Table of Contents

Volume 7, Issue 6

  March 15, 2008

  Pages 691 - 832

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Coordination of cell cycle exit and differentiation of neuronal progenitors

Panagiotis K. Politis, Dimitra Thomaidou and Rebecca Matsas
Pages 691 - 697
http://dx.doi.org/10.4161/cc.7.6.5550
Abstract | PDF

During development, co-ordinate regulation of cell cycle exit and differentiation of neuronal precursors is essential for generation of appropriate number of neurons and proper wiring of neuronal circuits. Recent studies have identified some of the molecules implicated in the regulation of these cellular events, but the complex machinery that orchestrates these processes into a coherent developmental program remains unclear. BM88/Cend1 is a neuronal protein associated in vivo with terminal neuron-generating divisions, marking the exit of proliferative cells from the cell cycle. Genetic studies in neural cell lines, neural stem/progenitor cells using the neurosphere system and in the developing chicken neural tube in vivo have shown that BM88/Cend1 is a dual function molecule co-ordinating cell cycle exit and differentiation of neuronal progenitors. These studies have thus shed light on a molecular determinant that participates, along with other known and possibly still unknown regulators, in the complex processes by which a progenitor cell becomes a mature neuron.

Open Access Article

Matrimony ties Polo down: Can this kinase get free?

S. Kendall Smith, Sue L. Jaspersen and R. Scott Hawley
Pages 698 - 701
http://dx.doi.org/10.4161/cc.7.6.5568
Abstract | PDF

Cell cycle progression in female meiotic systems is characterized by the presence of two or more pre-programmed arrests. One such arrest is invariable throughout all species—a lengthy G₂ arrest that separates the end of pachytene (by which time homologous chromosomes have condensed, paired, and undergone recombination1) from nuclear envelope breakdown (NEB). The termination of G₂ arrest (as defined by NEB) and the subsequent entry of the oocyte into prometaphase is regulated by an intracellular signaling cascade whose ultimate feature is the activation of the cyclin B-Cdk1 complex by the Cdc25 phosphatase family. In oocytes, activation of Cdc25 is often mediated by Polo-like kinases (Plks).(2-6) Recent work by Xiang et al. demonstrated that in Drosophila female meiosis, Polo’s role in promoting NEB is regulated by a meiosis-specific stoichiometric inhibitor called Matrimony (Mtrm), which binds to the C-terminal Polo-box domain (PBD) of Polo.(7) In addition to a PBD-binding site, Mtrm contains putative Plk and cyclin B-Cdk1 phosphorylation consensus motifs. These motifs suggest a unique mechanism of Polo inhibition by Mtrm and a possible auto-amplification loop by which cyclin B-Cdk1-mediated destruction or dissociation of Mtrm from Polo allows for rapid and irreversible G₂ exit and entry into prometaphase.

Open Access Article

Double identity of SCAPER: A substrate and regulator of cyclin A/Cdk2

William Y. Tsang and Brian David Dynlacht
Pages 702 - 705
http://dx.doi.org/10.4161/cc.7.6.5611
Abstract | PDF

Cyclin A is a key regulator of DNA replication and mitosis, and cyclin A/Cdk2 activity is critical for progression of cells from G1/S to M phase of the cell cycle. There is abundant evidence that cyclin A is predominantly localized to, and functions in, the nucleus, and a number of nuclear cyclin A/Cdk2 substrates have been identified. Evidence supporting the presence of cyclin A and its associated activity in the cytoplasm have also been reported, but the biological significance of this cyclin/Cdk pool during cell cycle progression remains controversial. Recently, we identified and characterized a new cyclin A/Cdk2 substrate named SCAPER which is localized to the endoplasmic reticulum. By sequestering cyclin A/Cdk2, SCAPER is capable of directing the activity of this kinase complex away from the nucleus and regulating cyclin A/Cdk2 equilibrium in distinct subcellular compartments. This work paves new avenues for understanding the role of cytoplasmic cyclin A/Cdk2 and its potential contribution to cancer and tumor formation.




