scholarly journals Patterns of tumor progression predict small and tissue-specific tumor-originating niches

2018 ◽  
Author(s):  
Thomas Buder ◽  
Andreas Deutsch ◽  
Barbara Klink ◽  
Anja Voss-Böhme
Keyword(s):  
Tumor Cells ◽  
Malignant Tumors ◽  
Tumor Development ◽  
Tumor Formation ◽  
Tissue Type ◽  
Human Tissues ◽  
Cell Type ◽  
Tissue Specific ◽  
Specific Tumor ◽  
A Cell

AbstractCancer development is a multistep process in which cells increase in malignancy through progressive alterations. The early phase of this process is hardly observable which aggravates an understanding of later tumor development. We shed light on this initial phase with a cell-based stochastic model calibrated with epidemiological data from the tissue scale. Our model allows to estimate the number of tumor cells needed for tumor formation in human tissues based on data on the diagnosed ratios of benign and malignant tumors. We find that the minimal number of cells needed for tumor formation is surprisingly small and largely depends on the tissue type. Our results point towards the existence of tumor-originating niches in which the fate of tumor development is early decided. Our estimate for the human colon agrees well with the size of the stem cell niche in colonic crypts. Our estimates might help to identify the tumor-originating cell type, e.g. our analysis suggests for glioblastoma that the tumors originate from a cell type competing in a range of 300 - 1900 cells.SummaryWe estimate the number of tumor cells needed for tumor formation in human tissues and propose the existence of small and tissue-specific tumor-originating niches which might help to find tumor-originating cell types, in particular in glioblastoma.

scholarly journals Cell and tissue type independent age-associated DNA methylation changes are not rare but common

2018 ◽  
Author(s):  
Tianyu Zhu ◽  
Shijie C Zheng ◽  
Dirk S. Paul ◽  
S. Horvath ◽  
Andrew E. Teschendorff
Keyword(s):  
Dna Methylation ◽  
Cell Types ◽  
Tissue Type ◽  
Tissue Cell ◽  
Cell Type ◽  
Tissue Specific ◽  
Cell Tissue ◽  
A Cell ◽  
High Degree ◽  
Do So

AbstractAge-associated DNA methylation changes have been widely reported across many different tissue and cell types. Epigenetic ‘clocks’ that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. However, the relative amount of age-associated DNAm changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. Here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue DNA methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. We further show that ELOVL2 is not unique and that many other CpG sites, some mapping to genes in the Wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. We propose that while most age-associated DNAm changes are shared between cell-types that the putative functional effect is likely to be tissue-specific.

scholarly journals EMeth: An EM algorithm for cell type decomposition based on DNA methylation data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hanyu Zhang ◽  
Ruoyi Cai ◽  
James Dai ◽  
Wei Sun
Keyword(s):  
Dna Methylation ◽  
Tumor Cells ◽  
T Regulatory Cells ◽  
Simulated Data ◽  
Cell Types ◽  
Computational Method ◽  
Methylation Data ◽  
Cell Type ◽  
A Cell ◽  
Type Decomposition

AbstractWe introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.

scholarly journals Tissue-Specific Transcriptional Targeting of a Replication-Competent Retroviral Vector

2002 ◽  
Vol 76 (24) ◽  
pp. 12783-12791 ◽  
Author(s):  
Christopher R. Logg ◽  
Aki Logg ◽  
Robert J. Matusik ◽  
Bernard H. Bochner ◽  
Noriyuki Kasahara
Keyword(s):  
Tumor Cells ◽  
Viral Vectors ◽  
High Efficiency ◽  
Leukemia Virus ◽  
Transduction Efficiency ◽  
Promoter Strength ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Tissue Specific

