Cancer origins (theories and research)

[Rich66]

Genome Study Shows What Cancers Have in Common


http://abcnews.go.com/Technology/wir...9866394&page=1

CHICAGO (Reuters) - Genetic abnormalities -- missing DNA or duplicate DNA -- that fuel the growth of one type of cancer may actually be at work in several others, U.S. researchers said on Wednesday.
The finding, based on a large-scale study of the genetic make-up of 26 different types of cancers, suggests cancer has less to do with where in the body it occurs, and more to do with the genetic changes that cause it to grow.
"A lot of the events that cause cancer are common between cancers of different tissue types," said Matthew Meyerson of the Dana-Farber Cancer Institute and the Broad Institute of Harvard and the Massachusetts Institute of Technology in Boston, whose study appears in the journal Nature.
"You have breast cancer, lung cancer, cancer of the kidney -- many of the events that cause these cancers are going to be the same," Meyerson said in a telephone interview.

The team focused on specific aberrations in the genetic code known as somatic copy-number alterations, in which segments of a tumor's genome contain extra copies of a piece of DNA or lack the segment altogether. For the study, the team collected more than 2,500 cancer specimens representing more than 24 cancer types, including lung, prostate, breast, ovarian, colon, esophageal, liver, brain and blood cancers.
They combined this with publicly available data from another 600 tumor samples.
"What we're seeing here is that the copy number events that are happening in some of one cancer type are happening in some of another cancer type," Meyerson said.

Aneuploidy vs gene mutation:

http://chromocure.com/learn-about-cancer/

Normal human cells have 23 different chromosomes that come in pairs. They yield a total of 46 chromosomes. Such cells are said to be “diploid.� Cells found in solid tumors, on the other hand, typically have between 60 to 90 chromosomes (1). Their ploidy is “not good,� in other words, and the Greek version of that is “aneuploid.� It is a word that you will have a hard time finding in the cancer textbooks. Recall that the genes (of which there may be 40,000 or so in humans) are strung along the chromosomes, so that each chromosome contains thousands of genes. Any cell with a chromosome number different from 46, or with an abnormal complement of chromosomes that add up to 46, is an aneuploid cell. Thus, aneuploid cells contain an imbalance in the complement of genes and chromosomes compared to the normal or “diploid� cell. This imbalance in the chromosomes leads to a wide variety of problems, one of which is cancer.
Another problem caused by aneuploidy is Down's Syndrome. This results when a baby is born with three copies of chromosome 21 instead of the normal two. Just one extra copy of the smallest chromosome, with its thousand or so normal genes, is sufficient to cause the syndrome (2). Most Down's fetuses are spontaneously aborted. Nonetheless, the imbalance is small enough (47 chromosomes) to permit occasional live births. The level of aneuploidy is therefore far below the threshold of 60-90 chromosomes found in invasive cancer, but it gives these patients a head start toward developing the same cancers that normal people get. Down's Syndrome patients have up to a 30-fold increased risk of leukemia, for example, compared to the general population (3, 4).
There is one important difference between the small aneuploidy found in Down's Syndrome, and the more pronounced aneuploidy of cancer cells. With Down's, the defect occurs in the germ line and so the chromosomal error is present in every cell in the body. But the defect that gives rise to the unbalanced complement of chromosomes in cancer cells is “somatic�. That is, it occurs in a particular cell after the body is formed. In the course of life, cells constantly divide by a process called mitosis. When errors in mitosis occur, as they often do, the possibility exists that a daughter cell will be aneuploid.
Aneuploidy destabilizes a cell in much the same way that a dent disrupts the symmetry of a wheel. It leads to ever-greater distortions with each revolution. As aneuploid cells divide, their genomes become increasingly disorganized to the point where most of these cells stop dividing and die. But rarely, and disastrously, an aneuploid cell with the right number and combination of extra chromosomes wins the genetic lottery and keeps right on going. Then it has become a cancer cell.
Cells with a normal number of chromosomes are intrinsically stable and not prone to transformation into cancer. What, therefore, causes normal cells to become aneuploid? That is a hotly contested question. It is known, however, that if radioactive particles strike the nucleus of a cell, chromosomes can be shattered. When that damaged cell then divides by mitosis, an error may arise. Chromosomal imbalance may then result. In short, radiation can cause aneuploidy. And certain chemicals, such as tars, also give rise to aneuploid cells. Tars and radiation sources are known carcinogens. In fact, all carcinogens that have been examined so far do cause aneuploidy.
That is a very convincing argument for the aneuploidy theory of cancer, but in order to understand the controversy one must understand the alternative theory. Everyone has heard of it because it is in the newspapers all the time. It is the gene-mutation theory of cancer. According to this theory, certain genes, when they are mutated, turn a normal cell into a cancer cell. This theory has endured since the 1970s, and more than one Nobel Prize has been awarded to researchers who have made claims about it. One prize-winner was the former director of the National Institutes of Health, Harold Varmus. According to some researchers, the mutation of just one, or perhaps several genes, may be sufficient to transform a normal cell into a cancer cell.
IIn contrast, chromosomal imbalance disrupts the normal balance and interactions of many thousands of genes, because just one chromosome typically contains several thousand genes. And a cancer cell may have several copies of a given chromosome. For this reason alone, aneuploidy is likely to be far more devastating to the life of a cell than a small handful of gene mutations.
The fundamental difference between the aneuploidy theory and the reigning gene-mutation theory may be put this way. If the whole genome is a biological dictionary, divided into volumes called chromosomes, then the life of a cell is a Shakespearean drama. If one were to misspell a word here and there, in Hamlet for example, such “mutations� would be irrelevant to the vast majority of readers, or theater-goers. A multicellular organism is at least as resistant to “gene mutations� as a Shakespeare play.
On the other hand, without “mutating� a single word, one could transform the script of Hamlet into a legal document, a love letter, a declaration of independence, or more likely gibberish, by simply shifting and shuffling, copying and deleting numerous individual words, sentences and whole paragraphs. That is the literary equivalent of what aneuploidy does. The most efficient means of rewriting a cell's script is the wholesale shifting and shuffling of the genes, which aneuploidy or chromosomal imbalance accomplishes admirably.
Aneuploidy is known to be an efficient mechanism for altering the properties of cells, and it is also conceded that aneuploid cells are found in virtually all solid tumors. Bert Vogelstein of Johns Hopkins University has said that “at least 90 percent of human cancers are aneuploid.� The true figure may be 100 percent. For references supporting the claim that cancers are invariably aneuploid see Li et al. 2000 (5).
Nonetheless, the presence of mutations in a handful of genes continues to be viewed as a significant, even a causal factor in carcinogenesis, even though any given mutated gene is found in only a minority of cancers. Cells with mutated genes can indeed be found in cancerous as well as normal cells, but the most likely reason is that they are innocuous. Hence they are readily accommodated during the expansion of barely viable aneuploid cells as they compete for survival with their more viable chromosomally balanced counterparts. The current emphasis in cancer research on the search for mutant genes in a perpetual background of aneuploidy is a classic example of not seeing the forest for the trees.
Thomas Kuhn remarked that the great theoretical advances of Copernicus, Newton, Lavoisier, and Einstein had less to do with definitive experiments than with looking at old data from a new perspective. Sufficient (indeed overwhelming) evidence is already in hand to convict aneuploidy of the crime of cancer and release gene mutations from custody (5-16). Nevertheless, the gene-mutation theorists, when faced with the undeniable evidence that aneuploidy is necessary for cancer, have adopted a fall-back position. They argue that gene mutations must initiate the aneuploidy, (17) or as the Scientific American reported, referring to a researcher in Vogelstein's lab, “[Christoph] Lengauer insists aneuploidy must be a consequence of gene mutations� (18).
There would be no need for him to “insist� if there were proof that gene mutations really do cause cancer. What would gravely weaken the aneuploidy theory would be confirmed cases of diploid cancer (in which the tumor cells have balanced chromosomes), and with the culprit genes found lurking in every cell. That would go a long way toward proving the gene mutation theory. But where has that been demonstrated? It would be a front-page story. The truth is that researchers have not yet produced any convincing examples of diploid cancer.
In fact, the evidence is going the other way. There is a growing list of carcinogens that do not mutate genes at all. In addition, there are no cancer-specific gene mutations. Even tumors of a single organ rarely have uniform genetic alterations. And, in a rebuttal that should be decisive, no genes have yet been isolated from cancers that can transform normal human or animal cells into cancer cells. Furthermore, the latent periods between the application of a carcinogen and the appearance of cancer are exceedingly long, ranging from many months to decades. In contrast, the effects of mutation are instantaneous.