PERSPECTIVES

Open Access Article

Deciphering developmental stages of adult myelopoiesis

Cornelis J. Pronk, Joanne Attema, Derrick J. Rossi, Mikael Sigvardsson and David Bryder
Pages 706 - 713
http://dx.doi.org/10.4161/cc.7.6.5565
Abstract | PDF

The ability to subfractionate minor cellular subsets by multiparameter flow cytometry and to evaluate such cells for functional properties has been used to ascertain lineal relationships and detail developmental hierarchies in the hematopoietic system for more than 20 years. However, steady advances in technology combined with the use of novel cell surface markers continues to redefine the developmental landscape as novel subpopulations are purified and characterized. We recently used such an approach to stage progenitor cell hierarchy involved in myeloid development with the use of two markers, Slamf1 and Endoglin that have recently been shown to be associated with hematopoietic stem cells. Here, we provide additional characterization of these cellular subsets to further refine their developmental potential. Little or no alterations in lineage potential were observed in these subsets when evaluated in a BCL2 transgenic setting or in response to various growth factor combinations, although BCL2 significantly enhanced their in vitro readout. Gene expression patterns of functionally opposing transcription factors that are known to play key roles for the appropriate development into separate myeloid lineages were associated with the functional activity of prospectively isolated subsets. Multiple genes traditionally associated with early lymphopoiesis were observed in early candidate granulocyte/monocyte, but not early megakaryocytic and/or erythroid progenitor cells. When functionally evaluated, such early granulocyte/monocyte precursors displayed a latent lymphoid activity, which was pronounced in subsets bearing high expression of the tyrosine kinase receptor FLT3.

Open Access Article

JAK2 activation in myeloproliferative neoplasms: A potential role for heterodimeric receptors

Gary W. Reuther
Pages 714 - 719
http://dx.doi.org/10.4161/cc.7.6.5567
Abstract | PDF

The various roles and importance of JAK2 in cell signaling have been appreciated for some time. In 2005, a point mutation in JAK2 (JAK2-V617F) was identified in a number of neoplastic myeloproliferative disorders, ushering in a new era of JAK2 research. This discovery uncovered a new therapeutic target to treat these neoplasms and in turn possibly prevent their progression into cancer. A thorough understanding of the mechanism of JAK2-V617F-mediated activation will enhance our knowledge of how JAK2 contributes to these diseases. While mutationally activated, JAK2-V617F still requires homodimeric cytokine receptors to provide a scaffold upon which the JAK2 molecules trans-activate each other via phosphorylation. We have recently shown that in addition to homodimeric receptors, single components of heterodimeric cytokine receptors may substitute for homodimeric receptors in activation of this mutant JAK2. While mutations in homodimeric cytokine receptors have been found in JAK2-negative myeloproliferative neoplasms, it is possible that components of heterodimeric receptors also contribute to these disorders through aberrant expression or mutational activation.

Open Access Article

A context dependent role for Wnt signaling in tumorigenesis and stem cells

Igor Matushansky, Robert G. Maki and Carlos Cordon-Cardo
Pages 720 - 724
http://dx.doi.org/10.4161/cc.7.6.5569
Abstract | PDF

The Wnt signal transduction pathway coordinates myriad activities, from development and differentiation to proliferation and tumorigenesis. What is perhaps most remarkable is that Wnt signaling is able to accomplish this diverse set of activities in a cell-specific and differentiation stage-dependent manner. In this review, we will highlight the diverse effect of Wnt signaling on three types of tissue stem cells and their corresponding malignancies.

Open Access Article

The pluripotency regulator Oct4: A role in somatic stem cells?

Christopher J. Lengner, G. Grant Welstead and Rudolf Jaenisch
Pages 725 - 728
http://dx.doi.org/10.4161/cc.7.6.5573
Abstract | PDF

Since its discovery as a critical regulator of pluripotency in embryonic stem (ES) cells and the inner cells mass of the developing blastocyst, the Pou domain-containing transcription factor Oct4 has become a proxy for “stemness” in numerous studies of somatic stem cells as it’s presence is often taken as evidence of pluripotency in these cells. Recent studies, however, have demonstrated that not only is Oct4 dispensable for maintaining potency in somatic stem cell compartments, but also that the methods applied to detect Oct4 and the interpretation of the resulting data may be flawed. Here we contrast pathways known to govern pluripotency in embryonic stem cells with those in adult stem cells and critically discuss the concept of pluripotency in adult stem cells of the mammalian soma.

