Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Central nervous system (CNS) tumors are the most common solid neoplasms in children. Medulloblastomas (MEDs) resemble embryonic neuroectodermal stem cells and their immature, uncommitted neuronal and glial progeny. Apoptosis is a basic physiological process wherein the cell initiates a sequence of events culminating in the fragmentation of its DNA, nuclear collapse, and finally, disintegration of the cell into small, membrane-bound apoptotic bodies. Expression of Fas (APO-1, CD95) receptor (FasR) and programmed or active cell death (PCD) was studied in childhood MEDs with varying stages of malignancy, and cell differentiation features. The majority of neoplastically transformed, neuroectodermal in origin cells, particularly in MEDs, express FasR, whereas normal cells in the CNS do not. FasR is a transmembrane glycoprotein, which belongs to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily. Apoptosis within childhood PNETs/MEDs is triggered by the binding of FasR to its natural ligand (FasL) or by cross-linking with anti-section i FasR antibodies. The resence of FasL has also been detected in childhood glial tumors. Therefore, a spontaneous, cellular immunophenotype (IP) regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in childhood brain tumors during neoplastic growth and progression. During our systematic immunocytochemical screening, we employed formalin fixed, paraffin-wax embedded tissue sections, as well as frozen sections of 34 primary human childhood PNETs/MEDs. The use of a sensitive, indirect, six step immunoperoxidase or alkaline phosphatase conjugated streptavidin-biotin antigen detection technique, modified by us, provided excellent immunocyto-chemical results. A systematic observation of the presence of apoptosis related markers (especially FasR) and cells in PCD was carried out. A strong expression (intensity of staining: "A"-the highest possible; number of stained neoplastic cells: +3 to +4, between 50% to 90%) of FasR, was detected employing 4 microns thick, formalin fixed, paraffin-wax embedded tissue slides. The panel of normal tissues employed as positive and negative tissue controls demonstrated presence of FasR in the prenatal thymus, mature tonsils and colon epithelium. Certainly, the coexpression of FasR, FasL, and other PCD-related proteins have also been reported in other human malignancies: breast cancer, colorectal carcinomas, large granular lymphocytic leukemia of T or NK cell origin, melanomas, lung, prostate, pancreas, and hepatocellular carcinomas. The coexpression of both FasR and FasL on several neoplastic cell types may represent an effective mechanism for tumor escape of the cellular immunological response of the host. It has been well established that brain tumors and melanomas produce their autocrine FasL, and even become capable of switching their signal transduction from the PCD pathway to a tumor growth, proliferative pathway. It seems that the therapeutical use of FasR-FasL (main apoptotic pathway) represents a new and exciting immunotherapeutical possibility in the treatment of primary childhood neuroectodermal tumors.
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PMID:Fas (APO-1, CD95) receptor expression and new options for immunotherapy in childhood medulloblastomas. 1065 26

We have performed immunophenotypical (IP) analyses of tumor infiltrating leukocytes (TIL) in both childhood brain tumors (medulloblastomas[MEDs]/primitive neuroectodermal tumors [PNETs] and astrocytomas [ASTRs]) and malignant melanomas (both primary and metastatic) employing a well-characterized library of monoclonal antibodies (MoABs) directed against leukocyte differentiation/activation associated antigens. The antigens were detected by an indirect, biotinstreptavidin conjugated alkaline phosphatase (AP) immunocytochemical technique. Our systematic cell-surface antigen expression profile analysis of 76 primary childhood brain tumors (34 MEDs/PNETs and 42 ASTRs) identified CD8+ CTL in 58/76 brain tumors. CD4+, MHC class II restricted helper lymphocytes were present in 65/76 brain tumors and represented 1-10% of the observed cells. Macrophages were present in 74/76 childhood brain tumor cases observed by us. Leukocyte common antigen (LCA) expression was demonstrated in all 76 brain tumors studied. MoAB UJ 308 detected the presence of premyelocytes and mature granulocytes in 60/76 brain tumors. They were localized perivascularly, within the tumor tissue, or close to necrotic regions. Natural killer (NK) cells were not defined in the childhood brain tumors observed in this study. The IP characteristics of the heterogeneous leukocytic infiltrate of 30 primary (PMs) and 10 metastatic melanomas (MMs) was also investigated by us. We established the presence of some type of melanoma infiltrating host's immunological effector cells in all 40 observed melanoma cases. More specifically, we found NK cells, macrophages and granulocytes in 30/30 PMs and 10/10 MMs. These effector cells represented the vast majority (> 80%) of the melanoma infiltrating immunocompetent cells. T lymphocytes were observed in 20/30 PMs and 6/10 MMs, but their numbers represented only between 5% to 10% of the heterogeneous leukocytic infiltrate. B cells were found in 22/30 PMs and 8/10 MMs, their numbers representing less than 5%. Presence of cells of the dendritic reticulum, involved in antigen presentation was not determined in any of the observed PMs and MMs. The notion that infiltration of the neoplastically transformed mass of cells by TIL is always a prognostically positive phenomenon has changed in recent years as research on extracellular matrix remodeling and angiogenesis have identified numerous secreted factors which are common to both neoplastically transformed cells and infiltrating leukocytes.
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PMID:Controversies on the prognostic significance of tumor infiltrating leukocytes in solid human tumors. 1092 5