BMC Biol. 2010 Jun 25;8:88.
Altered metabolism in cancer.

Locasale JW, Cantley LC.
Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA.

Jason W Locasale: jlocasal@bidmc.harvard.edu;

Lewis C Cantley: lcantley@hms.harvard.edu

FREE TEXT
Abstract

Cancer cells have different metabolic requirements from their normal counterparts. Understanding the consequences of this differential metabolism requires a detailed understanding of glucose metabolism and its relation to energy production in cancer cells. A recent study in BMC Systems Biology by Vasquez et al. developed a mathematical model to assess some features of this altered metabolism. Here, we take a broader look at the regulation of energy metabolism in cancer cells, considering their anabolic as well as catabolic needs. See research article: http://www.biomedcentral.com/1752-0509/4/58/

PMID: 20598111 [PubMed - in process]PMCID: PMC2892450Free PMC Article
A new view of carcinogenesis and an alternative approach to cancer therapy (Pro-Ox/h202+glycolysis inhib)

FREE TEXT
Dr. M. López-Lázaro
Associate Professor
Department of Pharmacology, Faculty of Pharmacy, C/ Profesor Garcia Gonzalez, 2, 41012, Sevilla, Spain
Tel: +34 954 55 63 48. Fax: +345 954 23 37 65.
Email: mlopezlazaro@us.es

Abstract
Over the last few decades, cancer research has focused on the idea that cancer is caused by genetic alterations and that this disease can be treatable by reversing or targeting these alterations. The small variations in cancer mortality observed during the last 30 years indicate, however, that the clinical applications of this approach have been very limited so far. The development of future gene-based therapies that may have a major impact on cancer mortality may be compromised by the high number and variability of genetic alterations recently found in human tumors. This article reviews evidence that, in addition to acquiring a complex array of genetic changes, tumor cells develop an alteration in the metabolism of oxygen. Although both changes play an essential role in carcinogenesis, the altered oxygen metabolism of cancer cells is not subject to the high genetic variability of tumors and may therefore represent a more reliable target for cancer therapy. The utility of this novel approach for the development of therapies that selectively target tumor cells is discussed.