Open Access Article

Unbiased vs. biased approaches to the identification of cancer signatures: the case of lung cancer

Fabrizio Bianchi, Francesco Nicassio and Pier Paolo Di Fiore
Pages 729 - 734
http://dx.doi.org/10.4161/cc.7.6.5591
Abstract | PDF

Expression profiling analysis of human cancers is a promising approach to obtain precise molecular classification of cancers, to develop stratification tools for therapeutic regimens, and to predict the biological behavior of neoplasia. Direct profiling of human cancers (herein defined as “the unbiased approach”) presents, however, intrinsic problems connected with the high genetic noise embedded in the system. This, in turn, leads to fitting of the noise in the data (the so-called “overtraining”) with consequent instability of the identified signatures, when applied on different cohorts of patients. To circumvent these problems, “biased approaches” - which exploit the molecular knowledge of cancer obtained in model systems - are being developed. Biased approaches, however, are not problem-free, in that they provide information limited to single oncogenic events, thereby failing, at least in principle, to capture the complex repertoire of alterations of human cancers. In this review, we compare the two approaches and provide a test case, from our studies, of how “integrated” strategies, which combine biased and unbiased approaches, might lead to the identification of stable and reliable predictive signatures in cancer.

Open Access Article

A new model of tumor susceptibility following tumor suppressor gene inactivation

Itsuki Ajioka and Michael A. Dyer
Pages 735 - 740
http://dx.doi.org/10.4161/cc.7.6.5612
Abstract | PDF

Since the cloning of the first tumor suppressor gene 22 years ago, we have learned a great deal about the role of tumor suppressor pathways in human cancer. One general principle is that some tumor suppressor pathways (e.g., p53 and Rb pathways) are inactivated in virtually every human cancer. Thus, one might predict that inheritance of a genetic lesion in such a pathway would cause the rapid onset of tumors originating from different tissues. However, this is not true for the Rb pathway. Children with a defective copy of the RB1 gene show increased susceptibility to retinoblastoma but not to other developmental tumors of the nervous system. Moreover, after RB1 inactivation, certain retinal cell types are more susceptible to tumorigenesis than others. Our recent studies on the role of the Rb family of genes in retinal development and retinoblastoma have led to a new hypothesis that explains this paradox. We propose that cells that require the Rb family for their cell fate specification and/or differentiation are less susceptible to tumorigenesis than those that do not require the Rb family for these processes. If correct, this hypothesis would allow us to predict which cell types in the developing nervous system are susceptible to tumorigenesis after inactivation of the Rb family and may establish a general principle of tissue- and cell type–specific susceptibility to tumorigenesis. In this perspective, we discuss our recent findings that have changed our views on tumor initiation and progression following Rb family inactivation.




REVIEWS

Open Access Article

Regulation of mRNA Translation during cellular division

Gilad Sivan and Orna Elroy-Stein
Pages 741 - 744
http://dx.doi.org/10.4161/cc.7.6.5596
Abstract | PDF

Protein synthesis is a mulistep, multifactorial process of mRNA translation, on which cells expend more energy than on any other activity. Cellular division into two daughter cells involves temporary inhibition of protein synthesis. Similar to many translational control paradigms, global translation during mitosis is inhibited at the level of 5'cap-dependent initiation. The down regulation of global translation is accompanied by 5'cap-independent translational activation of specific mRNAs whose protein products have a role in the progression of cellular division. Recently, the elongation step was highlighted as a major target of translational control during mitosis, in addition to the initiation step. Stalling of translating ribosomes not only protects mRNAs during mitosis but also allows rapid resumption of active translation immediately upon entry into the G1 phase of the cell cycle, an added dimension of energy saving. This review focuses on recent information related to translational regulation during cellular division and raises a new challenge regarding mechanism(s) employed by mRNAs whose translation is not sensitive to the elongation block.