The homeobox was originally described as a conserved DNA motif of about 180 base pairs. The protein domain encoded by the homeobox, the homeodomain, is thus about 60 amino acids long. The homeodomain is a DNA-binding domain, and many homeobox genes have now been shown to bind to DNA and regulate the transcription of other genes. Thus homeodomain proteins are basically transcription factors, most of which play a role in development. The homeobox genes seem to represent another class of oncofetal antigens involved in both normal development and carcinogenesis, as well as tumor progression. It has been shown that HOX-B3 and HOX-B4 are preferentially expressed in primitive CD34+, lineage-committed hematopoietic stem cells (HSCs) in human bone marrow. HOX-B3 overexpression in HSCs causes defective lymphoid development and progressive myeloproliferation, while HOX-B4 leads to selective expansion of HSCs without altering their differentiation. The HOX-C6 gene product leads to cell differentiation in neuroblastomas, while also being associated with the neoplastically transformed mammary cell phenotype and progression in primary cutaneous lymphomas. The expression pattern of these three homeobox gene products (HOX-B3, HOX-B4, and HOX-C6) was examined immunocytochemically in childhood MEDs/PNETs employing an indirect alkaline phosphatase conjugated technique on formalin-fixed, paraffin-embedded tissue sections. Strong staining intensity (A, B) of HOX-B3 and HOX-B4 was registered in all MEDs/PNETs, with immunoreactivity in between 50% and 90% (+3), but usually over 90% (+4) of the tumor cells. HOX-C6 was detected at medium intensity (mostly B) in 50% to 90% (+3) of the MED/PNET cells. This report is the first to describe the expression of these three homeobox gene products in MEDs/PNETs, and provides further evidence for the role of these proteins in the progression of human malignancies. The value of these genes and proteins in the early diagnosis and possible treatment of various human neoplasms, including childhood brain tumors, should be assessed in further immunocytochemical and molecular biological experiments.
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PMID:Immunocytochemical detection of the homeobox B3, B4, and C6 gene products in childhood medulloblastomas/primitive neuroectodermal tumors. 1092 6

Matrix metalloproteinases (MMP) are a family of zinc-dependent enzymes which degrade various components of the extracellular matrix (ECM) and play an important role in facilitating neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and tumor invasion. Expression of MMP-2, -3, -9, -10, and -13 was investigated in both spontaneous and xenografted (cells derived from an established cell-line [DAOY#3]) childhood medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed tissue that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found only in the spontaneous MEDs/PNETs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells in the spontaneous cases, and the staining intensity was also the strongest possible (A,B). Focal (surrounding less than 10% of the neoplastically transformed cells) but strong (A,B) immunoreactivity for collagenase-3 (MMP-13) was also only detected in spontaneous MEDs/PNETs, an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates. Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of B and B,C intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in the spontaneous cases. Staining for MMP-2 was negative in the xenografted MEDs/PNETs. The only positive immunoreactivity in the xenografted MEDs/PNETs was observed in the case of MMP-9, with expression of strong intensity in the ECM surrounding over 90% of the neoplastically transformed xenografted MED/PNET cells (++++; A,B). It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The data presented here suggest that there are significant differences in the pathophysiology of spontaneous and xenografted human neoplasms, which further establishes the already detected limitations of such models in preclinical cancer research.
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PMID:Significant differences in the matrix metalloproteinase expression profiles of spontaneous medulloblastomas/primitive neuroectodermal tumors as compared with their xenografted, established tumor cell line derived counterparts. 1121 45

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in embryonic tissues during human ontogenesis and most human malignancies, but it is not present in the majority of normal adult tissues. Survivin is also a chromosomal passenger protein required for physiological cell divison. Survivin blocks apoptosis, via its BIR domain, by either directly or indirectly blocking the function of the members of the caspase cascade. The expression of this apoptosis inhibitor protein in medulloblastomas (MEDs) was examined for the first time. During the immunohistochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did, in fact, demonstrate the presence of survivin in 10 to 50 per cent of medulloblastoma (MED) cells with medium intensity immunoreactivity (++, B) in this neuroectodermal brain tumor. These results indicate that survivin is probably not only a diagnostic marker, but also an important prognostic marker for MEDs/PNETs and may be useful in the future grading of malignancy in MEDs, much as grading is done today for astrocytomas (ASTRs). Furthermore, the almost exclusive neoplastic expression of survivin will allow development of new antineoplastic, immunotherapeutic strategies.
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PMID:Survivin expression in childhood medulloblastomas: a possible diagnostic and prognostic marker. 1564 11