Hydrogen peroxide seems to be a key player in oxidative stress-induced cancer cell death. Many anticancer agents, such as paclitaxel, doxorubicin and arsenic trioxide, produce H2O2 (87,90,92), and H2O2 is known to be an efficient inducer of cell death in cancer cells (36,93,107). Interestingly, cancer cells seem more susceptible to H2O2-induced cell death than non-malignant cells (108-110). Using several cancer and normal cell lines, Chen et al. (108) observed that high concentrations of ascorbic acid selectively killed cancer cells and that this effect was mediated by H2O2.

The dependency of cancer cells for glycolytic energy seems to increase as malignant transformation occurs (69). It has been proposed that this increased dependency on glycolysis for energy generation represents an important metabolic difference between normal and malignant cells which may serve for developing therapeutic strategies to preferentially kill cancer cells (44,112,113). Several glycolysis inhibitors have shown anticancer effects (e.g. 2-deoxy-D-glucose, lonidamine, 3-bromopyruvate, dichloroacetate, etc) and some of them have entered clinical trials (37,44,112,114). For example, it has been shown that dichloroacetate, a known glycolysis inhibitor that has been used in humans for decades in the treatment of lactic acidosis and inherited mitochondrial diseases, induced marked anticancer effects in mice (115). The authors found that dichloroacetate in the drinking water at clinically relevant doses for up to 3 months prevented and reversed tumor growth in vivo, without apparent toxicity and without affecting hemoglobin, transaminases, or creatinine levels.

4.3. Combination of pro-oxidant agents with glycolysis inhibitors for anticancer therapy.
Although ROS can induce cancer cell death, tumor cells are known to develop mechanisms that prevent ROS from reaching cytotoxic levels. The glutathione and thioredoxin antioxidant systems are crucial for detoxifying ROS. These antioxidant systems are activated in cancer cells and play an important role in the development of resistance to many anticancer agents (120-126). Likewise, although the inhibition of glycolysis is an attractive anticancer strategy, in vivo experiments suggest that the inhibition of glycolysis may not be sufficient to induce potent anticancer effects. Accordingly, although the glycolysis inhibitor 2-deoxy-D-glucose is an efficient inducer of cell death in vitro (127), its anticancer in vivo activity is not very high when used as a
single agent. The anticancer activity of 2-deoxy-D-glucose has been explored in combination with chemotherapeutic drugs and radiation, and some of these combinations have entered clinical trials (44,112,128-132).
Pro-oxidant agents could be combined with glycolysis inhibitors to maximize their anticancer activity. Evidence indicates that pro-oxidant agents can increase the cellular levels of H2O2 and that glycolysis inhibitors can reduce the capacity of cells to detoxify H2O2. Experimental data have shown that malignant cells are more susceptible to glucose deprivation than non-transformed cells, and that an increase in the levels of H2O2 may mediate the cytotoxic effect induced by glucose deprivation (53,133-135).

..increased basal levels of hydrogen peroxide and their higher dependence on glycolysis for their survival make cancer cells more susceptible than normal cells to the treatment with pro-oxidant agents and glycolysis inhibitors. Because this alteration in the metabolism of oxygen seems to be a common feature of tumor cells, this therapeutic approach could be used for the treatment of a wide range of patients with cancer.

Thought: IV (or oral liposomal) Vit C, DCA, Metformin and Zoledronic Acid?



Earlier Lopez-Lazaro paper:
Anticancer Agents Med Chem. 2008 Apr;8(3):305-12.
The warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen?

PURCHASE TEXT

López-Lázaro M.
Department of Pharmacology, University of Seville, Spain. mlopezlazaro@us.es
Cells can obtain energy through the oxygen-dependent pathway of oxidative phosphorylation (OXPHOS) and through the oxygen-independent pathway of glycolysis. Since OXPHOS is more efficient in generating ATP than glycolysis, it is recognized that the presence of oxygen results in the activation of OXPHOS and the inhibition of glycolysis (Pasteur effect). However, it has been known for many years that cancer cells and non-malignant proliferating cells can activate glycolysis in the presence of adequate oxygen levels (aerobic glycolysis or Warburg effect). Accumulating evidence suggests that the persistent activation of aerobic glycolysis in tumor cells plays a crucial role in cancer development; the inhibition of the increased glycolytic capacity of malignant cells may therefore represent a key anticancer strategy. Although some important knowledge has been gained in the last few years on this growing field of research, the basis of the Warburg effect still remains poorly understood. This communication analyzes why cancer cells switch from OXPHOS to glycolysis in the presence of adequate oxygen levels, and how these cells manage to avoid the inhibition of glycolysis induced by oxygen. Several strategies and drugs that may interfere with the glycolytic metabolism of cancer cells are also shown. This information may help develop anticancer approaches that may have clinical relevance.

PMID: 18393789 [PubMed - indexed for MEDLINE]



Transl Oncol. 2009 Aug 18;2(3):138-45.
Cancer abolishes the tissue type-specific differences in the phenotype of energetic metabolism.