Open Access Article

Potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: Implications for broad anti-tumor efficacy

Randall W. Alfano, Stephen H. Leppla, Shihui Liu, Thomas H. Bugge, Nicholas S. Duesbery and Arthur E. Frankel
Pages 745 - 749
http://dx.doi.org/10.4161/cc.7.6.5627
Abstract | PDF

Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase (MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin (LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.




BRIEF REPORTS

Open Access Article

Conditional deletion of cyclin-dependent kinase 5 in primary sensory neurons leads to atypical skin lesions

Brenda Saikkonen, Tej Kumar Pareek, Nitin Agarwal, Alfredo Molinolo, Martin Kriete and Ashok B. Kulkarni
Pages 750 - 753
http://dx.doi.org/10.4161/cc.7.6.5494
Abstract | PDF

The key role of cyclin-dependent kinase 5 (Cdk5) in neuronal function has been well established but understanding of its importance in sensory pathways is in its infancy. Recently we described the important role of Cdk5 in pain signaling. Our studies indicated that conditional deletion of Cdk5 in small sensory neurons causes hypoalgesia. In current study, we identified development of atypical non-healing skin lesions in these mutant mice during the general colony maintenance. Detailed examination of these lesions clearly distinguishes them from ulcerative dermatitis. Here we hypothesize that these skin lesions are due to general sensation loss in these mice as evident from deep skin scratches that turn into unhealed wounds.

Open Access Article

The adenovirus E1B-55K oncoprotein induces SUMO modification of p53

Stefan Muller and Thomas Dobner
Pages 754 - 758
http://dx.doi.org/10.4161/cc.7.6.5495
Abstract | PDF

The ability of adenovirus to induce cell transformation depends on the E1A and E1B-55K oncoproteins. While E1A functionally inactivates the retinoblastoma tumour suppressor, E1B-55K primarily interferes with the function of p53. In adenovirus transformed cells E1B-55K can directly affect p53-dependent transactivation. In virus-infected cells E1B-55K additionally cooperates with the viral E4orf6 protein to induce ubiquitin-dependent degradation of p53. Here we unravel a novel activity of E1B-55K by demonstrating that it drastically stimulates the post-translational modification of p53 by the ubiquitin-like SUMO modifier. Consistent with this finding the extent of p53 SUMOylation is highly elevated in adenovirus transformed cell lines. E1B-55K-mediated SUMOylation depends on the direct interaction of E1B-55K with p53 and additionally requires SUMO modification of E1B-55K. These data suggest that E1B-55K exploits both ubiquitin and ubiquitin-like systems to target host cell proteins and thus shed new light on the molecular mechanisms of E1B-55K function. Moreover, the data expand the emerging concept of dual-specificity factors that act in both the SUMO and ubiquitin pathway and identify E1B-55K as the first viral protein that shares this dual activity.




PRIORITY REPORT

Open Access Article

The let-7 microRNA reduces tumor growth in mouse models of lung cancer

Aurora Esquela-Kerscher, Phong Trang, Jason F. Wiggins, Lubna Patrawala, Angie Cheng, Lance Ford, Joanne Barnes Weidhaas, David Brown, Andreas G. Bader and Frank J. Slack
Pages 759 - 764
http://dx.doi.org/10.4161/cc.7.6.5834
Abstract | PDF

MicroRNAs have been increasingly implicated in human cancer and interest has grown about the potential to use microRNAs to combat cancer. Lung cancer is the most prevalent form of cancer worldwide and lacks effective therapies. Here we have used both in vitro and in vivo approaches to show that the let-7 microRNA directly represses cancer growth in the lung. We find that let-7 inhibits the growth of multiple human lung cancer cell lines in culture, as well as the growth of lung cancer cell xenografts in immunodeficient mice. Using an established orthotopic mouse lung cancer model, we show that intranasal let-7 administration reduces tumor formation in vivo in the lungs of animals expressing a G12D activating mutation for the K-ras oncogene. These findings provide direct evidence that let-7 acts as a tumor suppressor gene in the lung and indicate that this miRNA may be useful as a novel therapeutic agent in lung cancer.




