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Objective: In the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is a challenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE. Methods: Formalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible. Results: In tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm. Conclusion: Our findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis. Trial registration number and date: BO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886. [ABSTRACT FROM AUTHOR]

Previously, from the adhesive cell line of Zajdela rat ascitic hepatoma, we obtained daughter sublines of two types (holoclonal and meroclonal), the cells of which differed in morphology (fibroblast- and epithelium-like, respectively), clonogenicity in tests in vitro, and tumorigenicity in vivo. To identify the potential role of Zajdela hepatoma adherent cells in processes of epithelial–mesenchymal transition (EMT) and metastasis, we compared all its sublines with monolayer lines of other hepatocellular tumors by the parameters that determine invasive and migratory properties of the cells. We have established that the cells of the holoclonal sublines are characterized by an increased activity of matrix metalloproteinase (MMP) 1, individual type of migration, and high motility rate as compared with the cells of other lines. The cells of all monolayer lines of Zajdela hepatoma secreted active forms of MMP-9 and translocated the intracellular domain of epithelial cell adhesion molecule (EpCAM) to their nucleus, which indicates the acquisition of an invasive phenotype by the cells and activation of Wnt/β-catenin signaling pathway. Our results indicate that the clonal sublines that we obtained from Zajdela ascitic hepatoma are consisted of the cells in transitional states between the epithelial and mesenchymal phenotypes. [ABSTRACT FROM AUTHOR]

Despite long-standing and large-scale studies on the nature of cancer and the development of numerous antitumor drugs, the incidence of cancer is growing and the five-year survival rate of cancer patients diagnosed at the advanced stages of the disease remains unacceptably low. The author considers the causes of such failures, which lie in the very nature of malignant cells: they can adapt to and resist practically any systemic therapeutic intervention. In this context, considerable hopes are pinned on oncolytic viruses, which are medical agents of a new type, able to produce an integrated effect on the disease. In addition to their direct ability to kill tumor cells selectively, oncolytic viruses stimulate natural processes of immune surveillance and removal of cancer cells. Besides, oncolytic viruses can kill tumor-initiating cancer stem cells that are highly resistant to chemo- and radiotherapy, and overcome the immunosuppression of the tumor microenvironment. These features make oncolytic viruses unique anticancer agents that combat cancer cells by multiple natural mechanisms. To incorporate viral cancer therapy into mainstream medical practice, it is necessary to intensify basic research on viral oncolysis mechanisms, to develop new therapeutic viral strains and tests for their personalized selection, and to improve methods of the local and systemic delivery of oncolytic viruses to tumor locations. Trials of drugs that would accelerate the introduction of new viral strains into medical practice will also require cardinal changes. Achievements in this sphere will help to overcome many old problems in the therapy of metastatic forms of malignant diseases. [ABSTRACT FROM AUTHOR]

The effects of Fructus Sorbi aucupariae extract, originally saturated with anthocyans, on the development of Lewis lung carcinoma and B-16 melanoma in C57Bl/6 mice and the efficiency of cyclophosphamide treatment were studied. Antitumor activity of the extract and potentiation of the antimetastatic activity of the cytostatic were demonstrated. Studies on melanoma B-16 model revealed an increase in the counts of stromal progenitor cells in the tumor node and their accelerated maturation after treatment with the extract. No effects towards the tumor stem and committed cells were detected. [ABSTRACT FROM AUTHOR]

Studies of the actions of niclosamide against tumor cells and normal human cells (human embryo kidney cells and pulmonary embryo fibroblast cells) showed higher levels of cytotoxic activity against tumor cells, including melanoma (the Mel-8, Mel-10, MS lines) and colorectal cancer (the Caco-2, COLO 320 HSR, and SW827 cells). Niclosamide was shown to have a high level of cytotoxic activity against cells with the multidrug resistance phenotype due to high levels of expression of MDR1 protein on the plasma membrane (the Mel-8 and MCF-7Adr lines). The proportion of tumor stem cells (TSC) was measured by flow cytometry as the proportion of cells forming side populations (SP). Niclosamide was found to act on TSC cells either more effectively (colorectal cancer line SW 837, (decreases in SP fraction size) or with the same effectiveness as the main population of tumor cells (SP fraction size unaltered). [ABSTRACT FROM AUTHOR]