FULL TEXT



Acebo P, Giner D, Calvo P, Blanco-Rivero A, Ortega AD, Fernández PL, Roncador G, Fernández-Malavé E, Chamorro M, Cuezva JM.
Departamento de BiologÃ*a Molecular, Centro de BiologÃ*a Molecular Severo Ochoa, C.S.I.C.-U.A.M., Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain.
Nowadays, cellular bioenergetics has become a central issue of investigation in cancer biology. Recently, the metabolic activity of the cancer cell has been shown to correlate with a proteomic index that informs of the relative mitochondrial activity of the cell. Within this new field of investigation, we report herein the production and characterization of high-affinity monoclonal antibodies against proteins of the "bioenergetic signature" of the cell. The use of recombinant proteins and antibodies against the mitochondrial beta-F1-ATPase and Hsp60 proteins and the enzymes of the glycolytic pathway glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase M2 in quantitative assays provide, for the first time, the actual amount of these proteins in normal and tumor surgical specimens of breast, lung, and esophagus. The application of this methodology affords a straightforward proteomic signature that quantifies the variable energetic demand of human tissues. Furthermore, the results show an unanticipated finding: tumors from different tissues and/or histological types have the same proteomic signature of energetic metabolism. Therefore, the results indicate that cancer abolishes the tissue-specific differences in the bioenergetic phenotype of mitochondria. Overall, the results support that energetic metabolism represents an additional hallmark of the phenotype of the cancer cell and a promising target for the treatment of diverse neoplasias.

PMID: 19701498 [PubMed - in process]

These findings could support that a common origin for tumors arises from an undifferentiated progenitor cell and that cancer cells undergo a process of dedifferentiation to acquire the traits of embryonic stem cells [27]. In this regard, we suggest that the bioenergetic signature of the tumors and, hence, the expression of markers of energetic metabolism partially respond to the installment of the reductive metabolic program (mainly glycolytic) that sustains cellular proliferation [15,28]. Conversely, the suppression of the tissue-specific differences in the bioenergetic signature of the tumors and its drastic reduction in certain tissues (Table 1) strongly support that containment of the mitochondrial bioenergetic activity in the cancer cell is an event required for tumor progression. Indeed, tumors with a low bioenergetic signature have a worse prognosis [6–8,10] and the activity of mitochondria has been shown to act as a tumor suppressor [12,14,29].
Owing to the convergence of breast, lung, and esophageal tumors
on the same bioenergetic signature, it seems that energetic metabolism affords a common target for cancer therapy. In this regard,
several groups and biotech companies are currently targeting the proteins of energetic metabolism as a promising approach to eradicate
different types of tumors especially in combined therapy [30–33].
Overall, and because the bioenergetic signature provides a predictive
marker of the response of tumors to chemotherapy [9], in agreement
with the role of mitochondrial oxidative phosphorylation in the execution of cell death [11,13,14], we suggest that its translation to the clinics will benefit cancer patients.

Med Hypotheses. 2010 Jan 18. [Epub ahead of print]
Oxidative stress therapy for solid tumors - A proposal.

McCarty MF, Barroso-Aranda J, Contreras F.
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, Tijuana, B.C. 22504, Mexico.
Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials. Copyright © 2009. Published by Elsevier Ltd.

PMID: 20089364 [PubMed - as supplied by publisher]



PLoS One. 2009 Sep 15;4(9):e7033.
Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect.

Chen Y, Cairns R, Papandreou I, Koong A, Denko NC.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
BACKGROUND: The unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, "aerobic glycolysis" generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage. METHODS/FINDINGS: We carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg's observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 (MRPL12) or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth. CONCLUSIONS: We interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.

PMID: 19753307 [PubMed - indexed for MEDLINE]





Nutr Metab (Lond). 2010 Jan 27;7(1):7. [Epub ahead of print]
Cancer as a metabolic disease.

Seyfried TN, Shelton LM.
ABSTRACT: Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.

PMID: 20181022 [PubMed - as supplied by publisher]




Theor Biol Med Model. 2010 Jan 19;7:2.
Cancer proliferation and therapy: the Warburg effect and quantum metabolism.

Demetrius LA, Coy JF, Tuszynski JA.
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
BACKGROUND: Most cancer cells, in contrast to normal differentiated cells, rely on aerobic glycolysis instead of oxidative phosphorylation to generate metabolic energy, a phenomenon called the Warburg effect. MODEL: Quantum metabolism is an analytic theory of metabolic regulation which exploits the methodology of quantum mechanics to derive allometric rules relating cellular metabolic rate and cell size. This theory explains differences in the metabolic rates of cells utilizing OxPhos and cells utilizing glycolysis. This article appeals to an analytic relation between metabolic rate and evolutionary entropy - a demographic measure of Darwinian fitness - in order to: (a) provide an evolutionary rationale for the Warburg effect, and (b) propose methods based on entropic principles of natural selection for regulating the incidence of OxPhos and glycolysis in cancer cells. CONCLUSION: The regulatory interventions proposed on the basis of quantum metabolism have applications in therapeutic strategies to combat cancer. These procedures, based on metabolic regulation, are non-invasive, and complement the standard therapeutic methods involving radiation and chemotherapy.

