign mammary tissue. We identified a strong correlation between bcl-2 immunoreactivity and oestrogen receptor positivity (P = 0.03), while bcl-2 expression also correlated significantly with small tumour size (P = 0.006) and low nuclear grade (P = 0.01), but it did not correlate with the expression of p53. bcl-2 presence tended to diminish with disease progression (P = 0.06). Quantitatively increased bcl-2 immunostaining was significantly associated with older patients (P = 0.02) as well as with presence of progesterone receptors (P = 0.01). Thirty-seven tumours (26%) were judged positive for p53 protein expression. The p53 positivity status was independent of all classical histopathological variables; however, high p53 expression was negatively linked to oestrogen receptors (P = 0.005). CONCLUSION: In breast cancer, bcl-2 protein is associated with a prognostically favourable phenotype and appears to be related to hormonal regulation, rather than to disabled p53 gene function.

Adult↗

PubMed2006

Targeted therapy by disabling crossroad signaling networks: the survivin paradigm.

Embedded in the concept of targeted cancer therapy is the expectation that disabling a single oncogenic pathway will eliminate the tumor cells and leave the normal tissues unscathed. Although validated by clinical responses in certain malignancies, challenges exist to generalize this approach to most tumors, as multiple genetic lesions, chromosomal instability, insensitivity of the cancer stem cell compartment, and emergence of drug resistance complicate the identification and therapeutic exploitation of a single, driving oncogenic pathway. Instead, broader therapeutic prospects may be offered by targeting crossroad signaling networks that are selectively exploited in cancer and oversee multiple aspects of tumor cell maintenance. One such pathway is centered on survivin, a cancer gene that intersects cell proliferation, cell survival, and the cellular stress response. Several clinical trials targeting survivin with a collection of approaches from immunotherapy to small-molecule antagonists are currently under way. By simultaneously disabling multiple signaling circuitries, targeting survivin may provide a novel perspective in rational cancer therapy selective for specific cancer mechanisms but broadly applicable to disparate tumors regardless of their genetic makeup.

Genetic Therapy↗

PubMed2026

Interplay between DNA and RNA methylation shapes cancer cell plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Humans↗

PubMed2025

PKCζ, CTNNBIP1 and ALDH1A3 Expression in Luminal B Breast Cancer Indicates Decreased Hormone Therapy Effectiveness.

BACKGROUND/AIM: The role of catenin β interacting protein 1 (CTNNBIP1), a negative regulator of the canonical Wnt/β-catenin signaling pathway, in luminal A and B breast cancer stem cells treated with hormone therapy is unknown. This study investigated the relationship between CTNNBIP1 and aldehyde dehydrogenase 1 family member A3 (ALDH1A3) expression and its impact on disease-specific survival in luminal A and B breast cancer. Given that high protein kinase ζ (PKCζ) expression, together with elevated CTNNBIP1 or ALDH1A3, is linked to poor prognosis in luminal B tumors, we also examined their combined influence. MATERIALS AND METHODS: Gene expression and clinical data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=2,509) were analyzed using Kaplan-Meier and Cox proportional hazards models. Findings were validated with The Cancer Genome Atlas Pan-Cancer Atlas (TCGA; n=1,084). RESULTS: CTNNBIP1 high ALDH1A3 high indicated a poor prognosis in patients with luminal B breast cancer treated with hormone therapy in the METABRIC dataset and aromatase inhibitors as hormone therapy in the TCGA data set, suggesting that high CTNNBIP1 and ALDH1A3 expression contributed to decreased effectiveness of hormone therapy in patients with luminal B breast cancer. PKC ζ high CTNNBIP1 high ALDH1A3 high was associated with a poor prognosis in patients with luminal B breast cancer treated with hormone therapy and aromatase inhibitors, suggesting that high PKC ζ , CTNNBIP1 and ALDH1A3 expression contributed to decreased effectiveness of hormone therapy in patients with luminal B breast cancer. CONCLUSION: PKC ζ and CTNNBIP1 may be involved in the progression of ALDH1A3-positive luminal B breast cancer. In luminal B breast cancer, PKC ζ , CTNNBIP1 and ALDH1A3 could serve as molecular drug targets and prognostic biomarkers to predict the effectiveness of hormone therapy.

