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Showing papers on "Carcinogenesis published in 2004"


Journal ArticleDOI
23 Apr 2004-Science
TL;DR: To determine if PI3Ks are genetically altered in tumorigenesis, they were sequenced in human for the first time and the results allowed us to assess the importance of phosphatidylinositol 3-kinases in neoplasia.
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways important for neoplasia, including cell proliferation, adhesion, survival, and motility ([ 1 ][1]–[ 3 ][2]). To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in human

3,396 citations


Journal ArticleDOI
TL;DR: A 'census' of cancer genes is conducted that indicates that mutations in more than 1% of genes contribute to human cancer.
Abstract: A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

3,136 citations


Journal ArticleDOI
18 Nov 2004-Nature
TL;DR: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.
Abstract: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.

2,725 citations


Journal ArticleDOI
08 Oct 2004-Science
TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Abstract: Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

2,700 citations


Journal ArticleDOI
06 Aug 2004-Cell
TL;DR: It is shown that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size, which is linked to increased epithelial apoptosis during tumor promotion.

2,366 citations


Journal ArticleDOI
23 Sep 2004-Nature
TL;DR: It is shown that the inflammatory process triggers hepatocyte NF-κB through upregulation of tumour-necrosis factor-α (TNFα) in adjacent endothelial and inflammatory cells, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.
Abstract: The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumour development, the latter accounting for approximately 20% of human cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor kappaB (NF-kappaB), a hallmark of inflammatory responses that is frequently detected in tumours, may constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-kappaB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kappaB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkappaB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kappaB inhibition through anti-TNFalpha treatment or induction of IkappaB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-kappaB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.

2,301 citations


Journal ArticleDOI
18 Nov 2004-Nature
TL;DR: It is revealed that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated and this has important therapeutic implications.
Abstract: It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.

2,215 citations


Journal ArticleDOI
TL;DR: The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants.
Abstract: The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

1,727 citations


Journal ArticleDOI
TL;DR: The NF-kappaB proteins themselves and proteins regulated by it have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis, and metastasis as mentioned in this paper.

1,537 citations


Journal ArticleDOI
TL;DR: This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
Abstract: ▪ Abstract Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFκB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.

1,487 citations


Journal ArticleDOI
TL;DR: The contribution of dietary folate and methylene terahydrofolate reductase polymorphisms to methylation patterns in normal and cancer tissues is under intense investigation and may be of potential use in early detection of tumors and for determining the prognosis.
Abstract: DNA methylation is an important regulator of gene transcription, and its role in carcinogenesis has been a topic of considerable interest in the last few years. Alterations in DNA methylation are common in a variety of tumors as well as in development. Of all epigenetic modifications, hypermethylation, which represses transcription of the promoter regions of tumor suppressor genes leading to gene silencing, has been most extensively studied. However, global hypomethylation has also been recognized as a cause of oncogenesis. New information concerning the mechanism of methylation and its control has led to the discovery of many regulatory proteins and enzymes. The contribution of dietary folate and methylene terahydrofolate reductase polymorphisms to methylation patterns in normal and cancer tissues is under intense investigation. As methylation occurs early and can be detected in body fluids, it may be of potential use in early detection of tumors and for determining the prognosis. Because DNA methylation...

Journal ArticleDOI
TL;DR: Despite the dramatic gene expression changes in all cell types, genetic alterations were detected only in cancer epithelial cells and chemokines may play a role in breast tumorigenesis by acting as paracrine factors.

Journal ArticleDOI
TL;DR: Exons 18–21 of the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.
Abstract: Recently it has been reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene occur in a subset of patients with lung cancer showing a dramatic response to EGFR tyrosine kinase inhibitors. To gain further insights in the role of EGFR in lung carcinogenesis, we sequenced exons 18-21 of the tyrosine kinase domain using total RNA extracted from unselected 277 patients with lung cancer who underwent surgical resection and correlated the results with clinical and pathologic features. EGFR mutations were present in 111 patients (40%). Fifty-two were in-frame deletions around codons 746-750 in exon 19, 54 were point mutations including 49 at codon 858 in exon 21 and 4 at codon 719 in exon 18, and 5 were duplications/insertions mainly in exon 20. They were significantly more frequent in female (P < 0.001), adenocarcinomas (P = 0.0013), and in never-smokers (P < 0.001). Multivariate analysis suggested EGFR mutations were independently associated with adenocarcinoma histology (P = 0.0012) and smoking status (P < 0.001), but not with female gender (P = 0.9917). In adenocarcinomas, EGFR mutations were more frequent in well to moderately differentiated tumors (P < 0.001) but were independent of patient age, disease stages, or patient survival. KRAS and TP53 mutations were present in 13 and 41%, respectively. EGFR mutations never occurred in tumors with KRAS mutations, whereas EGFR mutations were independent of TP53 mutations. EGFR mutations define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.