During the process of programmed cell death (PCD), the cell disintegrates into small, membrane-bound apoptotic bodies. Caspase-3 is ubiquitously expressed in normal and neoplastically-transformed human cells and serves as an executioner in the apoptotic or PCD pathway. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase-conjugated antigen detection technique was employed. The results demonstrated the presence of apoptotic activity within the cellular microenvironment of childhood medulloblastoma/primitive neuroectodermal tumor. The observations identified the cytoplasmic presence of caspase-3 in more than 20% of neoplastic cells. The immunocytochemical expression pattern demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells in about 5% of the tumor cells. Caspase-3 presence was also detected in the tumor infiltrating lymphocytes (TILs), representing the host's immune, mostly CD8+, cytotoxic, tumor-associated antigen (TAA)-directed effector cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that the grade and intensity of apoptosis may not only have diagnostic and prognostic significance, but could also play a leading role in the biological (fourth modality) antineoplastic treatment of these highly malignant, neuroectodermal brain tumors.
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PMID:Immunocytochemical detection of members of the caspase cascade of apoptosis in childhood medulloblastomas. 1599 45

Overactivation of epidermal growth factor receptor (EGFR) signaling has been recognized as an important step in the pathogenesis and progression of multiple forms of cancer of epithelial origin. Reports regarding EGFR family members in brain tumors are sparse and, thus, the significance of EGFR expression in childhood brain tumors is unclear. In this study, the expression of the EGFR family members was analyzed in 22 medulloblastomas. During the immunohistochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results demonstrated the presence of c-erbB-2 (HER-2) and c-erbB-4 (HER-4) in 10 to 50% of the neoplastic cells of high-grade glial tumors with high immunoreactivity, while c-erbB-3 (HER-3) was only detected in less than 10% of the neoplastically-transformed cells. In a follow-up, 70% of children, usually under 4 years of age, with c-erbB-2 (HER-2)-positive MEDs/PNETs, succumbed to the cancer. The Kaplan-Meier estimation revealed a significant correlation between c-erbB-2 expression and survival (p = 0.002), suggesting that c-erbB-2 (HER-2) is probably a prognostic marker for limited survival. Medulloblastoma is the most common malignant brain tumor that occurs during childhood. Multimodality treatment regimens have substantially improved survival in this disease; however, the tumor is incurable in about one-third of patients with medulloblastoma, and the current treatment has a detrimental effect on long-term survivors. As such, the results of this study further support the idea that targeting EGFR alone, or in combination with its downstream mediators, represents a promising new approach for the management of childhood brain tumors. Moreover, c-erbB-2 (HER-2) expression may also be of use in better classifying brain tumors.
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PMID:Epidermal growth factor receptor (EGFR) expression in childhood brain tumors. 1609 49

The overexpression of COX enzymes has been demonstrated in human neoplasms at various sites, including the colon, gastrointestinal tract, lung, skin and recently in brain tumors. In this study, COX-2 receptor overexpression in primary childhood brain tumors was determined and the distribution pattern of COX-2 receptors was examined. A sensitive, 4-step, alkaline phosphatase conjugated antigen detection technique was used and a specific monoclonal antibody for medulloblastomas/ primitive neuroectodermal tumors (MEDs/PNETs), anaplastic, high-grade astrocytomas (ASTRs) and in glioblastoma multiformes (GMs) was employed. All of the 14 MEDs/PNETs observed demonstrated high levels of immunoreactivity (overexpression), with the highest immunostaining intensity (grades A and B). However, of the 14 subtypes of astrocytic tumors examined, the COX-2 receptor expression level did not even approach those of the MEDs/PNETs levels. However, significant differences were found when comparing low grade pilocytic ASTRs to high grade anaplastic ASTRs and glioblastomas. In two low grade pilocytic ASTRs, the expression level never exceeded 20%, while in high grade glial tumors (6 anaplastic ASTRs and 6 GMs) 30 to 50% of the tumor cells overexpressed COX-2 receptors, documenting an increase in COX-2 receptor overexpression with the increasing grade of the astrocytic tumor. In view of these findings, it would appear likely that COX-2 inhibitors may represent a chemo-preventive tool in treating childhood brain tumors, which are the leading cause of solid tumor cancer death in children under the age of 20.
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PMID:Cyclooxygenase-2 (COX-2) overexpression in childhood brain tumors. 1690 Jul 83