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Objectives: This review is to explore whether potential gene interactions in the cell cycles of gametes, zygotes, and embryonic stem (ES) cells are associated with the development of cancer., Methods: MEDPILOT at the Central Library of the University of Cologne, Germany (Zentralbibliothek Köln) that covers 5,800 international medical journals and 4,300 E-journals was used to collect data. The initial searches were done in December 2012 and additional searches in October 2013-May 2015. The search terms included "cancer development," "gene interaction," and "ES cells," and the time period was between 1998 and 2015. A total of 147 articles in English language only were included in this review., Results: Transgenerational gene translation is implemented in the zygote through interactions of epigenetic isoforms of transcription factors (TFs) from parental gametes, predominantly during the first two zygote cleavages. Pluripotent transcription factors may provide interacting links with mutated genes during zygote-to-ES cell switches. Translation of post-transcriptional carcinogenic genes is implemented by abnormally spliced, tumor-specific isoforms of gene-encoded mRNA/non-coding RNA variants of TFs employing de novo gene synthesis and neofunctionalization. Post-translationally, mutated genes are preserved in pre-neoplastic ES cell subpopulations that can give rise to overt cancer stem cells. Thus, TFs operate as cell/disease-specific epigenetic messengers triggering clinical expression of neoplasms., Conclusion: Potential gene interactions in the cell cycle of gametes, zygotes, and ES cells may play some roles in the development of cancer.

Unlabelled: This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e.g. pi)RNA transmitted between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic genes., In Conclusion: Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production. Clinically, classification of leukemias should be based on their epigenetic presentation.

Objectives: Processing of epigenomic transcriptional information by cell cycle phase G(1) and decision-making at checkpoint G(1)/S are the final organizational steps preceding gene replication in transcriptional reorientation programs (i.e., switches from proliferation to cycle arrest and neoplastic transformation). Further analyses of cycle progression will open up new approaches in antineoplastic therapy., Materials and Methods: The following bibliographic databases were consulted: Central Medical Library Cologne, PubMed (English), the last search was done on April 23,2008 and key words searched were: cell cycle, cell memory, DNA methylation, embryonal/neoplastic stem cells, enzyme-modulated chromatin, G(1)-G(1)/S checkpoint, genomic/epigenomics, genomic viral DNA, histones, telomere/telomerases, transcription factors, neoplastic transformation, senescence., Results: Gene transcription and epigenomic surveillance form a functional entity. In proliferation programs, transcriptional information is mediated by chromatin and DNA methylation, analyzed and processed in G(1) phase, and converged on the parental checkpoint G(1)/S for final decision-making on DNA replication. Genomic reorientation appears to be associated with transcriptional instability, which normally is corrected, possibly during the G(2)/M phase, to new levels of epigenomic equilibria. We speculate that daughter stem cells inherit persistent neoplasm-specific transcriptional instabilities through failure of the parental G(1)/S checkpoint. Foreign, silenced, potentially oncogenic DNA sequences, i.e. regular components of the human genome such as endogenous retroviruses, could conceivably be activated for expression in neoplastic transformation by epigenomic histone deacetylase/acetyl transferase/histone methyltransferase-mixed lineage leukemia deregulations., Conclusions: Failure of cell cycle G(1)/S decision-making for DNA replication is the final and possibly a major cause in neoplastic transformation. Therefore, further analysis of the dynamics of G(1)-G(1)/Sphases could provide new opportunities for therapeutic strategies.

