Angela M OttoTechnische Universität München | TUM · Munich Institute of Biomedical Engineering
Angela M Otto
PD Dr. rer. nat. habil.
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111
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Introduction
In the past years, my central interest has been: The biochemistry of tumor metabolism in conditions mimicking a precarious tumor micro-environments - using different defined cell culture conditions of cancer cells as a model system for analyzing tumor heterogeneity and chemosensitiity.
Being retired, my lab is closed.
Additional affiliations
Publications
Publications (111)
The original version of the scheme was published in:
Angela M. Otto, Josef Hintermair, and Cornelia Janzon;
NADH-Linked Metabolic Plasticity of MCF-7 Breast Cancer
Cells Surviving in a Nutrient-Deprived Microenvironment
Journal of Cellular Biochemistry 116:822–835 (2015)
as a Fig. 7. Relationships between NADH-levels, the activity of plasma me...
In cancers, tumor cells are exposed to fluctuating nutrient microenvironments with limiting supplies of glucose and glutamine. While the metabolic program has been related to the expression of oncogenes, only fractional information is available on how variable precarious nutrient concentrations modulate the cellular levels of metabolites and their...
The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Un...
Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (kpl) of hyperpolarized [1-13C]pyruvate to [1-13C]lactate depend on monocarboxylate transporters (MCT) and lactate dehydrogenase (LDH); these are also indicators of tumor malignancy. An unr...
The Warburg effect is a hallmark of cancer metabolism; it is synonymous for a high rate of aerobic glycolysis and lactate production, which is associated with malignant growth. This paradigm has led to metabolism-based methodologies as diagnostic tools, one being the conversion of hyperpolarized [1-13C]pyruvate to [1-13C]lactate, measured by magnet...
Graphical abstract to:
Grashei, M.; Biechl, P.; Schilling, F.; Otto, A.M. Conversion of Hyperpolarized [1-(13)C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment. Cancers (Basel) 2022, 14, doi:10.3390/cancers14071845.
To explain why the kpl (rate) for the LDH-catalyzed reaction correlated...
Even though the mTOR complex has been known for decades as a nutrient sensor, being thus in focus for drug targeting in metabolic disease and cancer metabolism, it has remained puzzling how it is able to get a sense of glucose availability in cells. Now, a small metabolite of the glycolytic pathway, dihydroxyacetone phosphate, has been identified b...
Introduction: Metabolic imaging for cancer diagnostic and response to chemotherapy requires fundamental understanding of metabolic plasticity in a precarious nutrient microenvironment. An approach for experimentally discerning metabolic pathways is 13 C-glucose-derived metabolite profiling in a well-defined culture system consisting of medium with...
Preoperative characterization of thyroid nodules is challenging since thyroid scintigraphy fails to distinguish between benign and malignant lesions. Galectin-3 is widely expressed in the majority of well-differentiated thyroid carcinomas and in a large fraction of undifferentiated thyroid cancer types but not in normal thyrocytes and benign thyroi...
Tumors are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metab...
Thyroid nodules present a challenging preoperative characterization. The routine thyroid scan via radio-iodine scintigraphy provides functional information based on radio-iodine uptake mediated by sodium/iodide symporter (NIS), but fails to distinguish among benign and malignant lesions. Galectine-3 (Gal-3) expression in the thyroid is restricted t...
Cancers are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These meta...
Virtually everyone working in cancer research is familiar with the “Warburg effect”, i.e., anaerobic glycolysis in the presence of oxygen in tumor cells. However, few people nowadays are aware of what lead Otto Warburg to the discovery of this observation and how his other scientific contributions are seminal to our present knowledge of metabolic a...
Major contributions of the 2nd annual meeting of the International Society of Cancer Metabolism, held in Venice, September 16–19, 2015, are here described and discussed. Among these, the impact of cancer metabolism on local and systemic aggressiveness was analyzed in the context of interactions between cancer and stroma, microenvironmental changes,...
Objective:
(13)C metabolic MRI using hyperpolarized (13)C-bicarbonate enables preclinical detection of pH. To improve signal-to-noise ratio, experimental procedures were refined, and the influence of pH, buffer capacity, temperature, and field strength were investigated.
Materials and methods:
Bicarbonate preparation was investigated. Bicarbonat...
Characteristic of the tumor microenvironment are fluctuating gradients of reduced nutrient levels and released lactate. A fundamental issue is how tumor cells modulate their metabolic activity when both glucose and glutamine levels become limiting in the presence of high exogenous lactate. For functional analyses, the activities of pyruvate kinase,...
Hyperpolarization of [1-13C]pyruvate in solution allows real-time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods fo...
Introduction. The variability of the tumor microenvironment requires high metabolic plasticity to maintain cell growth and survival. With the wealth of knowledge on the molecular components in energy metabolism, the question often remains as how do these act and interact in quantitative terms. Such information is paramount for evaluating metabolic...