ALDH1A3↗

PubMed2005

Radial glia cells are candidate stem cells of ependymoma.

Tumors of the same histologic type often comprise clinically and molecularly distinct subgroups; however, the etiology of these subgroups is unknown. Here, we report that histologically identical, but genetically distinct, ependymomas exhibit patterns of gene expression that recapitulate those of radial glia cells in the corresponding region of the central nervous system. Cancer stem cells isolated from ependymomas displayed a radial glia phenotype and formed tumors when orthotopically transplanted in mice. These findings identify restricted populations of radial glia cells as candidate stem cells of the different subgroups of ependymoma, and they support a general hypothesis that subgroups of the same histologic tumor type are generated by different populations of progenitor cells in the tissues of origin.

Animals↗

PubMed2006

Metastasis: a question of life or death.

The metastatic process is highly inefficient--very few of the many cells that migrate from the primary tumour successfully colonize distant sites. One proposed mechanism to explain this inefficiency is provided by the cancer stem cell model, which hypothesizes that micrometastases can only be established by tumour stem cells, which are few in number. However, recent in vitro and in vivo observations indicate that apoptosis is an important process regulating metastasis. Here we stress that the inhibition of cell death, apart from its extensively described function in primary tumour development, is a crucial characteristic of metastatic cancer cells.

Animals↗

PubMed1996

Detection of cancer cells in peripheral blood stem cells of women with breast cancer by RT-PCR and cell culture.

The benefit of high-dose therapy and blood stem cell reinfusion for women with high-risk breast cancer is currently under investigation. Contaminations of autologous blood stem cells with cancer cells have been described. Cancer micrometastases may be detected by immunocytochemistry, culture techniques and cytokeratin-19 mRNA reverse transcriptase PCR. Women with breast cancer received adjuvant HD-CTM with peripheral blood stem cell (PBSC) support after surgical therapy and 4 cycles conventional chemotherapy. Peripheral blood stem cells were mobilised by G-CsF and harvested after the third or fourth cycle of standard therapy. Aliquots of PBSC-collections (10(7)-2*10(7) cells) were subjected to CK19-mRNA reverse transcriptase PCR. RNA was extracted by standard methods and reverse transcription was performed with MMV-RT. Integrity of RNA was checked by coamplification of housekeeping sequences. Aliquots of the RT-mix were subjected to PCR-amplification with outer and inner primer pairs, subsequently. A second aliquot of 2*10(7) cells was cultured over 42 days in liquid culture. Cytospins were prepared weekly from cultured cells and evaluated by light microscopy with or without prior immunocytochemistry. Ten leukaphereses from 6 women were available for PCR-analysis and cell culture. Six leukaphereses were negative for CK19-mRNA and for detection of cancer cells by culture technique, two samples were positive for CK19-mRNA and culturally enriched cells and two samples were positive for CK19-mRNA and negative for cultured cancer cells. No sample was positive for cultured cells and negative for CK19-mRNA. Overall, the results corresponded in 80%. Two sensitive techniques for the detection of cancer micrometastases were applied to aliquots from 10 leukaphereses of six breast cancer patients with corresponding results in 80%. PCR-mediated detection of cancer cells was confirmed by culture technique and light microscopy, however, further comparison of CK19-PCR with standard techniques like cell culture and immunocytochemistry is still necessary.

Breast Neoplasms↗

PubMed2026

Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.

Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify potential combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.

Humans↗

PubMed2006

Future directions in the second-line treatment of non-small cell lung cancer.

Single-agent chemotherapy has shown limited activity as second-line treatment in metastatic non-small cell lung cancer (NSCLC), with short-lived responses and modest survival benefit over best supportive care or placebo. There are multiple ways to improve the poor outcome of patients whose disease progresses after first-line chemotherapy. First, individualizing second-line chemotherapy could optimize its effect; the discovery of dramatic responses and significant improvement in survival in patients with epidermal growth factor receptor (EGFR) gene mutations who are treated with EGFR tyrosine kinase inhibitors may lead to the application of other novel therapeutic approaches. Cancer vaccines, using autologous tumor cells genetically modified with granulocyte-macrophage colony-stimulating factor, constitute a new therapeutic option for patients with chemoresistant advanced NSCLC. Vaccines based on lymphocyte-defined tumor antigens, such as melanoma-associated antigen-3, toll-like receptor 9, and mucin 1, are also in the first stages of testing and have shown promising preliminary results. New approaches in gene therapy, including a p53-based method, are currently being investigated. The ultimate goal of gene therapy is to target cancerous stem cells, the importance of which is beginning to be recognized in NSCLC through the study of abnormalities in the wingless (Wnt) pathway. At the preclinical level, small interfering RNA sequences have been used successfully to neutralize multiple abnormal components of the Wnt pathway.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Stem cells of ependymoma.