Journal ArticleDOI
24 Nov 2004-Cell
TL;DR: A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis, and a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels ofMDM2 RNA and protein and the subsequent attenuation of the p53 pathway.

Journal ArticleDOI
18 Nov 2004-Nature
TL;DR: The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.
Abstract: Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.

Journal ArticleDOI
TL;DR: The mitotic-checkpoint molecule survivin — the inactivation of which induces the death of p53-deficient cells by mitotic catastrophe — is of particular interest.
Abstract: Defects in cell-death pathways are hallmarks of cancer. Although resistance to apoptosis is closely linked to tumorigenesis, tumour cells can still be induced to die by non-apoptotic mechanisms, such as necrosis, senescence, autophagy and mitotic catastrophe. The molecular pathways that underlie these non-apoptotic responses remain unclear. Several apoptotic and non-apoptotic pathways of cell death have been defined in normal physiology and during tumorigenesis, and these could potentially be manipulated to develop new cancer therapies. The mitotic-checkpoint molecule survivin — the inactivation of which induces the death of p53-deficient cells by mitotic catastrophe — is of particular interest.

Journal ArticleDOI
20 Sep 2004-Oncogene
TL;DR: Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-Renewing cancer cells and tumor formation, which suggests that agents that target the defective self- renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases.
Abstract: Solid tumors arise in organs that contain stem cell populations. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases.

Journal ArticleDOI
TL;DR: Evidence of an essential role for NF-κB during distinct steps of breast cancer progression is provided and the cooperation of Ras- and TGF-β–dependent signaling pathways in late-stage tumorigenesis depends critically on NF-σB activity is suggested.
Abstract: The transcription factor NF-κB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-κB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-β–dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity.

Journal ArticleDOI
TL;DR: A list of endogenous DNA-damaging agents, processes and DNA adduct levels is presented and the respective roles of endogenous versus exogenous DNA damage in carcinogenesis are discussed.
Abstract: DNA damage plays a major role in mutagenesis, carcinogenesis and ageing. The vast majority of mutations in human tissues are certainly of endogenous origin. A thorough knowledge of the types and prevalence of endogenous DNA damage is thus essential for an understanding of the interactions of endogenous processes with exogenous agents and the influence of damage of endogenous origin on the induction of cancer and other diseases. In particular, this seems important in risk evaluation concerning exogenous agents that also occur endogenously or that, although chemically different from endogenous ones, generate the same DNA adducts. This knowledge may also be crucial to the development of rational chemopreventive strategies. A list of endogenous DNA-damaging agents, processes and DNA adduct levels is presented. For the sake of comparison, DNA adduct levels are expressed in a standardized way, including the number of adducts per 10(6) nt. This list comprises numerous reactive oxygen species and products generated as a consequence (e.g. lipid peroxides), endogenous reactive chemicals (e.g. aldehydes and S-adenosylmethionine), and chemical DNA instability (e.g. depurination). The respective roles of endogenous versus exogenous DNA damage in carcinogenesis are discussed.

Journal ArticleDOI
TL;DR: It is shown that Fbw7, a component of the SCFFbw 7 ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c- myc ubiquitination in vitro.
Abstract: Myc proteins regulate cell growth and division and are implicated in a wide range of human cancers. We show here that Fbw7, a component of the SCFFbw7 ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro. Phosphorylation of c-Myc on threonine-58 (T58) by glycogen synthase kinase 3 regulates the binding of Fbw7 to c-Myc as well as Fbw7-mediated c-Myc degradation and ubiquitination. T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer. Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis.

Journal ArticleDOI
16 Dec 2004-Oncogene
TL;DR: The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets.
Abstract: Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a distinguishing feature from normal NSCs, these tumor stem cells can reform spheres even after the induction of differentiation. Furthermore, only these tumor stem cells were able to form tumors and generate both neurons and glial cells after in vivo implantation into nude mice. The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets.

Journal ArticleDOI
28 Oct 2004-Nature
TL;DR: It is reported that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers and how oncogenic inactivation may reverse tumorigenesis in the most clinically difficult cancers is shown.
Abstract: Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.

Journal ArticleDOI
TL;DR: It is shown that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals, indicating that with respect to oncogenesis, although a deregulation/ increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization.
Abstract: The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the expression of mesenchymal markers. Here, we show that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals. Hence, Snail favors changes in cell shape versus cell division, indicating that with respect to oncogenesis, although a deregulation/increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization. Finally, the resistance to cell death conferred by Snail provides a selective advantage to embryonic cells to migrate and colonize distant territories, and to malignant cells to separate from the primary tumor, invade, and form metastasis.

