scholarly journals Eradicating Metastatic Cancer and the Evolutionary Dynamics of Extinction

2019 ◽  
Author(s):  
Robert Gatenby ◽  
Joel S. Brown
Keyword(s):  
Cancer Cells ◽  
Acute Lymphocytic Leukemia ◽  
Evolutionary Dynamics ◽  
Metastatic Cancer ◽  
Lymphocytic Leukemia ◽  
Initial Population ◽  
Basic Principles ◽  
Curative Therapy ◽  
Single Drug ◽  
Extinction Threshold

We propose the traditional goal of cancer therapists to develop a single drug or drug combination that can, by itself, eliminate all cancer cells within a host has neglected potential treatments that may achieve curative outcomes by strategically combining agents that are individually effective but non-curative. We derive basic principles for such an approach from the eco-evolutionary dynamics of background extinctions in which a “first strike” reduces the size and heterogeneity of the initial population and is followed immediately by demographic and ecological “second strikes” that push the population below an extinction threshold. This proposed strategy appears identical to the empirically-derived curative therapy in childhood Acute Lymphocytic Leukemia.

Motility of leukemic lymphocytes

1990 ◽  
Vol 48 (3) ◽  
pp. 368-369
Author(s):  
Manoj Raje ◽  
Karvita B. Ahluwalia
Keyword(s):  
Quantitative Data ◽  
Laser Doppler Velocimetry ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cellular Space ◽  
Differentiated Cells ◽  
Poorly Differentiated ◽  
Solid Tissues ◽  
Well Differentiated ◽  
Reduced Mobility

In Acute Lymphocytic Leukemia motility of lymphocytes is associated with dissemination of malignancy and establishment of metastatic foci. Normal and leukemic lymphocytes in circulation reach solid tissues where due to in adequate perfusion some cells get trapped among tissue spaces. Although normal lymphocytes reenter into circulation leukemic lymphocytes are thought to remain entrapped owing to reduced mobility and form secondary metastasis. Cell surface, transmembrane interactions, cytoskeleton and level of cell differentiation are implicated in lymphocyte mobility. An attempt has been made to correlate ultrastructural information with quantitative data obtained by Laser Doppler Velocimetry (LDV). TEM of normal & leukemic lymphocytes revealed heterogeneity in cell populations ranging from well differentiated (Fig. 1) to poorly differentiated cells (Fig. 2). Unlike other cells, surface extensions in differentiated lymphocytes appear to originate by extrusion of large vesicles in to extra cellular space (Fig. 3). This results in persistent unevenness on lymphocyte surface which occurs due to a phenomenon different from that producing surface extensions in other cells.

Deregulated expression of prostate apoptosis response gene-4 in less differentiated lymphocytes and inverse expressional patterns of par-4 and bcl-2 in acute lymphocytic leukemia

2001 ◽  
Vol 2 (2) ◽  
pp. 103-107 ◽  
Author(s):  
Simone Boehrer ◽  
Kai U Chow ◽  
Elena Puccetti ◽  
Martin Ruthardt ◽  
Shahrzad Godzisard ◽  
...  
Keyword(s):  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Response Gene ◽  
Gene 4

scholarly journals Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu-An Chen ◽  
Yong-Da Sie ◽  
Tsung-Yun Liu ◽  
Hsiang-Ling Kuo ◽  
Pei-Yi Chou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cancer Cells ◽  
Room Temperature ◽  
Metastatic Cancer ◽  
Normal Cells ◽  
Tgfβ Receptor ◽  
Membrane Type ◽  
Cell Invasiveness ◽  
And Control ◽  
Metastatic Cancer Cells

AbstractMetastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

scholarly journals TAMI-57. MEDULLOBLASTOMA UTILIZE GABA TRANSAMINASE TO SURVIVE IN THE CEREBROSPINAL FLUID MICROENVIRONMENT AND PROMOTE LEPTOMENINGEAL DISSEMINATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii225-ii226
Author(s):  
Vahan Martirosian ◽  
Krutika Deshpande ◽  
Hao Zhou ◽  
Keyue Shen ◽  
Vazgen Stepanosyan ◽  
...  
Keyword(s):  
Energy Source ◽  
Cerebrospinal Fluid ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Leptomeningeal Metastases ◽  
Metabolic Phenotype ◽  
Leptomeningeal Disease ◽  
Neural Cells ◽  
Gaba Transaminase