Ependymomas are tumours that arise throughout the central nervous system. Little is known regarding the aberrant cellular and molecular processes that generate these tumours. This lack of knowledge has hampered efforts to reduce the significant mortality and morbidity that are associated with ependymoma. Here, we review recent data that suggest that radial glia are cells of origin of ependymoma, and discuss the processes that might transform these neural progenitors into ependymoma cancer stem cells.

Brain Neoplasms↗

PubMed1977

[Definition of the population groups with high-risk for breast cancer].

Based on the epidemiologic literature, the major risk factors for mammary cancer are discussed. The problem in defining population groups with a high potential for breast cancer stems from the fact that for most of the criteria of higher risk only a two- or threefold increase in incidence is observed. In addition, many of the risk factors are not independent but show interactions with other factors. In the individual woman it is possible to decide whether she has a high potential for developing breast cancer or not, but the criteria for high or low risk are not at present sufficiently contrasted to justify the exclusion of certain low-risk groups from screening procedures.

Adolescent↗

PubMed2000

The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance.

Discovered in 1986 as a DNA binding activity that recognized the immunoglobulin light chain intronic enhancer, NF-kappaB has been studied intensively for its role in controlling expression of genes involved in immune and inflammatory function. However, more recently, NF-kappaB has been implicated in controlling cell growth and oncogenesis. The link between NF-kappaB and cancer stems, in part, from the fact that this transcription factor is capable of inducing gene products that control proliferative responses and that suppress apoptotic cascades, such as those induced by tumor necrosis factor (TNF), expression of oncoproteins, and genotoxic stress. This latter observation is likely to be important in developing new approaches aimed at improving the efficacy of cancer chemotherapy.

Animals↗

PubMed1998

Matrix metalloproteinases and metastatic cancer.

The rationale for matrix metalloproteinase (MMP) inhibition as a means to treat disease progression in breast cancer stems from the apparent involvement of MMPs in the hydrolysis of basement membranes during tumour cell invasion and subsequent metastasis. MMP-mediated matrix remodelling also appears to promote the growth of tumour cells, possibly by facilitating the proliferation and migration of endothelial cells and the neovascularization of tumour tissue. We found that transfection of the C127 breast cancer cell line by MMP-2 (gelatinase A), but not by MMP-1 or MMP-3 (collagenase and stromelysin respectively), gave rise to an invasive and metastatic phenotype. We were surprised to find that this phenotype depended not only on the catalytic properties of MMP-2 but also on properties associated with the MMP-2 non-catalytic C-terminal domain. Experiments with a synthetic gelatinase inhibitor revealed that a single dose could prevent the lungs of nude mice being colonized by the MMP-2 transfectants, and that the inhibitor had to be administered during or shortly after injection of the cells, indicating that an early event, such as the extravasation of the cells into the lung, is gelatinase-dependent in this system. In other studies employing long-term treatment with CT1746, an orally active gelatinase inhibitor, we have previously demonstrated a reduction in primary tumour growth rates, localized spread, and spontaneous metastasis, even when the treatment was commenced several days after tumour implantation. Furthermore, additive effects were recorded when gelatinase inhibitor therapy was combined with cytotoxic drug treatment. Since the gelatinase inhibitors can also inhibit bone resorption in vitro, these observations point to their potential for delaying disease recurrence and reducing rates of bone loss following conventional therapeutic strategies, in metastatic breast cancer.

Animals↗

PubMed1997

Expression of the antiapoptotic protein bcl-2 is not dependent on the tumor suppressor p53 protein in Indian breast carcinoma.