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Objective: This study has investigated the existence of label-retaining cell and its distribution in gastric cancer, in the hope that this information will assist investigations on gastric cancer stem cells. Methods: The gastric carcinoma cell line BGC-823 was labeled with BrdU in vitro and then engrafted into the right axilla of nude mice, which developed tumors. Label-retaining cells were quantified by immunohistochemical methods. Results: BrdU positive cells constituted about 96% of the cells in xenograft tumors after 10 days. Subsequently, BrdU positive cells gradually decreased, at the 80th day, label-retaining cells steadily occupied about 0.5%. This set of population cell localized in the margin of cancer nests, which had no difference in cellular morpha. Conclusion: The study demonstrates the presence of label-retaining cells in human gastric cancer xenografts in nude mice and the label-retaining cells may be related with cancer stem cells, which are most likely the cause for spread, metastasis and recurrence. [ABSTRACT FROM AUTHOR]

The goal of this work was to study cellular mechanisms of tumor progression and metastasizing. As a result of explantation of cells of rat Zajdela ascitic hepatoma, we obtained two transplantable cell cultures-monolayer (ZH-ad) and suspension (ZH-fl)-that differ in levels of cell differentiation and tumorigenicity. By using tumor-specific immune serum, we revealed tumor-associated antigens, synthesis of which is reduced or inhibited in ZH-ad cells, in outer membranes of the ZH-fl cells. Intraperitoneal injection into rat of 0.5-12 × 10 ZH-fl cells leads to development of an ascitic tumor and death of 100% of animals, whereas, in the case of administration of ZH-ad cells, to achieve a tumorigenic effect, the minimal dose needs to be elevated to 20 × 10 cells. Clonogenic analysis of the ZH-fl cells revealed three types of the formed clones-nonadhesive sphere colonies and two types of monolayer clones differing in proliferative potential, shape of colonies, and cell composition. Upon reaching a critical size, the spheres disintegrated, with separation of single cells and islands of different sizes, some of them being attached with monolayer formation. Three clonal cell lines were obtained: 1C as a result of expansion of a spherical clone and 4G and 10E from monolayer clones. We established that there is tumorigenicity of the 1C cell line, which, at a dose of 107 cells, led to the development of ascites and to the death of 50% of animals. The presented results indicate the existence in the ZH-fl cell population of tumor-initiating cells generating spherical clones-floating multicellular islets that, in culturing in the complete growth medium, are partly differentiated and are attached with monolayer formation. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Putative CD133 brain tumor stem cells have been shown to be located in niches and as single cells. This is the first study providing insight into the different phenotypes of CD133 cells in glioblastoma according to localization. Paraffin sections were stained by double immunofluorescence with CD133 and the candidate stem cell markers Sox2, Bmi-1, EGFR, podoplanin and nestin, the proliferation marker Ki67 and the endothelial cell markers CD31, CD34, and VWF. Cell counting showed that the CD133 cells in the niches had a significantly higher expression of Sox2, EGFR and nestin compared to CD133 single cells, but only a 3% Ki67 labeling index versus 14% found for CD133 single cells. Only low endothelial cell marker expression was found in the niches or the CD133 tumor areas, while 43% CD133/CD31 and 25% CD133/CD34 single cells were found. CD133 blood vessels within CD133 niches were less proliferative and more often Bmi-1 than CD133 blood vessels outside niches. In conclusion, different CD133 cell phenotypes exist according to the in situ localization, and also the phenotype of CD133 blood vessels vary according to the localization. CD133 niches contain stem-like cells with a lower proliferation index than CD133 single cells, which have an endothelial differentiation profile suggesting a role in angiogenesis. [ABSTRACT FROM AUTHOR]

Copyright of Der Gynäkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome. [ABSTRACT FROM AUTHOR]