PMID: 20085650 [PubMed - in process]




Free Radic Biol Med. 2010 Sep 11. [Epub ahead of print]
Oxidative stress, inflammation, and cancer: How are they linked?
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB.


LINK

Abstract
Extensive research during last two decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, cardiovascular, neurological and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

PMID: 20840865 [PubMed - as supplied by publisher]









Cell Cycle. 2009 Sep 15;8(18):2901-6. Epub 2009 Sep 16.
Reduced proliferation and enhanced migration: two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1.

Evdokimova V, Tognon C, Ng T, Sorensen PH.
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, CA. v.evdokimova@gmail.com
Hyperproliferation induced by various oncogenic proteins, including activated Ras, is the most prominent and well characterized feature of cancerous cells. This property has been exploited in the development of the most successful anti-cancer treatments to target rapidly dividing cells. Here we argue that hyperproliferation may in fact be detrimental to survival during particular stages of cancer progression such as dissemination from primary tumor and establishing metastatic outgrowth. Our recent work has demonstrated that elevation of YB-1 protein levels, which is frequently observed in human cancers, is associated with reduced proliferation rates in disseminated mesenchymal-like breast carcinoma cells. In breast cancer cell lines with activated Ras-MAPK signaling, YB-1 inhibited cellular proliferation, while inducing an epithelial-to-mesenchymal transition (EMT). The underlying mechanism involves YB-1-mediated translational repression of pro-growth transcripts and activation of the messages encoding EMT-associated proteins, many of which are also known to inhibit proliferation. In addition to the lack of epithelial polarity, increased mobility and invasiveness, YB-1-overexpressing cells displayed a remarkable ability to shut down proliferation and survive in anchorage-independent conditions. These findings support the view that while an increase in proliferation is important for the initiation and maintenance of primary tumors, growth inhibition could ultimately be crucial for survival of carcinoma cells in the circulation and secondary organs, thereby leading to the development of a more malignant phenotype.

PMID: 19713745 [PubMed - indexed for MEDLINE]


Semin Cancer Biol. 2009 Feb;19(1):25-31. Epub 2008 Dec 14.
Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis.

Robey RB, Hay N.
White River Junction VA Medical Center, White River Jct, VT 05009-0001, United States. R.Brooks.Robey@Dartmouth.edu



Abstract

The serine/threonine kinase Akt - also known as protein kinase B (PKB) - has emerged as one of the most frequently activated protein kinases in human cancer. In fact, most, if not all, tumors ultimately find a way to activate this important kinase. As such, Akt activation constitutes a hallmark of most cancer cells, and such ubiquity presumably connotes important roles in tumor genesis and/or progression. Likewise, the hypermetabolic nature of cancer cells and their increased reliance on "aerobic glycolysis", as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. In this review, we address the specific contributions of Akt activation to the signature metabolic features of cancer cells, including the so-called "Warburg effect".

PMID: 19130886 [PubMed - indexed for MEDLINE]PMCID: PMC2814453Free PMC Article





J Biol Chem. 2010 Mar 5;285(10):7324-33. Epub 2009 Dec 17.
Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition.

Fan Y, Dickman KG, Zong WX.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
Abstract

The high glucose consumption of tumor cells even in an oxygen-rich environment, referred to as the Warburg effect, has been noted as a nearly universal biochemical characteristic of cancer cells. Targeting the glycolysis pathway has been explored as an anti-cancer therapeutic strategy to eradicate cancer based on this fundamental biochemical property of cancer cells. Oncoproteins such as Akt and c-Myc regulate cell metabolism. Accumulating studies have uncovered various molecular mechanisms by which oncoproteins affect cellular metabolism, raising a concern as to whether targeting glycolysis will be equally effective in treating cancers arising from different oncogenic activities. Here, we established a dual-regulatable FL5.12 pre-B cell line in which myristoylated Akt is expressed under the control of doxycycline, and c-Myc, fused to the hormone-binding domain of the human estrogen receptor, is activated by 4-hydroxytamoxifen. Using this system, we directly compared the effect of these oncoproteins on cell metabolism in an isogenic background. Activation of either Akt or c-Myc leads to the Warburg effect as indicated by increased cellular glucose uptake, glycolysis, and lactate generation. When cells are treated with glycolysis inhibitors, Akt sensitizes cells to apoptosis, whereas c-Myc does not. In contrast, c-Myc but not Akt sensitizes cells to the inhibition of mitochondrial function. This is correlated with enhanced mitochondrial activities in c-Myc cells. Hence, although both Akt and c-Myc promote aerobic glycolysis, they differentially affect mitochondrial functions and render cells susceptible to the perturbation of cellular metabolic programs.