Background and aim. The microenvironment of tumor cells is characterized by a gradual deprivation of nutrients and oxygen, an accumulation of lactate, and increased acidification. The question is how variable combinations of these components change tumor cell growth and metabolic activity in quantitative terms. The aim here is to investigate how ex...
The detection of tumors noninvasively, the characterization of their progression by defined markers and the monitoring of response to treatment are goals of medical imaging techniques. In this article, a method which measures the apparent diffusion coefficients (ADCs) of metabolites using hyperpolarized 13 C diffusion-weighted spectroscopy is prese...
Unlabelled:
Abnormalities of tumor metabolism can be exploited for molecular imaging. PET imaging of (18)F-FDG is a well-established method using the avid glucose uptake of tumor cells. (13)C MR spectroscopic imaging (MRSI) of hyperpolarized [1-(13)C]pyruvate and its metabolites, meanwhile, represents a new method to study energy metabolism by vis...
Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will co...
Animal cells export the content of vesicles by exocytosis, a process in which a vesicle and the plasma membrane fuse and ultimately form a pore. The initial event leading to the breakthrough of the membranes for pore formation is not well understood. Here we present a mathematical approach which suggests that this process is initiated by single ele...
Cell cultivation is a fundamental tool in tissue engineering as well as in biomedical research. Choice of cell source and the control of cultivation parameters will determine the biological relevance and quality of the results. There are numerous biochemical and cellular assays available to test the vitality, i.e. the metabolic and functional activ...
Living cells react to external influences such as pharmacological agents in an intricate manner due to their complex internal signal processing. Cell reactions are an impact on vitality, cell-cell or cell-matrix interaction and morphological changes. A number of published techniques on impedance spectroscopy (IS) of adherent cells with planar elect...
Die Probenvorbereitung mit superparamagnetischen Mikropartikeln steigert die Nachweisempfindlichkeit der chromatographischen Trennung und Detektion von sekretierten Peptiden aus Zellkulturen.
The effective isolation and purification of proteins from biological fluids is the most crucial step for a successful protein analysis when only minute amounts are available. While conventional purification methods such as dialysis, ultrafiltration or protein precipitation often lead to a marked loss of protein, SPE with small-sized particles is a...
One of the goals of animal cell technology is to replace animal experiments by appropriate in-vitro technologies. Many methods
of analysing cellular parameters are end-point determinations. The advantage of the introduced system, however, is that monitoring
cell culture is non-invasive and can also provide kinetic information on changes in cellular...
For monitoring of the metabolic and morphologic activity of living cells a six channel version of a cell based assay called intelligent mobile lab (IMOLA) was prepared (Wiest et al., 2006). IMOLA employs biochips which contain microsensors for measurement of cellular respiration, extracellular acidification and changes in orphology of the cells. Th...
Tumor cells change their genetic expression pattern as they progress to states of increasing malignancy. Investigations at the DNA and RNA level alone cannot provide all the information resulting after the translation and processing of the corresponding proteins, which is one reason for a poor correlation between mRNA and the respective protein abu...
Eur.J.Cell Biology, 86S1, Suppl. 57
Tumor cells are changing their genetic expression pattern as they progress to states of increasing malignancy. Investigations at the DNA and RNA level alone do not provide all the information resulting after the translation and processing of the corresponding proteins, which explains reports on a poor correlation between mRNA and the respective pro...
The recent development of an electronic test system based on silicon sensor-chips allows the continuous parallel recording of relative changes in extracellular acidification, oxygen consumption and electric impedance in living cells. The objective of this proof-of-principle study therefore, was to clarify whether this system can also be applied to...
Mit Mikrosensoren sind Messungen zellphysiologischer Parameter von lebenden Zellen möglich. Die Sensormessung ist extrazellulär und so angelegt, dass sie keine Beeinträchtigung oder Störung des zellulären Lebens bewirkt. Dabei reicht das Spektrum der testbaren zellulären Proben sehr weit.
To study the interplay of drugs and energy metabolism of tumor cells, metabolic changes induced by chloroacetaldehyde and cytochalasin B were analyzed in colon carcinoma cells LS174T.
O(2)-consumption and extracellular acidification were recorded using a bioelectronic sensor-chip system, which monitors these parameters in a culture continuously for...
During recent years, sensor chip-based systems have been developed which monitor functional changes of living cells. Key elements of such cellular assays are silicon or glass chips with integrated sensors for physico-chemical parameters, i.e. pH, pO2, electric impedance
and temperature. Analysis of these primary parameters yields information about...