Copyright of HNO is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A common assumption of classical neuroscience was that neurons and glial cells were derived from separate pools of progenitor cells and that, once development was completed, no new neurons were produced. The subsequent disproving of the “no new neuron” dogma suggested that ongoing adult neurogenesis was supported by a population of multipotent neural stem cells. Two germinal regions within the adult mammalian brain were shown to contain neural progenitor cells: the subventricular zone (SVZ) along the walls of the lateral ventricles, and the subgranular zone (SGZ) within the dentate gyrus of the hippocampus. Surprisingly, when the primary progenitors (stem cells) of the new neurons in these regions were identified, they exhibited structural and biological markers of astrocytes. The architecture of these germinal regions and the pattern of division of neural stem cells have raised fundamental questions about the mechanism of adult neurogenesis. This review describes studies on the origin of adult neural stem cells, the features distinguishing them from astrocytes in non-germinal regions, and the control mechanisms of the proliferation and differentiation of these cells. Astrocytic adult neural stem cells are part of a developmental lineage extending from the neuroepithelium to radial glia to germinal astrocytes. Adult neural stem cells appear to be strongly influenced by their local microenvironment, while also contributing significantly to the architecture of these germinal zones. However, environment alone does not seem to be sufficient to induce non-germinal astrocytes to behave as neural stem cells. Although emerging evidence suggests that significant heterogeneity exists within populations of germinal zone astrocytes, the way that these differences are encoded remains unclear. The further characterization of these cells should eventually provide a body of knowledge central to the understanding of brain development and disease. [ABSTRACT FROM AUTHOR]

Adult stem cells can be identified by label-retaining cell (LRC) approach based on their ability to retain nucleoside analog, such as bromodeoxyuridine (BrdU). We hypothesized that mouse nasopharynx contains a small population of epithelial stem/progenitor cells that may be detected by the LRC technique. To identify LRCs in mice nasopharyngeal epithelia, neonatal mice were intraperitoneally injected with BrdU twice daily for 3 consecutive days. After an 8-week chase, long-term BrdU-labeled LRCs (∼2% of cells) were detected in the adult mice nasopharyngeal epithelia by immunostaining with BrdU antibody and some of LRCs (∼12% of cells) were found to be recruited into the S phase of cell cycle with an additional radioactive thymidine-labeling technique, indicating that the stem cells also divide, most likely asymmetrically. To further investigate whether the LRCs existed in human nasopharyngeal carcinoma (NPC) tissues, three NPC cell lines (5-8F, 6-10B and TMNE) were labeled with BrdU in vitro and then individually engrafted into the back of nude mice, which developed tumors. Again, label-retaining stem cells were found in all the three kinds of NPC xenograft tumors (∼0.3% of cells), around 16% of which were also labeled with radioactive thymidine. Thus, this study has demonstrated for the first time the presence of epithelial LRCs in mouse nasopharyngx and human NPC tissues and these stem-like LRCs are not completely quiescent, as they will be recruited into the cell cycle to participate physiological or pathological process at any moment. More importantly, our data showed that NPC also contained stem cells, which are most likely the cause for NPC spread, metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Analyses of genome orthologs in cancer on the background of tumor heterogeneity, coupled with the recent identification that the tumor propagating capacity resides within a very small fraction of cells (the tumor stem cells-TSCs), has not been achieved. Here, we describe a strategy to explore genetic drift in the mitochondrial genome accompanying varying stem cell dynamics in epithelial ovarian cancer. A major and novel outcome is the identification of a specific mutant mitochondrial DNA profile associated with the TSC lineage that is drastically different from the germ line profile. This profile, however, is often camouflaged in the primary tumor, and sometimes may not be detected even after metastases, questioning the validity of whole tumor profiling towards determining individual prognosis. Continuing mutagenesis in subsets with a mutant mitochondrial genome could result in transformation through a cooperative effect with nuclear genes – a representative example in our study is a tumor suppressor gene viz. cAMP responsive element binding binding protein. This specific profile could be a critical predisposing step undertaken by a normal stem cell to overcome a tightly regulated mutation rate and DNA repair in its evolution towards tumorigenesis. Our findings suggest that varying stem cell dynamics and mutagenesis define TSC progression that may clinically translate into increasing tumor aggression with serious implications for prognosis.Oncogene (2006) 25, 6336–6344. doi:10.1038/sj.onc.1209649; published online 29 May 2006 [ABSTRACT FROM AUTHOR]