PMID: 20018866 [PubMed - indexed for MEDLINE]PMCID: PMC2844180 [Available on 2011/3/5]




http://www.urotoday.com/61/browse_ca...s06072010.html

UA 2010 - Is Prostate Cancer an Infectious Disease? - Session Highlights


SAN FRANCISCO, CA USA (UroToday.com) - In his state-of-the-art lecture, Dr. Eric Klein asked whether cancer, and in particular prostate cancer, is an infectious disease. He stated that numerous cancers are caused by infections and more cancers are caused by infections worldwide than occur in the US from all causes. There is epidemiological data that suggest there is increased risk of CaP with early sexual activity and increased number of partners, but decreased risk with frequent ejaculation. A prior history of any sexually transmitted disease or prostatitis is associated with increased risk of CaP. Variants in RNaseL and MSR1 are two examples of genetic links to CaP. Xenotropic murine leukemia related virus (XMRV) was first described in 2006. It is a novel retrovirus and a mutation in this gene is associated with CaP. It integrates into the host chromosomes and sits in cancer-associated fibroblasts. XMLV is not an oncogene, but likely integrates into the host to activate an oncogene. XMRV has been found in 23% of CAP tissue samples compared with only 6% of benign tissues. The antibody against XMRV is found in 30% of patients undergoing radical prostatectomy.
SMRV is also found in 67% of patients with chronic fatigue syndrome compared with 3.7% of controls. It suggests it may be transmitted through blood contact. In a monkey model of transmission, it is found in white blood cells and lymphoid tissue. At day 7, it can be isolated in prostate tissue. If left longer, at 5 months it can be found in the epididymis and seminal vesicles. Androgens added to CaP cells in culture stimulate XMRV replication and it was found that there is an androgen response element in the virus. Prostate epithelium is an early target of XMRV, and stroma becomes infected later on. He pointed out that there have been some negative studies as well, due to technical aspects and viral variants, he said. Globally, there are different areas of viral penetration but causality between XMRV and human disease remains to be proven.

Presented by Eric A. Klein, MD at the American Urological Association (AUA) Annual Meeting - May 29 - June 3, 2010 - Moscone Center, San Francisco, CA USA

http://www.the-scientist.com/blog/display/57670/

Surprise breast cancer source

Some breast cancer tumors may not originate from stem cells as previously believed, according to a study published in the September 3rd issue of Cell Stem Cell. The discovery is an important step in the development of treatments for these cancers.

"Understanding the origins of these types of breast cancer is not only critical for developing preventative strategies against the disease but also for developing new targeted therapies," said Matthew Smalley, a mammary cell biologist at the Breakthrough Breast Cancer Centre in London and lead author on the study.

For years, scientists have believed that most breast cancers originated from basal stem cells, which have the ability to give rise to any of the breast tissues. But comparing mice expressing mutant versions of the BRCA1 gene, which is known to cause breast cancer, in different breast cell types, Smalley and his colleagues discovered that BRCA1 tumors actually come from progenitor cells, which can only differentiate into a single tissue type.

The BRCA1 gene, which is expressed in all cells, repairs breaks in the cell's DNA when functioning correctly. People carrying a mutated version of the gene, however, are more likely to get tumors in several tissues, including the breast and ovaries. While the BRCA1 gene doesn't cause the majority of breast cancers, carriers of the mutated gene have a much higher chance -- between 50 to 80 percent -- of getting either breast or ovarian cancer during their lifetime, and the cancers are aggressive.

Scientists used to think that these cancers came from the breast's basal stem cells because the tumors and the basal stem cells express many of the same genes. Furthermore, because such tissue-specific stem cells are long-lived and divide frequently, some have suggested them as a likely source of many types of cancer.

To determine the true origin of BRCA1 tumors, Smalley and his colleagues inserted a mutant version of the gene into either basal stem cells or luminal progenitor cells, which give rise to the cells that line the mammary gland duct. While both sets of mutation-bearing mice developed tumors, the tumors were not the same. The tumors in the mice with the mutated BRCA1 gene in their luminal progenitor cells appeared most like BRCA1 breast cancers in humans with regard to their aggressive growth and genetic markers. The tumors on the mice with the mutated BRCA1 gene in their basal stem cells, on the other hand, had characteristics of a different type of rare malignant epithelial cell cancer. It is possible that different types of breast cancers derive from different cells of origin, said Smalley.

This work builds on previous discoveries by a team lead by Jane Visvander and Geoffrey Lindeman at the Walter + Eliza Hall Institute of Medical Research, who found that there are more luminal progenitors and that they grow inappropriately in human BRCA1 tumors. "Breast luminal progenitors, rather than stem cells, should now take center stage as the likely cells of origin for the majority of basal-like breast cancers," Lindeman, who as not involved in this study, said in an email.

Smalley said he will continue to study how these and other tumors form, and what features they have in common with their origin cells, as a possible target for therapeutics. "If we can identify molecular features which these tumors have in common with the cells which we now know they originate from" he said, "we will have identified key aspects of the biology of these cancers which, when disrupted, will have therapeutic benefit."