Reducing the blood supply of tumors is one modality to combat cancer. The objective of this study was to evaluate such an approach in the treatment of localized murine AML (acute myelogenous leukemia). For this purpose we designed an experimental model in which leukemic cells were embedded in 1% agar discs before subcutaneous implantation in C57Bl female mice. The C-1498 AML cell line (Frederick Inst., NCI, MD, USA) was used. Thirty experimental mice received on alternate days injections of 5 x 2.5 microg anti-VEGF (vascular endothelial growth factor) and 5 x 2.5 microg anti-Flk-1 (VEGFR2) antibodies to the site of cell implantation over a period of 10 d. Fifteen control mice received daily PBS injections. All mice were sacrificed 16 d after AML implantation. Of the 30 experimental animals, macroscopic examination showed in 21 animals (70%) small sized, pale tumors (0.5 g); in six mice (20%) the tumors were replaced completely by necrotic tissue, while in three mice (10%), there were large (2.5 g), highly vascularized tumors. In all 15 control mice large highly vascularized tumors were seen. A separate group of mice was studied for total survival following AML implantation. While 12 mice in the control group not treated with antibodies survived for 16 d post-implantation, survival was prolonged in 15 antibody treated mice by approximate 30 d to a total survival time of 48 d. Tumor specimens were processed for histology, immunohistochemistry (IHC) for CD31 endothelial cell antigen, and tube-like formation assay. The small, pale tumors of antibody treated animals consisted of degenerate hyaline material with remnant nests of leukemic cells, whereas large tumors showed sheets of leukemic cells and numerous blood vessels. Specimens processed for CD31 antigen showed scarce or absence of blood vessels in the small, pale tumors in contrast to intensive staining from a rich network of blood vessels in the large, highly vascularized tumors. Tube-like formation assays disclosed rudimentary Grade 1 endothelial cell tubes in the small, pale tumors as opposed to polygonal Grade 4 tube formation in control animals. In conclusion, this murine model of localized AML allows assessment of anti-angiogenic tumor regression. Anti-angiogenic antibodies against VEGF and Flk-1 have therapeutic effects in murine AML., ((c) Blackwell Munksgaard 2005.)

Embryonal stem (ES) cells are the earliest ontogenetically identifiable stem cells of the embryo proper for all subsequent mesenchymal stem cells and for highly specialized differentiated cells. This review characterizes, in a working hypothesis, the role of reversible EMT/MET (epithelialmesenchymal transition) as a manifestation of cell plasticity 1) in the development of ES cells to adult stem cells (hematopoietic stem cells) and 2) in metastasizing cancer cells. Animal studies support the concept that EMT/MET is a key manifestation of cell plasticity in the development of ES cells to adult stem cells, and in conversion of localized to metastasizing cancer cells. In fact, ES cells may persist to postnatal life, in cytologically verifiable form and/or within the frame of EMT/MET, as ultimate reservoir for adult stem cells. Furthermore, EMT could possibly serve as a conceptional link between physiologic and pathologic signaling pathways. Clonal confirmation in humans is necessary.

The life-long interdependencies/interactions between hemato- and endotheliopoiesis suggest that they form a supplementary functional entity. This view is compatible with the concept of stem cell plasticity as a reversible continuum and is substantiated by the common hematopoietic-endothelial stem cell, i.e., hemangioblasts, with bidirectional, reversible gene transcription and persistence in postnatal life. Indeed, embryonal stem cells/hemangioblasts appear to form a reservior in the adult with the possibility of dedifferentiation of more differentiated progenitor cells back to hemangioblasts. The recent detection of BCR/ABL fusion proteins in endothelial cells during vascular neoangiogenesis in CML suggests that endothelial cells are part of the neoplastic clone, and extends the concept of a functional entity to include CML angiogenesis. Thus, hemangioblasts rather than committed hematopoietic stem cells appear to be target cells for the first oncogenic hit in CML, which could occur as early as during the first steps of embryonal stem cell differentiation towards hemato-endotheliopoiesis and/or in hemangioblasts persisting in adults. The relation of the other leukemias to hemangioblasts is not known.

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.

Acute myeloid leukemia (AML) was induced in C57Bl mice through the i.v. innoculation of C-1498 cell line. One week later, i.e. at mid-term disease, the leukemic mice received an i.p. injection of 200 ng rmGM-CSF and 24 h later, two consecutive i.p. cytosine arabinoside (ara-C) injections at 6 h intervals (2 x 200 mg/kg). The leukemic mice received 3-4 weekly courses of combined therapy and survived 4-5 weeks following leukemia induction. Control mice received ara-C only and survived 2-3 weeks. Moreover, leukemic mice administered both GM-CSF and ara-C had a lower marrow leukemic load than mice treated with ara-C only. From these findings, we conclude that therapy of murine AML with combined rmGM-CSF and ara-C is more effective than ara-C only. Leukemic mice treated with GM-CSF and ara-C had a longer life expectancy and a smaller leukemic load than mice administered ara-C only.

A study of treated murine acute myeloid leukemia (AML) with an emphasis on the bone marrow stromal function is reported. Leukemia was induced in C57Bl mice through intraperitoneal (i.p.) inoculation of C-1498 myelogenous leukemic cells. The leukemic mice were administered: (1) total body lethal X-irradiation (t.b.i.); (2) two i.p. cytosine-arabinoside (Ara-C) injections followed by X-irradiation. Control mice received similar regimens. Bone marrow of experimental and control mice was processed for stromal cell cultures (SCC) and in vitro engraftment of hematopoietic cells onto the cultures. The results of this study indicate that the bone marrow stromal deficiency which occurs in leukemia is aggravated by Ara-C and irradiation treatments. Moreover, SCC of treated leukemic mice sustain in vitro hematopoiesis only to a limited degree. Stromal deficiency, as possible cause for graft failure in bone marrow transplanted leukemic patients, is discussed.