Journal ArticleDOI
TL;DR: An orthotopic xenograft model is developed in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin, allowing for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.
Abstract: The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

Journal ArticleDOI
19 Apr 2004-Oncogene
TL;DR: A deeper understanding of the role of eIF-4E in regulating the translation of the diverse gene products involved in all aspects of malignancy will improve the capacity to exploit eIF -4E as a therapeutic target and as a marker for human cancer progression.
Abstract: The contribution of the mRNA cap-binding protein, eIF-4E, to malignant transformation and progression has been illuminated over the past decade. eIF-4E overexpression has been demonstrated in human tumors of the breast, head and neck, colon, prostate, bladder, cervix and lung, and has been related to disease progression. Overexpression of eIF-4E in experimental models dramatically alters cellular morphology, enhances proliferation and induces cellular transformation, tumorigenesis and metastasis. Conversely, blocking eIF-4E function by expression of antisense RNA, or overexpression of the inhibitory eIF-4E binding proteins (4E-BPs), suppresses cellular transformation, tumor growth, tumor invasiveness and metastasis. Although eIF-4E regulates the recruitment of mRNA to ribosomes, and thereby globally regulates cap-dependent protein synthesis, eIF-4E contributes to malignancy by selectively enabling the translation of a limited pool of mRNAs--those that generally encode key proteins involved in cellular growth, angiogenesis, survival and malignancy (e.g. cyclin D1, c-myc, vascular endothelial growth factor, matrix metalloprotease 9). A deeper understanding of the role of eIF-4E in regulating the translation of the diverse gene products involved in all aspects of malignancy will improve the capacity to exploit eIF-4E as a therapeutic target and as a marker for human cancer progression.

Journal ArticleDOI
18 Nov 2004-Nature
TL;DR: A growing body of evidence suggests that aneuploidy is often caused by a particular type of genetic instability, called chromosomal instability, which may reflect defects in mitotic segregation in cancer cells.
Abstract: In contrast to normal cells, aneuploidy--alterations in the number of chromosomes--is consistently observed in virtually all cancers. A growing body of evidence suggests that aneuploidy is often caused by a particular type of genetic instability, called chromosomal instability, which may reflect defects in mitotic segregation in cancer cells. A better understanding of the molecular mechanisms leading to aneuploidy holds promise for the development of cancer drugs that target this process.

Journal ArticleDOI
20 Sep 2004-Oncogene
TL;DR: The identification of a brain tumor stem cells (BTSC) provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.
Abstract: Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and more recently in solid tumors such as breast cancer suggests that the tumor cell population is heterogeneous with respect to proliferation and differentiation. Recently, several groups have described the existence of a cancer stem cell population in human brain tumors of different phenotypes from both children and adults. The finding of brain tumor stem cells (BTSCs) has been made by applying the principles for cell culture and analysis of normal neural stem cells (NSCs) to brain tumor cell populations and by identification of cell surface markers that allow for isolation of distinct tumor cell populations that can then be studied in vitro and in vivo. A population of brain tumor cells can be enriched for BTSCs by cell sorting of dissociated suspensions of tumor cells for the NSC marker CD133. These CD133+ cells, which also expressed the NSC marker nestin, but not differentiated neural lineage markers, represent a minority fraction of the entire brain tumor cell population, and exclusively generate clonal tumor spheres in suspension culture and exhibit increased self-renewal capacity. BTSCs can be induced to differentiate in vitro into tumor cells that phenotypically resembled the tumor from the patient. Here, we discuss the evidence for and implications of the discovery of a cancer stem cell in human brain tumors. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC. Specific genetic and molecular analyses of the BTSC will further our understanding of the mechanisms of brain tumor growth, reinforcing parallels between normal neurogenesis and brain tumorigenesis.