G. Molyneux, et al., "BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells," Cell Stem Cell 7:403-17, 2010.

Read more: Surprise breast cancer source - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/di...#ixzz0yQEkHXQh

Hormones promote stem cell growth

Posted by Megan Scudellari

[Entry posted at 11th April 2010 06:00 PM GMT]

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Estrogen and progesterone promote the proliferation and activity of mouse mammary stem cells, according to new research published online today (April 11) at Nature -- possibly explaining the link between exposure to the hormones and breast cancer. Microphotography of a preparation of a healthy mammary gland Image: Wikimedia commons, Luis A. Pardo et al. "It's a pretty good paper," said John Stingl, a researcher at the Cancer Research UK Cambridge Research Institute, who did not participate in the study. In a very direct way, the researchers have successfully measured the effects of progesterone and estrogen on mammary stem cells, he said. Estrogen and progesterone levels have profound effects on breast development and breast cancer risk. There is a clear correlation between number of menstrual cycles (and thus lifetime exposure to these hormones) and breast cancer risk, for example, and therapeutic regimens that inhibit the binding or synthesis of estrogen reduce the rate of breast cancer recurrence for some patients by almost half. The mechanism by which these hormones work, however, remains elusive, said Stingl. One possible role is their effects on mammary stem cells (MaSCs), whose highly proliferative abilities make them suspects as causative agents in breast cancer. But there was no proof that MaSCs respond to hormones, Stingl said. And there was a major theoretical problem: MaSCs lack receptors for both hormones. The question then became, is it possible that cells with no receptors for progesterone or estrogen are still affected by their presence? To find out, Jane Visvader of the Walter and Eliza Hall Institute in Victoria, Australia, and her colleagues tested the activity of MaSCs in the absence of estrogen and progesterone. Removing the ovaries from young adult mice, the researchers saw a significant decrease in the number of mammary stem cells. Conversely, treating young mice with estrogen and progesterone pellets to expose them to far greater levels of hormones than normal, the team recorded an increase in the number of stem cells. Together, these results suggest the hormones do indeed promote MaSC growth. Visvader and her colleagues also assessed the size of MaSC populations during pregnancy and found an eleven-fold increase in the number of stem cells in the mammary glands during mid-pregnancy -- when females have highly elevated levels of progesterone -- compared to glands from virgin mice. The finding coincides with the observation that women have an increased risk of developing breast cancer for a short period following pregnancy. "This increase in the number of mammary stem cells [during pregnancy] provides a tantalizing mechanism to account for that [increased risk]," said Visvader. One concern is that what the researchers thought were MaSCs may actually have been other cell types, said Cathrin Brisken, a breast cancer researcher at the Ecole Polytechnique Fédérale in Lausanne, Switzerland. "The paper makes claims that are very reasonable, but doesn't provide the data for it," said Brisken. Accurately identifying and counting MaSCs requires rigorous assays, she said, and "one has to be really careful of whether given markers really identify a stem cell population." To address this concern, the researchers injected the suspected MaSCs into a fat pad to demonstrate the cells' capacity to grow into new mammary glands in vivo -- the gold standard for identifying MaSCs. Additionally, mice exposed to estrogen and progesterone grew fuller mammary glands than mice lacking ovaries, demonstrating increased activity of the transplanted MaSCs in the presence of the hormones. "The heart of the paper is the transplants," Stingl said, "and they've done those." But how progesterone and estrogen stimulate MaSC growth and activity is still unknown. Researchers suspect the effect occurs through paracrine signaling: Cells with progesterone and estrogen receptors sense the hormones, and then release a signal to the nearby stem cells. Visvader and her team identified one possible signal, RANKL, a ligand important for mouse mammary gland development, that seems to affect MaSC expansion during pregnancy, but "the whole system is not quite worked out yet," said Stingl.

Read more: Hormones promote stem cell growth - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/di...#ixzz0yQFYvFzl

14 December 2010
Cancer cells dupe the body's immune system
LINK

Cancers may be wounds that never heal, suggest the first live images of tumours forming.
It seems individual cancer cells send out the same distress signals as wounds, tricking immune cells into helping them grow into tumours. The finding suggests that anti-inflammatory drugs could help to combat or prevent cancer.
"Lifelong, if you take a small quantity of something that suppresses inflammation, such as aspirin, it could reduce the risk of cancer," says Adam Hurlstone of the University of Manchester, UK.
When tissue is wounded or infected it produces hydrogen peroxide. White blood cells called leukocytes are among the first cells to react to this trigger, homing in to kill the infectious agent, clean up the mess and rebuild damaged tissue. At first, the tissue becomes inflamed, but this subsides as the wound is cleared and rebuilding continues.
Now, a study in zebra fish shows that this process is also instigated and sustained by tumour cells.
Hurlstone and colleagues genetically engineered zebra fish so that skin cells and leukocytes would glow different colours under ultraviolet light. Some zebra fish were also engineered to have cancerous skin cells.
The team found that the cancerous skin cells secreted hydrogen peroxide, summoning leukocytes which helped them on their way to becoming a tumour. When the team blocked hydrogen peroxide production in the zebra fish, the leukocytes were no longer attracted to cancerous cells and the cancer colonies reduced in number.
More alarmingly, the researchers found that healthy skin cells adjacent to the cancerous ones also produced hydrogen peroxide, suggesting that cancer cells somehow co-opt them into triggering inflammation.
Journal reference: PLoS Biology, DOI: 10.1371/journal.pbio.1000562



Study: 40% of cancers stem from viruses

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http://www.fiercevaccines.com/story/...ses/2011-10-20

[Rich66]

UNIQUE STRATEGIES

A new concept for cancer therapy: out-competing the aggressor

Thomas S Deisboeck and Zhihui Wang
Complex Biosystems Modeling Laboratory, Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA

author email corresponding author email
Cancer Cell International 2008, 8:19doi:10.1186/1475-2867-8-19