This study deals with murine marrow stromal cells (MSC) during hematopoietic regeneration. Regenerative marrow was induced in infant mice by two consecutive i. p. injections of hydroxyurea (HU) (2 X 1,000 mg/kg) which kill most cells in DNA synthesis. Two days later the marrow becomes enriched in pluripotent stem cells (CFU-S) and committed progenitors. It was found that fibroblastoid colony-forming-units (CFU-F) become concentrated approximately four fold above controls and give rise to significantly larger fibroblastoid colonies than CFU-F in control marrow. In split-phase semisolid agar cultures, i. e. adherent cells of HU-treated marrow (in under layers) and normal bone marrow cells (in upper layers), inhibition of G/M colonies in the upper layer in observed. In control split-phase cultures of both under layers and upper layers of normal bone marrow, CFU-C inhibition is by far less pronounced. In liquid cultures, pre-established adherent layers of HU-treated marrow have a stimulatory effect on normal marrow CFU-C. It is concluded that during increased demand for pluripotent stem cells and progenitors, such as after HU administration, marrow stromal cells and possibly other adherent cells produce inhibitory factor(s) of CFU-C differentiation. The inhibitory activity possibly is an effective mechanism for stem cell pool preservation. The differing effect of adherent cells of HU-treated marrow on CFU-C in liquid and in semi-solid medium suggests production of two different factors with opposing influences on CFU-C, depending upon the culture conditions.

A suspension of fine carbon particles was added to cord blood of healthy premature and full-term infants, and the mixture was incubated for 3 h, after which the uptake of carbon particles by blood leukocytes was examined. The results were compared with those from the blood of adults. A gradient of phagocytic activity was observed. The most active uptake of carbon was by the leukocytes of premature infants, the least active by leukocytes of adults. In cord blood and blood of adults, phagocytic activity was evident in both monocytes and neutrophils. In addition, two types of what have been termed 'lymphocytoid' phagocytes were seen. These resemble lymphocytes in their morphology. One type possesses basophilic cytoplasm, and has been found only in premature cord blood. The presence of lymphocytoid phagocytes affords a further indication of the differences between the circulating lymphocyte population in the prenatal and perinatal period as compared with the adult.

The existence of pluripotential haemopoietic stem cells raises the possibility of stem cell competition when two or more differentiating stimuli are given either simultaneously or in close succession. The experiments now reported deal with the effects on guinea pig bone marrow of successive stimulation and they fall into two groups. In one group, erythropoiesis was first stimulated by means of hypoxia, after which granulopoiesis was stimulated by the intraperitoneal injection of typhoid vaccine. In another group, these two stimuli were given in the reverse order. Bone marrow changes were evaluated both quantitatively and by differential counts. The experimental animals were compared with controls given only one stimulus, either hypoxia or vaccine, and also with normal untreated animals. As judged by the output of granulocytes or erythrocytes, no stem cell shortage developed in the experimental animals. A marked fall in transitional cells in the bone marrow of the experimental animals is consistent with the view, though not affording actual proof, that the pluripotential stem cells are to be found in the transitional cell compartment.

A study of bone marrow of C57B1 mice administered cytosine-arabinoside (Ara-C) was carried out in long-term bone marrow culture (LTBMC). Two days after administration of two consecutive i.p. Ara-C injections (200 mg/kg each) at 6-h intervals, the bone marrow becomes hypocellular, yet in the process of regeneration, with an enriched and/or concentrated content of progenitors and stem cells. Ara-C-treated marrow was observed to sustain hematopoiesis in vitro better than physiological marrow; it produced a higher cell yield, a higher proportion of young-type myeloid cells, and higher levels of granulocyte-macrophage colony-forming cells and colony-forming units in diffusion chamber than control marrow. In addition, stromal cell cultures (SCC), devoid of hematopoiesis and engrafted with hematopoietic cells from LTBMC of Ara-C-treated marrow, were observed to produce hematopoietic cells for longer periods of time than SCC engrafted with control cells. In view of its increased capacity for regeneration, it is suggested that regenerative marrow should be used in autologous bone marrow transplantation in humans.