ABSTRACT The inability of replication-defective viral vectors to efficiently transduce tumor cells in vivo has prevented the successful application of such vectors in gene therapy of cancer. To address the need for more efficient gene delivery systems, we have developed replication-competent retroviral (RCR) vectors based on murine leukemia virus (MLV). We have previously shown that such vectors are capable of transducing solid tumors in vivo with very high efficiency. While the natural requirement of MLV infection for cell division imparts a certain degree of specificity for tumor cells, additional means for confining RCR vector replication to tumor cells are desirable. Here, we investigated the parameters critical for successful tissue-specific transcriptional control of RCR vector replication by replacing various lengths of the MLV enhancer/promoter with sequences derived either from the highly prostate-specific probasin (PB) promoter or from a more potent synthetic variant of the PB promoter. We assessed the transcriptional specificity of the resulting hybrid long terminal repeats (LTRs) and the cell type specificity and efficiency of replication of vectors containing these LTRs. Incorporation of PB promoter sequences effectively restricted transcription from the LTR to prostate-derived cells and imparted prostate-specific RCR vector replication but required the stronger synthetic promoter and retention of native MLV sequences in the vicinity of the TATA box for optimal replicative efficiency and specificity. Our results have thus identified promoter strength and positioning within the LTR as important determinants for achieving both high transduction efficiency and strict cell type specificity in transcriptionally targeted RCR vectors.

scholarly journals THE ROLE OF ALPHA-FETOPROTEIN RECEPTOR IN THE DELIVERY OF TARGETED PREPARATIONS IN ONCOLOGY

2017 ◽  
Vol 22 (1) ◽  
pp. 4-14
Author(s):  
H. M Treshalina ◽  
G. B Smirnova ◽  
S. A Tsurkan ◽  
J. R Tcherkassova ◽  
N. A Lesnaya
Keyword(s):  
Tumor Cells ◽  
Malignant Tumors ◽  
Human Tumor ◽  
Tumor Model ◽  
Mitochondrial Pathway ◽  
Alpha Fetoprotein ◽  
Malignant Cells ◽  
Tumor Models ◽  
A Cell ◽  
Afp Production

There was executed the analysis of thematic literature during from 1956 to 2015 devoted to receptors to fetal proteins, including to alpha-fetoprotein (AFP) known in medicine as oncomarker and used by malignant cells for the organization of tumoral homeostasis. As protein carrier, AFP similar to albumin takes of vitally important molecules in a space «hydrophobic pocket» and moves inside a cell, but as the cancer-embryonal antigen (CEA) - determines the existence of a malignant tumor, but not the type of a neoplasm. On the bounding of AFP with teratogen and their internalization and delivery in an embryo there is based the development of ways of «address» delivery of substances into a cell. This is realized by means of receptor mediated endocytosis via specific membranous receptors to AFP (ReCAF) with high selectivity concerning malignant cells of various genesis. Up to 90% of all malignant cells of the human and tumor models for human and mammalians express AFP receptors, including rather recently opened stem tumor cells - the most probable source of metastasing. AFP production and expression of receptors is selectively raised in malignant tumors of patients and human tumor models. The hyperproduction of AFP and hyperexpression of ReCAF are related to the histologic type of tumor model and are characteristic for embrional cell tumors and hepatoblastomas with initially low drug sensitivity or with the resistance. When choosing the model it is necessary to consider that in different types of tumor cells ReCAF have specific features in cultivation which are not pronounced in conditions of an animal organism. More differentiated tumors are characterized by the larger level of the AFP production and a hyperexpression of ReCAF. The use of subcutaneous tumor xenografts signal for AFP localizations with the hyperexpression of receptors, allows to reveal mostly evidentially the effectiveness of the therapeutic system at the preclinical level. Address delivery of therapeutic systems created on the basis of AFP or its fragments is capable of causing the change of their pharmacological properties. The therapeutic prize is possible due to the induction of process of apoptosis via the mitochondrial pathway, but at the same time the fall in the cytotoxic capacity of system is possible.

scholarly journals A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6435-6440 ◽  
Author(s):  
Natasha C. Lucki ◽  
Genaro R. Villa ◽  
Naja Vergani ◽  
Michael J. Bollong ◽  
Brittney A. Beyer ◽  
...  
Keyword(s):  
Small Molecule ◽  
Brain Cancer ◽  
Critical Role ◽  
Tumor Formation ◽  
Tumor Xenograft ◽  
Drug Candidate ◽  
Cell Type ◽  
Caspase 1 ◽  
A Cell