Abstract Medulloblastoma (MB) is a malignant pediatric brain tumor. Studies have shown heterogeneous cells amongst the tumor bulk which mirror normal neural cells in various neurodevelopmental stages. To discern exploited mechanisms promoting MB leptomeningeal disease, we drew conclusions from developmental neurobiology. In normal differentiation, the metabolic phenotype in proliferating neural progenitor cells evolves from a glycolysis-dependent to an oxidative phosphorylation-reliant energetic profile in quiescent differentiated neurons. Cancer cells mirror this evolution, which also grants them the capability to utilize alternative nutrients in the microenvironment as an energy source. Considering metastatic cells are typically in a dormant state and primarily utilize oxidative phosphorylation, we hypothesized metastatic MB cells emulate a quiescent neuron-like cellular profile to survive in the cerebrospinal fluid and form leptomeningeal metastases. To examine this, we query the expression of GABA catabolic enzyme GABA transaminase (ABAT) in MB. GABA is found in the cerebellar and leptomeningeal microenvironments, and is utilized by metastatic cancer cells in the CNS as an energy source. We correlate an increase in ABAT expression with neurodevelopment and show heterogeneous expression of this protein in primary MB tumors. MB cells with increased expression of ABAT were slower-dividing, expressed a genetic and metabolic phenotype reminiscent of quiescent neuron-like cells, and had increased capability to metabolize GABA. Conversely, lower expression of ABAT was associated with an increased proliferation rate and correlated with a progenitor-like cellular profile. Transplantation of MB cells into the leptomeningeal compartment decreased proliferative capacity and enhanced ABAT expression. Xenograft models showed MB cells with ABAT knockdown had increased growth in the cerebellar microenvironment. Conversely, MB cells with ABAT overexpression transplanted into the cerebrospinal fluid formed leptomeningeal metastases whereas ABAT knockdown cells could not. These results suggest ABAT expression in MB cells can be modulated by the tumor microenvironment and is required to form leptomeningeal metastases.

scholarly journals Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 97
Author(s):  
Odeya Marciano ◽  
Linoy Mehazri ◽  
Sally Shpungin ◽  
Alexander Varvak ◽  
Eldad Zacksenhaus ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Metastatic Cancer ◽  
Carcinoma Cells ◽  
Metabolic Adaptation ◽  
Hypoxic Stress ◽  
Lung Carcinoma Cells ◽  
Metabolic Role ◽  
Highly Sensitive ◽  
Anticancer Treatment

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.

scholarly journals Transcriptional landscape of cellular networks reveal interactions driving the dormancy mechanisms in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dilara Uzuner ◽  
Yunus Akkoç ◽  
Nesibe Peker ◽  
Pınar Pir ◽  
Devrim Gözüaçık ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Regulatory Networks ◽  
Metastatic Cancer ◽  
Interaction Network ◽  
Current Treatment ◽  
Cellular Mechanisms ◽  
Protein Protein Interaction ◽  
Cancer Dormancy ◽  
Protein Protein Interaction Networks ◽  
First Time

AbstractPrimary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy–cancer comparisons were mapped on protein–protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy–interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer.