FREE TEXT

Published:	12 December 2008

Abstract

Cancer expansion depends on host organ conditions that permit growth. Since such microenvironmental nourishment is limited we argue here that an autologous, therapeutically engineered and faster metabolizing cell strain could potentially out-compete native cancer cell populations for available resources which in turn should contain further cancer growth. This hypothesis aims on turning cancer progression, and its microenvironmental dependency, into a therapeutic opportunity. To illustrate our concept, we developed a three-dimensional computational model that allowed us to investigate the growth dynamics of native tumor cells mixed with genetically engineered cells that exhibit a higher proliferation rate. The simulation results confirm in silico efficacy of such therapeutic cells to combating cancer cells on site in that they can indeed control tumor growth once their proliferation rate exceeds a certain level. While intriguing from a theoretical perspective, this bold, innovative ecology-driven concept bears some significant challenges that warrant critical discussion in the community for further refinement.


Background and hypothesis

Amongst the distinct hallmarks of cancer are uncontrolled growth and extensive cellular heterogeneity [1]. The 'ecology' concept here is based on the analogy that the host organ serves as 'bio-habitat' for a rapidly expanding heterogeneous tumor cell population, and that the organ's distinct microenvironmental conditions on site only support a certain tumor growth rate and overall tumor mass – prior to the onset of metastasis [2]. If so, one wonders if a tumor could be 'out-competed' for habitat dominance by an autologous cell population that has been engineered to outgrow the tumor cell populations, yet – other than the native cancer cells – can be therapeutically controlled. One can imagine a primary, autografted tumor cell line established from the patient's own tumor (biopsied at the time of operation) that has been genetically engineered to carry an on-off switch that can trigger programmed cell death, or apoptosis, 'on demand'. The corner stone of this innovative concept is to therapeutically skip any number of tumor progression steps by deliberately inserting an autologous cell population that securely outperforms even the most aggressive native cancer cell clone (see Figure 1).




Future Oncol. 2010 Aug;6(8):1313-23.
Modern approach to metabolic rehabilitation of cancer patients: biguanides (phenformin and metformin) and beyond.

Berstein LM.
N.N.Petrov Research Institute of Oncology, Pesochny-2, Leningradskaja 68, St Petersburg 197758, Russia. levmb@endocrin.spb.ru.


TEXT

Abstract

Comparing the experience accumulated for more than 40 years in the Laboratory of Endocrinology of Petrov Institute of Oncology (St Petersburg, Russia) with similar approaches practiced elsewhere, evidence supports the reasonability of metabolic rehabilitation of patients suffering from breast cancer or other hormone-dependent malignancies. The primary objective of such approaches is to improve treatment results by ameliorating hormonal-metabolic disturbances, including excess body fat, glucose intolerance, insulin resistance and manifestations of endocrine-genotoxic switchings, and modify tissue and cellular targets or mechanisms related or nondirectly related to the aforementioned disturbances. The relevant measures may be categorized as pharmacological (antidiabetic biguanides exemplified with metformin being most popular but not exclusive) and nonpharmacological (rational nutrition, moderate physical activity and so forth) and used separately or in different combinations.

PMID: 20799876 [PubMed - in process]




Common cell pathway could lead to new treatments for autoimmune diseases and cancer
Published on July 8, 2011


LINK

The study, published in the July 2011 issue of the journal Blood, details for the first time how the JAK-STAT pathway is activated by the protein CK2. This is important because both the pathway and protein have been previously identified as being overactive in cancer and autoimmune diseases, said the study's senior author Etty (Tika) Benveniste, Ph.D., professor and chair of the UAB Department of Cell Biology and associate director for basic science in the UAB Comprehensive Cancer Center.
"There should be a time-limited response from both of these that should be of benefit to the host, but something happens in cancer and autoimmune diseases and neither is turned off, helping diseased cells grow," Benveniste said. "In discovering that the CK2 protein activates the JAK-STAT pathway, we can now look for ways to shut down both, which is important in cancer treatment, because if you shut down only one of these, cells can still grow. These findings will help enable the development of drugs to target blocking both the pathway and the protein, of which the ultimate goal is causing cell death in tumors."

"Through this study, we provided clear evidence that activation of the JAK-STAT signaling pathway is dependent on the presence and/or activity of CK2 in tumor cells," Benveniste said. "There are a number of pharmaceutical companies that are generating inhibitors for both of these and some are in clinical trials now. Because of our observations, companies that produce these inhibitors can now test drugs that inhibit both on patients. Some of that is starting to happen now in people with myleoproliferative disorders, and future studies are planned on glioblastoma multiforme, the deadliest brain tumor, and breast cancer."

The research team, Benveniste said, wanted to know if the CK2 protein was involved in making the JAK-STAT pathway overactive because previous studies in their laboratory identified the tumor suppressor PML as a regulator of the JAK-STAT pathway, and PML is a building block of CK2.

Blood. 2011 Jul 7;118(1):156-66. Epub 2011 Apr 28.
A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway.

Zheng Y, Qin H, Frank SJ, Deng L, Litchfield DW, Tefferi A, Pardanani A, Lin FT, Li J, Sha B, Benveniste EN.

LINK

Source

Departments of Cell Biology and.

Abstract

JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.

PMID:

21527517

[PubMed - in process]