One hundred and twenty-one febrile episodes (FE) were studied in 58 aplastic children with acute leukemia. All patients received a prophylactic regimen of trimethoprim-sulfamethoxazole (TS) and colistin sulfate orally, and amphotericin B locally from the beginning of their antineoplastic therapy. Eighty episodes were analysed retrospectively. Forty-one episodes in 24 patients were treated prospectively with a standard regimen of gentamicin + cefotaxime. The results show that the prophylactic regimen does not eradicate potentially pathogenic organisms from the throat, urine, or stools. Sixty-three per cent of FE were of unknown origin (FUU). 40.5% of all isolated organisms were TS resistant. In the prospective group, 9 of 41 FE (22%) responded to gentamicin + cefotaxime with lysis of fever within 48 hours, and 63% required no further antibiotics. Defeverescence occurred in the whole group within 5 +/- 4 days. No patients were lost to infectious complications. The combination of gentamicin + cefotaxime as initial therapy of a febrile episode must be supplemented within 48 to 72 hours by additional antibiotics in the absence of clinical improvement.

During fetal life, haematopoiesis is in a physiologic state of rapid expansion. The activity of the pluripotent haematopoietic stem cell compartment of the bone marrow probably is reflected by the number and proliferative potentiality of CFUc in the blood circulation. We have studied, by the methylcellulose culture technique and without addition of exogenous colony stimulating factor (CSF), blood CFUc in pre-term and full-term newborn infants, in full-term infants 10 to 17 d of age, and in adults. Two groups of pre-term infants were studied: otherwise healthy infants and sick infants, including infants small-for-date and in perinatal distress. In healthy pre-term infants and in full-term infants 147 +/- 25 (SD) and 105 +/- 41 (SD) colonies per 100 000 lymphoid cells were formed, respectively. This is clear evidence for the presence in the blood of both. CFUc and CSF producing cells. By contrast, there was no or only slight spontaneous colony formation by sick pre-term infants, by older infants, and by adult.

Cord blood from 16 premature infants and 10 full-term infants, and blood from 10 healthy adults, was incubated for 30 minutes with tritiated thymidine, after which an autoradiographic study was made of spontaneously labeling cells. Apart from a varying number of erythroblasts, myelocytes, and an occasional blast cell, two main types of spontaneously labeling cells were observed: transitional cells and large lymphoid cells, previously shown to be phagocytic. Spontaneously labeling cells were 12 times more frequent in cord blood of premature and full-term infants than in the blood of adults. No transitional cells were seen in adult blood.

71 patients with resectable osterosarcoma received chemotherapy for one year including high-dose methotrexate (18 x 200 mg/kg), adriamycin (5 x [2 x 45] mg/m2) and cyclophosphamide (6 x 1200 mg/m2). During the initial 15 weeks adriamycin was used preferentially and cytostatic agents were applied in a higher frequency than later on. 41/71 patients are continuously free of disease with a median follow up of 39 (24-54) months. The latest appearance of pulmonary metastases was observed at 28 months so far. 18/27 (67%) patients with extension of tumor lesion beyond 1/3 long bones length by x-ray examination relapsed in contrast to 12/43 (28%) patients with smaller lesions. 1 patient died from adriamycin induced cardiomyopathy. Generally therapy was well tolerated. An average of 70-80% of planned drug dosages could be realized without measurable influence of individual differences on outcome.

A study of murine adherent marrow cells (AMC) under conditions of high and low concentrations of hematopoietic stem cells and progenitors was carried out. In one group of weanling mice, decreased marrow cellularity and increased concentrations of CFU-S, CFU-D, and CFU-C were observed two days after administration of two consecutive intraperitoneal (i.p.) cytosine arabinoside (Ara-C) injections (2 x 200 ng/kg, at 6 h interval). Fibroblast colony-forming units (CFU-F) of this marrow were studied. In a second group of mice, which were given three i.p. phenylhydrazine (PHZ) injections (3 x 60 mg/kg on days 0, 1, and 3), CFU-S and CFU-C levels were unchanged or lowered 6 days after the start of PHZ administration. In these animals, however, the number of CFU-D was four times higher than in controls. The study of CFU-F in experiments of groups 1 and 2 indicated a high concentration of these progenitors in group 1 and lower concentration in group 2. Furthermore, fibroblastoid colonies produced in vitro by CFU-F of Ara-C-treated marrow were significantly larger than colonies from control marrow, and they markedly inhibited G/M colonies in split-phase agar cultures. By contrast, fibroblastoid colonies produced by PHZ-treated marrow were of regular size and did not inhibit G/M colonies from test bone marrow.