Chemotherapeutic drugs affect the metabolism of tumor cells regardless of the specific target of action. Basic parameters of cell metabolism are extrusion of acids into the microenvironment and oxygen consumption. To analyze these changes on living cells in real-time, a test system based on multiparametric chips with an array of sensors for monitor...
Thymosin beta4 is regarded as the main G-actin sequestering peptide in the cytoplasm of mammalian cells. It is also thought to be involved in cellular events like cancerogenesis, apoptosis, angiogenesis, blood coagulation and wound healing. Thymosin beta4 has been previously reported to localise intracellularly to the cytoplasm as detected by immun...
Tumor interstitium exhibits a microenvironment that differs from corresponding normal tissues. Tumor phenotype shows, for example, an elevated intracellular pH (pHi), a lowered extracellular pH (pHe), a low oxygen concentration and low glucose levels. These differences are caused by cell biological (so called intrinsic) factors, e.g. a higher acidi...
An alternative assay for replacing animal experiments should serve the specific microphysiological needs of the cells and be endowed with multiparametric signal monitoring. These requirements are provided by a test system in which the key elements are biocompatible electronic sensor-chips. It is also connected to a medium perfusion set-up, which al...
Cells are able to respond in an extremely sensitive way to changes in their environment. Electronic microstructures on sensor chips can be applied to analyse such responses by recording properties of cell metabolism and cell morphology. These parameters are linked intimately to the cellular signalling network and can thus be used as sensitive indic...
Die vorgestellten biohybriden Bauelemente und chipbasierten Systeme erlauben die Analyse metabolischer und elektrischer Signale von Zellen und Geweben on-line und in Echtzeit. Da diese Systeme für eine realitätsnahe Abbildung der Mikroumgebung sorgen, bieten sie sich als ideale Systeme für den Ersatz von Tierversuchen an. Eine vollautomatische Proz...
Multiparametric silicon sensor chips mounted into biocompatible cell culture units have been used for investigations on cellular microphysiological patterns. Potentiometric, amperometric and impedimetric microsensors are combined on a common cell culture surface on the chip with an area of approximately 29 mm2. Extracellular acidification rates (wi...
A constraint in the reliability of predictive chemosensitivity assays is linked to the fact that they analyze only a single cellular or biochemical parameter. A multiparametric test system using microsensor chips has been developed which can detect online microphysiological changes in living cells. Tumor cells were grown directly on glass- or silic...
Many different assays have been developed for testing the chemosensitivity of tumor cells in vitro, usually based on a single biochemical or cellular parameter. A multiparametric test system has been developed that accommodates on a single chip numerous sensors for metabolic parameters, deltapH and deltapO2, as well as for morphological changes. Th...
Elevated expression of the beta-thymosin isotypes T beta(4), T beta(10), and T(15) appears to be involved in the manifestation of a malignant phenotype of human tumor cells, including those of mammary carcinomas. This has evoked an interest in these peptides as diagnostic/prognostic tumor markers. If increased levels of beta-thymosins correspond to...
The beta-thymosins constitute a family of highly conserved and extremely water-soluble 5 kDa polypeptides. Thymosin beta4 is the most abundant member; it is expressed in most cell types and is regarded as the main intracellular G-actin sequestering peptide. There is increasing evidence for extracellular functions of thymosin beta4. For example, thy...
Summary form only given. Cells are the "atoms" of all living systems. Their nanostructure consists of electrodynamic components (membranes) involved in cellular signal transduction. Frequency modulated ion currents (Ca<sup>2+</sup> oscillations) induced by extracellular molecular "messages" encode specific information. On the other hand, it could b...
Most mammary carcinomas contain estrogen receptors (ER), which are an important factor in diagnosis and prognosis, and in deciding on the type of therapy. ER-positive tumors are most commonly treated with the antiestrogen tamoxifen or with a combination of chemotherapeutic drugs. An important aspect for further treatment and anticipating possible s...
The beta-thymosins are a family of highly conserved polar 5 kDa peptides originally thought to be thymic hormones. About 10 years ago, thymosin beta(4) as well as other members of this ubiquitous peptide family were identified as the main intracellular G-actin sequestering peptides, being present in high concentrations in almost every cell. beta-Th...
Estrogene, sowohl die körpereigenen als auch die pflanzlichen Ursprungs, spielen eine vielfältige Rolle bei Auslösung und Wachstum von Mammacarcinomen. In neuerer Zeit gewinnen Phytoestrogene vermehrte Aufmerksamkeit, da diese als Bestandteil der Nahrung zu einem verminderten Brustkrebsrisiko beitragen. Um den Wirkmechanismus solcher Phytoestrogene...
Phytoestrogene sind Bestandteil unserer Nahrung und können das Risiko, an Brustkrebs zu erkranken, deutlich mindern; das zeigen epidemiologische Studien der letzten Jahre. Nachdem im ersten Teil dieses zweiteiligen Artikels Grundlagen der zellulären und biochemischen Wirkmechanismen endogener Estrogene beschrieben wurden, wird im zweiten Teil erört...