Tissue homeostasis and the maintenance of cell populations depend on a delicate balance between the rates of cell proliferation and cell death. Programmed cell death or apoptosis is believed to play a major role in physiological processes which, when defective, could contribute to the pathogenesis and progression of tumors. A role for altered programmed cell death in cancer stems from the description of alterations on tumor-associated genes involved in the regulation of apoptosis such as p53 and bcl-2. The p53 gene promotes apoptosis in cells with genetic damage, while bcl-2 is an antiapoptotic gene. It is therefore possible that the balance between p53 and bcl-2 may have significant implications for the pathobiology of breast cancer. This study was therefore undertaken to evaluate the expression of these two proteins with opposite functions and their relation to the total growth fraction of the tumor as measured by PCNA immunoreactivity. A significant correlation was observed between expression of p53 and PCNA. In contrast, bcl-2 expression did not correlate with the expression of p53. There was also no correlation observed between expression of bcl-2 and PCNA. A significant correlation was observed between expression of p53 and the grade of the tumor and stage of the disease. Our results thus support the hypothesis that accumulation of p53 is associated with a high tumor proliferation rate, an association that might be expected in view of the role of wild-type p53 as a negative regulator of cell proliferation. Another important observation was the lack of relationship between bcl-2 expression and PCNA immunoreactivity, supporting the hypothesis that bcl-2 is not a major regulator of proliferation.

Apoptosis↗

PubMed2001

Sympathetic blockade for the relief of chronic pain.

The sympathetic blocks are useful in many ways for relief of chronic pain. The sympathetic block can be caused at pre- and paravertebral sympathetic ganglia eg, stellate ganglia, coeliac plexus and lumbar sympathetic ganglia. Indications for sympathetic blockade are: Complex regional pain syndrome, phantom limb pain, central pain, acute pancreatitis, pancreatic cancer and cancer pain from upper abdominal viscera. Stellate ganglion blockade is required for the diagnosis, prognosis and therapy for painful and other conditions associated with sympathetic dysfunctions of head, neck and upper extremity. Coeliac plexus block is indicated in pain due to intra-abdominal cancer, stemming from organs innervated by coeliac plexus. Lumbar sympathetic block is indicated for diagnosis, prognosis and therapy for painful and other conditions associated with sympathetic dysfunctions like complex regional pain syndrome I and II, herpes zoster, amputation stump pain and inoperable peripheral vascular vasospastic diseases of the lower limb. Indications for superior hypogastric block are the prognostic and therapeutic purposes of cancer pelvic organs--uterus, cervix, bladder, prostate, urethra, testes and ovaries.

Anesthetics, Local↗

PubMed2005

OCT4 expression on a case of poorly differentiated (insular) carcinoma of the thyroid gland and minireview.

Poorly differentiated (insular) carcinoma of the thyroid gland is rare and defined as follicular-cell neoplasms that show limited evidence of structural follicular cell differentiation and occupy both morphologically and behaviourally an intermediate position between differentiated (follicular and papillary carcinomas) and undifferentiated (anaplastic) carcinomas. The authors report a case of a 37-year-old Thai woman who presented with a prolonged left thyroid nodule. Final pathological diagnoses of her mass were poorly differentiated (insular) carcinoma with lymphovascular invasion and nodular goiter. The tumor cell arrangements were nest (insular) and trabecular patterns with some follicular formations. Immunohistochemistry of the tumor cells revealed negative immunostaining for OCT4. Expression of OCT4 gene is involved in the regulation and maintenance of pluripotency of embryonic stem cells, germ cells, and in tumor cells. The authors believe that poorly differentiated (insular) carcinoma of the thyroid gland probably develops from the remnant of thyroid stem cells and is not associated with dedifferentiation (anaplasia or loss of cellular differentiation) from nodular goiter or cells of other thyroid carcinomas. Although there was negative immunostain for OCT4 in the presented case, the authors assumed that the tumor cells behave with an intermediate position between thyroid stem cells and prothyrocytes Also they do not behave with thyroblasts. Additionally, the tumor may be associated with new cellular dedifferentiation. However, there is only one case of immunohistochemistry of OCT4 in poorly differentiated (insular) carcinoma of the thyroid gland. Thus, prognosis of the presented still is mainly correlated with clinical and histological findings. Further research on expression of OCT4 gene on thyroid cancers and other malignant tumors relating to tumorigenic cancer cells (cancer stem cells) may be useful to prognostic evaluation and administration of a new chemotherapy and/or radiotherapy that is specific for tumor-initiating cells.

Adult↗