New Therapeutic Approach to Reduce Methotrexate Toxicity after High-Dose Chemotherapy in a Child with Acute Lymphocytic Leukemia: Efficacy and Safety of Hemoadsorption with HA-230 Adsorber

2021 ◽  
pp. 1-5
Author(s):  
Vitaliy Sazonov ◽  
Zaure Tobylbayeva ◽  
Askhat Saparov ◽  
Bolatbek Jubaniyazov ◽  
Samat Issakov ◽  
...  
Keyword(s):  
Acute Lymphocytic Leukemia ◽  
Pediatric Patients ◽  
High Dose Chemotherapy ◽  
The Body ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Successful Implementation ◽  
Efficacy And Safety ◽  
Related Complication ◽  
Dose Methotrexate

Background: High-dose methotrexate (HDMTX) is likely to cause a number of side effects and manifest itself as hepatotoxicity, nephrotoxicity, mucositis, and neurotoxicity. A several studies demonstrated the efficacy of extracorporeal detoxification methods such as plasma exchange, hemodialysis (HD), HD filtration, and hemoperfusion for the treatment of MTX delayed clearance. However, none of the existing methods as effective as expected and limited for general implementation due to a procedure-related complication. Case Report: Here, we report a successful implementation of HA-230 hemoadsorption procedure to remove cumulated MTX from the body and reduce its toxicity in a child with ALL after high-dose chemotherapy. Results and Conclusion: Based on our results, single-hemoadsorption procedure with the HA-230 adsorber in case of delayed methotrexate clearance was safe and well-tolerated in a pediatric patient with ALL and would significantly improve the patient’s condition. Further studies need to demonstrate its safety and efficacy in a large number of pediatric patients.

scholarly journals Amoebic Foraging Model of Metastatic Cancer Cells

Symmetry ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1140
Author(s):  
Daiki Andoh ◽  
Yukio-Pegio Gunji
Keyword(s):  
Bayesian Inference ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Gait Patterns ◽  
Lévy Walk ◽  
Levy Walk ◽  
Unicellular Organisms ◽  
Living Organisms ◽  
Walk Algorithm ◽  
Metastatic Cancer Cells

The Lévy walk is a pattern that is often seen in the movement of living organisms; it has both ballistic and random features and is a behavior that has been recognized in various animals and unicellular organisms, such as amoebae, in recent years. We proposed an amoeba locomotion model that implements Bayesian and inverse Bayesian inference as a Lévy walk algorithm that balances exploration and exploitation, and through a comparison with general random walks, we confirmed its effectiveness. While Bayesian inference is expressed only by P(h) = P(h|d), we introduce inverse Bayesian inference expressed as P(d|h) = P(d) in a symmetry fashion. That symmetry contributes to balancing contracting and expanding the probability space. Additionally, the conditions of various environments were set, and experimental results were obtained that corresponded to changes in gait patterns with respect to changes in the conditions of actual metastatic cancer cells.

scholarly journals Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 965
Author(s):  
Victoria R. Gabriele ◽  
Robabeh M. Mazhabi ◽  
Natalie Alexander ◽  
Purna Mukherjee ◽  
Thomas N. Seyfried ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metastatic Cancer ◽  
Energy Levels ◽  
Nanoparticle Concentration ◽  
Visible Radiation ◽  
Laser Illumination ◽  
Wide Range ◽  
Low Glucose ◽  
Melanin Nanoparticles ◽  
Metastatic Cancer Cells

Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under exposure to (nonionizing) visible radiation. To study these effects in detail, we developed highly monodispersed melanin nanoparticles (both uncoated and glucose-coated). In order to study the effect of significant cellular uptake of these nanoparticles, we employed three cancer cell lines: VM-M3, A375 (derived from melanoma), and HeLa, all known to exhibit strong macrophagic character, i.e., strong nanoparticle uptake through phagocytic ingestion. Our main observations are: (i) metastatic VM-M3 cancer cells massively ingest melanin nanoparticles (mNPs); (ii) the observed ingestion is enhanced by coating mNPs with glucose; (iii) after a certain level of mNP ingestion, the metastatic cancer cells studied here are observed to die—glucose coating appears to slow that process; (iv) cells that accumulate mNPs are much more susceptible to killing by laser illumination than cells that do not accumulate mNPs; and (v) non-metastatic VM-NM1 cancer cells also studied in this work do not ingest the mNPs, and remain unaffected after receiving identical optical energy levels and doses. Results of this study could lead to the development of a therapy for control of metastatic stages of cancer.

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