The induction of cell death along with cell-cycle arrest is one of the foremost mechanisms regulating cell growth. In the human breast carcinoma cell line MCF-7 we investigated two chemotherapeutic agents, the antiestrogen tamoxifen and the DNA-damaging drug cisplatin, for the relative contribution of these mechanisms to growth inhibition in cultur...
Changes in estradiol (E2)-binding parameters can be detected within minutes, while the estrogenic responses are manifested after several hours or days of continuous exposure to the steroid. The goal of this study was to determine the time of commitment for the induction of transcription-dependent responses in the human breast cancer cell line MCF-7...
The platinum(II) complex PtCl2(meso-6), which has the estrogenic ligand meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine (meso-6), has been reported to be an effective antitumor drug for estrogen-receptor(ER)-positive tumors in animal experiments. The goal of this study was to investigate whether the observed biological effects could be a...
The cisplatin analog [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II) [PtCl2(1)], by virtue of its estrogenic 1,2-diphenylethylenediamine ligand 1, was intended to function as a cytotoxic estrogen. This article reports on the reversible and irreversible interactions of this compound with plasma and plasma proteins in...
The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB231 and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexe...
The inhibiting effect of [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) (meso-Pt(1)Cl2) (I) on the estrogen receptor-pos. (ER+) breast cancer in vivo is due to its cytotoxic as well as its estrogenic properties. In in vitro expts. on the ER+ MCF-7 breast cancer cell line meso-Pt(1)Cl2 can react with bionucleophils i...
The Pt complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]diaqua -Pt(II) sulfate (meso-6-PtSO4) was designed with the concept of combining the cytotoxic cisplatin with an estrogen receptor (ER)-binding ligand for targeting to ER+ mammary tumor cells. This Pt complex selectively inhibits growth of ER+ mammary tumors in rodents. To s...
Several investigators have discussed the possible combination of tamoxifen and interferon (IFN) in the treatment of breast cancer patients. The rationale in combining these drugs is that IFN induces the expression of estrogen receptors and therefore increases the sensitivity of breast cancer cells toward the growth-inhibitory activity of tamoxifen....
An approach to the investigation how growth factors and hormones regulate mammalian cell proliferation is to study the activity of enzymes involved in DNA replication. Quiescent cultures of Swiss mouse 3T3 cells were stimulated with prostaglandin F2 alpha, insulin, and/or hydrocortisone for a time at which less than 50% of the cells had initiated D...
This chapter discusses the microtubules and DNA replication. The investigations of the role of microtubules in regulating DNA replication reflect two different schools of thought: one studied lymphocytes with the working hypothesis that cell surface-associated microtubules were required for the transmission of the mitogenic signal; the other studie...
When quiescent confluent cultures were incubated at increased temperature and then incubated at 37 degrees C prior to a second increase of temperature (46 degrees C) it appeared that heat-induced morphological alteration and ability to proliferate could be influenced by the previous thermal history of the cells. Incubations for 20 min in a temperat...
Confluent quiescent Swiss mouse 3T3 cells can be stimulated to initiate DNA synthesis and to divide by epidermal growth factor (EGF) and prostaglandin F2 alpha (PGF2 alpha), two mitogens of unrelated structure. Heat treatment at 46 degrees C for up to 20 min of confluent quiescent cells, which has no mitogenic effect, can enhance the stimulatory ef...
Quiescent Swiss mouse 3T3 cells react to a heat treatment at 46 degrees C for 20 min by changing their flat, well-extended morphology to a round appearance with retracted cytoplasmic processes during the subsequent 2 h at 37 degrees C. The percentage of morphologically changed cells was used to quantify changes in heat sensitivity, or resistance, i...
Prostaglandin F2 alpha (PGF2 alpha); which stimulates DNA synthesis in resting 3T3 cells, also stimulates the incorporation of [32P]PO4 into phosphatidylinositol. The effect is selective for PGF2 alpha when compared with PGE1, PGE2, and PGF2 beta. Epidermal growth factor (EGF) also stimulates DNA synthesis but does not affect phosphatidylinositol t...
The regulation of mammalian cell proliferation is composed basically of two types of control: one is exerted by the interaction of the cell with its extracellular environment; the other is exerted by the genetic program expressed in the cell.
Among a number of prostaglandins, PGF2 alpha had the highest specific activity for stimulating the initiation of DNA synthesis in confluent resting Swiss 3T3 cells. At a saturating concentration of 8.5 X 10(-7) M, PGF2 alpha stimulated 21% of the cells to incorporate [ methyl-3H ]thymidine within 28 h. To elicit similar effects, prostaglandins F1 a...