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

scholarly journals Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

2001 ◽  
Vol 21 (6) ◽  
pp. 2144-2153 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Boris C. Bastian ◽  
Aram Hezel ◽  
Dan Pinkel ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Mutation ◽  
Comparative Genomic ◽  
Cell Type ◽  
Specific Expression ◽  
Rb Pathway ◽  
High Incidence ◽  
A Cell ◽  
Cell Type Specific

ABSTRACT The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising inINK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on theINK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53 −/−melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

Hydrogen peroxide regulates angiogenesis-related factors in tumor cells

2017 ◽  
Vol 95 (6) ◽  
pp. 679-685 ◽  
Author(s):  
Ana Jerónimo ◽  
Gonçalo Rodrigues ◽  
Filipe Vilas-Boas ◽  
Gabriel G. Martins ◽  
Ana Bagulho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Angiogenic Factors ◽  
Related Factors ◽  
Tumor Neovascularization ◽  
A Cell ◽  
Vessel Network ◽  
Xenografted Tumor

Tumor angiogenesis is required for tumor development and growth, and is regulated by several factors including ROS. H2O2 is a ROS with an important role in cell signaling, but how H2O2 regulates tumor angiogenesis is still poorly understood. We have xenografted tumor cells with altered levels of H2O2 by catalase overexpression into zebrafish embryos to study redox-induced tumor neovascularization. We found that vascular recruitment and invasion were impaired if catalase was overexpressed. In addition, the overexpression of catalase altered the transcriptional levels of several angiogenesis-related factors in tumor cells, including TIMP-3 and THBS1. These two anti-angiogenic factors were found to be H2O2-regulated by two different mechanisms: TIMP-3 expression in a cell-autonomous manner; and, THBS1 expression that was non-cell-autonomous. Our work shows that intracellular H2O2 regulates the expression of angiogenic factors and the formation of a vessel network. Understanding the molecular mechanisms that govern this multifunctional effect of H2O2 on tumor angiogenesis could be important for the development of more efficient anti-angiogenic therapies.

Hypoxia boosts aerobic glycolysis of carcinoma：a complex process for tumor development

2021 ◽  
Vol 14 ◽  
Author(s):  
Xiuqin Zheng ◽  
Hui Fan ◽  
Yang Liu ◽  
Zhonghong Wei ◽  
Xiaoman Li ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Tricarboxylic Acid Cycle ◽  
Tumor Development ◽  
Hypoxic Conditions ◽  
The Stability ◽  
Cancer Tissues

: Hypoxia, a common feature in malignant tumors, is mainly caused by insufficient oxygen supply. Hypoxia is closely related to cancer development, affecting cancer invasion and metastasis, energy metabolism and other pathological processes, and is not conducive to cancer treatment and prognosis. Tumor cells exacerbate metabolic abnormalities to adapt to the hypoxic microenvironment, especially to enhance aerobic glycolysis. Glycolysis leads to an acidic microenvironment in cancer tissues, enhancing cancer metastasis, deterioration and drug resistance. Therefore, hypoxia is a therapeutic target that cannot be ignored in cancer treatment. The adaptation of tumor cells to hypoxia is mainly regulated by hypoxia inducible factors (HIFs), and the stability of HIFs is improved under hypoxic conditions. HIFs can promote the glycolysis of tumors by regulating glycolytic enzymes, transporters, and participates in regulating the TCA (tricarboxylic acid) cycle. In addition, HIFs indirectly affect glycolysis through its interaction with non-coding RNAs. Therefore, targeting hypoxia and HIFs are important tumor therapies.

scholarly journals Hsp90 Inhibitors NVP-AUY922 and NVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cells along with a Cell Type-Specific Cytotoxicity

2012 ◽  
Vol 5 (5) ◽  
pp. 356-IN16 ◽  
Author(s):  
Natalia Niewidok ◽  
Linda-Jacqueline Wack ◽  
Sarah Schiessl ◽  
Lavinia Stingl ◽  
Astrid Katzer ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Type ◽  
Hsp90 Inhibitors ◽  
Specific Cytotoxicity ◽  
A Cell ◽  
Cell Type Specific
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