REPORTS

Open Access Article

Cut1/separase-dependent roles of multiple phosphorylation of fission yeast cohesin subunit Rad21 in post-replicative damage repair and mitosis

Yoh Adachi, Aya Kokubu, Masahiro Ebe, Koji Nagao and Mitsuhiro Yanagida
Pages 765 - 776
http://dx.doi.org/10.4161/cc.7.6.5530
Abstract | PDF

Cohesin is a multiprotein complex essential for sister-chromatid cohesion. It plays a pivotal role in proper chromosome segregation and DNA damage repair. The mitotic behavior of cohesin is controlled through its phosphorylation, which possibly induces the dissociation of cohesin from chromosomes and enhances its susceptibility to separase. Here, we report using mass spectrometry and anti-phospho antibodies that the central domain of Rad21, the separase-target subunit of Schizosaccharomyces pombe cohesin, is regulated by various kinase-induced phosphorylation at nine residues, indicating the multiple roles for S. pombe cohesin. In vegetative and non-dividing G0 cells, Rad21 is phosphorylated by unknown S/TP-consensus kinases, in mitotic and non-mitotic cells by polo/Plo1 and CDK, and in DNA-damaged cells by Rad3/ATR. While mitotic phosphorylation is implicated in the dissociation of Rad21 and its cleavage by separase in anaphase, the Rad3/ATR-dependent damage-induced phosphorylation occurs intensively at the time of repair completion, and only in post-replicative cells. This damage-induced Rad21 phosphorylation is involved in the recovery process of cells from checkpoint arrest, and needed for the removal of cohesin by separase after the completion of damage repair. These complex phospho-regulations of Rad21 indicate the functional significance of cohesin in cell adaptation to a variety of cellular conditions.

Open Access Article

The meiotic differentiation program uncouples S-phase from cell size control in Saccharomyces cerevisiae

David Stuart
Pages 777 - 786
http://dx.doi.org/10.4161/cc.7.6.5562
Abstract | PDF

Cell size homeostasis in proliferating cell populations is maintained in part by linking the initiation of a cell division cycle to growth such that a specific “size threshold” must be achieved prior to cell cycle initiation. In Saccharomyces cerevisiae the size threshold is responsive to environmental conditions and cell cycle entry is initiated at smaller sizes in poor growth medium and larger sizes in rich medium. In response to starvation for nitrogen and glucose diploid S. cerevisiae abandon proliferation and initiate gametogenesis (sporulation). The ability of both small and large cells to sporulate was investigated and the data reported here indicate that very small S. cerevisiae cells derived from the SK1 genetic background are able to sporulate. Although larger cells progress through the process more rapidly than small cells, sporulation of very small cells appears to be normal as they undergo meiotic recombination and form viable spores. Genetic analysis indicates that this trait is determined by multiple genes and may explain why some S. cerevisiae strains appear to display a minimal size threshold for sporulation. These data support a model where cell size controls can be bypassed or profoundly altered specifically to allow cellular differentiation in response to environmental signals.

Open Access Article

Aurora-C and Aurora-B share phosphorylation and regulation of cenp-A and borealin during mitosis

Scott D. Slattery, Rebecca V. Moore, Bill R. Brinkley and Rebecca M. Hall
Pages 787 - 795
http://dx.doi.org/10.4161/cc.7.6.5563
Abstract | PDF

Aurora-B and –C kinases are members of the Aurora serine/threonine kinase family of mitotic regulators. Aurora-B kinase is evolutionarily conserved from yeast to humans and has multiple functions in chromosome condensation, cohesion, biorientation, and in cytokinesis. In contrast, Aurora-C kinase has only been found in mammals, is upregulated in some tumor cell lines and tissues, and has a unique physiological role in spermiogenesis. Despite these known functions, little is known about the function of Aurora-C in mitosis. We have found that Aurora-C interacts with Borealin in addition to the other known members of the Aurora-B chromosomal passenger complex (CPC). We have also found that Aurora-C, like Aurora-B, phosphorylates the centromeric histone Centromere Protein-A (CENP-A) and Borealin in vitro. These molecular mechanisms are consistent with our observation that in the absence of Aurora-B, Aurora-C is sufficient for proper mitotic phosphorylation of CENP-A and centromeric localization of the CPC proteins. Thus, Aurora-C shares Aurora-B substrates and is capable of performing mitotic functions previously attributed only to Aurora-B.