Journal Article
TL;DR: In this article, the authors used oligonucleotide-based DNA microarrays to analyze transcriptional changes resulting from constitutive Ras signaling and found that Ras signaling leads to a significant induction of Interleukin-8 (IL-8) mRNA, which is accompanied by a corresponding increase in protein levels.
Abstract: 1749 Ras proteins are important regulators of cell proliferation and their constitutive activation is a key event in cancer development. To discover novel effector pathways that might contribute to the oncogenic properties of Ras, we used oligonucleotide-based DNA microarrays to analyze transcriptional changes resulting from constitutive Ras signaling. We performed the expression analyses with HeLa stable cell lines expressing activated RasG12→V transgenes under a tetracycline responsive promoter (Tet-Off™ Expression System). This system not only mediates tight on/off regulation of gene expression; it also permits the titration of protein levels on a single cell basis allowing the study of dose dependent aspects of gene activity. Ras signaling leads to a significant induction of Interleukin-8 (IL-8) mRNA, which is accompanied by a corresponding increase in protein levels. IL-8 is a chemotactic factor for leukocytes and closely associated with the initiation of an acute inflammatory response. Analysis of signal transduction pathways that link Ras to IL-8 up-regulation suggests a direct effect of Ras on the IL-8 promoter, mediated by the synergistic activation of both MAPK-cascades and the PI3K > NFκB pathway. In addition, the Ras-induced accumulation of IL-8 protein is dependent on the activation of p38 MAP-kinase through a post-transcriptional mechanism involving an increase in IL-8 mRNA stability. Investigation of the functional importance of IL-8 in the context of tumorigenesis shows that IL-8 plays a decisive role in RasV12-mediated acceleration of tumor growth in a nude mouse xenograft model. Ablation of IL-8 function is accompanied by a significant reduction in tumor size. This effect is not due to decreased cell proliferation rates, since we observe no change in the mitogenic index of tumors after inhibition of IL-8. However, tumors devoid of functional IL-8 show a marked reduction in vascularization accompanied by vast tissue necrosis. These observations can be correlated with an IL-8-mediated initiation of an early inflammatory reaction in developing neoplasms that triggers tumor vascularization. In addition, IL-8 may act directly to support angiogenesis by promoting endothelial cell proliferation and migration. These results provide a novel mechanism by which tumor cells harboring oncogenic Ras can appropriate inflammatory mediators to recruit immune cells to the tumor site and facilitate neo-angiogenesis, thus setting the stage for subsequent progression to malignancy.

Journal ArticleDOI
TL;DR: It is shown that thirteen of fifty-three breast cancers contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain, demonstrating that Pik3CA is the most mutated oncogene in breast cancer.
Abstract: The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation. It has recently been reported that somatic mutations within the PI3K subunit p110alpha (PIK3CA) are present in human colorectal and other cancers. Here we show that thirteen of fifty-three breast cancers (25%) contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain. These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis.

Journal ArticleDOI
TL;DR: The nature of normal stem cells (embryonal, germinal and somatic) is presented and their relationships to cancer are further expanded and cell signaling pathways shared by embryonic cells and cancer cells suggest a possible link between embryonic cellsand cancer cells.
Abstract: Our forefathers in pathology, on observing cancer tissue under the microscope in the mid-19th century, noticed the similarity between embryonic tissue and cancer, and suggested that tumors arise from embryo-like cells [1] , [2] [Recherches dur le Traitement du Cancer, etc. Paris. (1829); Editoral Archiv fuer pathologische Anatomie und Physiologie und fuer klinische Medizin 8 (1855) 23]. The concept that adult tissues contain embryonic remnants that generally lie dormant, but that could be activated to become cancer was later formalized by Cohnheim [3] , [4] [Path. Anat. Physiol. Klin. Med. 40 (1867) 1–79; Virchows Arch. 65 (1875) 64] and Durante [5] [Arch. Memori ed Osservazioni di Chirugia Practica 11 (1874) 217–226], as the “embryonal rest” theory of cancer. An updated version of the embryonal rest theory of cancer is that cancers arise from tissue stem cells in adults. Analysis of the cellular origin of carcinomas of different organs indicates that there is, in each instance, a determined stem cell required for normal tissue renewal that is the most likely cell of origin of carcinomas [6] [Lab. Investig. 70 (1994) 6–22]. In the present review, the nature of normal stem cells (embryonal, germinal and somatic) is presented and their relationships to cancer are further expanded. Cell signaling pathways shared by embryonic cells and cancer cells suggest a possible link between embryonic cells and cancer cells. Wilm’s tumors (nephroblastomas) and neuroblastomas are presented as possible tumors of embryonic rests in children. Teratocarcinoma is used as the classic example of the totipotent cancer stem cell which can be influenced by its environment to differentiate into a mature adult cell. The observation that “promotion” of an epidermal cancer may be accomplished months or even years after the initial exposure to carcinogen (“initiation”), implies that the original carcinogenic event occurs in a long-lived epithelial stem cell population. The cellular events during hepatocarcinogenesis illustrate that cancers may arise from cells at various stages of differentiation in the hepatocyte lineage. Examples of genetic mutations in epithelial and hematopoietic cancers show how specific alterations in gene expression may be manifested as maturation arrest of a cell lineage at a specific stage of differentation. Understanding the signals that control normal development may eventually lead us to insights in treating cancer by inducing its differentiation (differentiation therapy). Retinoid acid (RA) induced differentiation therapy has acquired a therapeutic niche in treatment of acute promyelocytic leukemia and the ability of RA to prevent cancer is currently under examination.