Open Access Article

The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest

Julia M. Sidorova, Nianzhen Li, Albert Folch and Raymond J. Monnat, Jr.
Pages 796 - 807
http://dx.doi.org/10.4161/cc.7.6.5566
Abstract | PDF

Werner syndrome is an autosomal recessive genetic instability and cancer predisposition syndrome with features of premature aging. Several lines of evidence have suggested that the Werner syndrome protein WRN plays a role in DNA replication and S-phase progression. In order to define the exact role of WRN in genomic replication we examined cell cycle kinetics during normal cell division and after methyl-methane-sulfonate (MMS) DNA damage or hydroxyurea (HU)-mediated replication arrest following acute depletion of WRN from human fibroblasts. Loss of WRN markedly extended the time cells needed to complete the cell cycle after either of these genotoxic treatments. Moreover, replication track analysis of individual, stretched DNA fibers showed that WRN depletion significantly reduced the speed at which replication forks elongated in vivo after MMS or HU treatment. These results establish the importance of WRN during genomic replication and indicate that WRN acts to facilitate fork progression after DNA damage or replication arrest. The data provide a mechanistic basis for a better understanding of WRN-mediated maintenance of genomic stability and for predicting the outcomes of DNA-targeting chemotherapy in several adult cancers that silence WRN expression.

Open Access Article

Regulation of the Rad53 protein kinase in signal amplification by oligomer assembly and disassembly

Nianhan Jia-Lin Ma and David F. Stern
Pages 808 - 817
http://dx.doi.org/10.4161/cc.7.6.5595
Abstract | PDF

Rad53, the ortholog of mammalian Chk2, is a major DNA damage checkpoint effector kinase in Saccharomyces cerevisiae. Despite extensive studies on the genetic requirements for Rad53 activation and its linkage downstream to checkpoint responses, the mechanism of Rad53 activation is not completely understood. Rad53-dependent signal amplification is thought to be a primary force that accelerates checkpoint signal transduction processes in response to DNA damage. Rad53 forms oligomers upon DNA damage in vivo. It is not clear how oligomer formation affects Rad53 activation and what is the mechanism of Rad53 oligomerization. Here, we monitor Rad53 oligomer assembly and disassembly in vitro. These processes are ATP-dependent and are regulated through phosphorylation. Mutations in FHA or SCD domains of RAD53 compromise intermolecular autophosphorylation activity and these domains are indispensable for Rad53 oligomerization. The mediator Rad9 is not necessary for Rad53 oligomerization. Rad53 kinase activity is required for disassembly of Rad53 oligomers in vivo after DNA damage. Moreover, induced oligomerization of Rad53 efficiently activates Rad53 in the absence of Mec1 in vivo. The results support the conclusions that Rad53/Chk2 homo-oligomerization is an evolutionarily conserved mechanism that drives Rad53/Chk2 activation and promotes signal amplification in DNA damage responses.

Open Access Article

PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

Kenneth Steadman, Wilfred D. Stein, Thomas Litman, Sherry X. Yang, Mones Abu-Asab, Sarah K. Dutcher and Susan Bates
Pages 818 - 829
http://dx.doi.org/10.4161/cc.7.6.5597
Abstract | PDF

Cancers arising in pancreas, lung, liver, and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status : (i) as monolayers attached to plastic culture dishes, (ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray (Affymetrix, Inc.). There was a striking overlap between (a) the genes expressed differentially between early monolayers and early spheroids and (b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for polyHEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids (and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers.




LETTER TO THE EDITOR

Open Access Article

DEAD-box RNA helicase p68 is not required for nuclear translocation of β-catenin in colon cancer cells

Volker M. Stucke, Delphine Gorses and Francesco Hofmann
Pages 830 - 832
http://dx.doi.org/10.4161/cc.7.6.5614
Abstract | PDF

Not available.