Cancer Biology

Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma

by Elana Fertig

Elana J Fertig, Qing Ren, Haixia Cheng, Hiromitsu Hatakeyama, Adam Dicker, Ulrich Rodeck, Michael Considine, Michael F Ochs and Christine H Chung (2012) BMC Genomics 13:160. Featured in http://www.biomedcentral.com/1741-7015/10/43/abstract.

Background: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been... more Background: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D.

Results: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines.

Conclusions: Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies.

Mitochondrial NADH-dehydrogenase polymorphisms as sporadic breast cancer risk factor.

by Anna M. Czarnecka

Breast cancer is the most frequently diagnosed
female cancer all over the world. Although the molecularmore Breast cancer is the most frequently diagnosed
female cancer all over the world. Although the molecular
genetics of this disease has been the focus of many projects
for over 20 years, the number of prognostic markers used in
clinics is still unsatisfactory. Mitochondrial DNA mutations
have been reported in many breast cancer studies. To
investigate the possible role of mitochondrial inherited
polymorphisms in breast cancer development we analyzed
the sequence of NADH-dehydrogenase genes in cancer
samples and their corresponding normal tissues. We detected
increased incidence of mtDNA polymorphisms, in particular
very rare polymorphisms such as A4727G, G9947A,
A10044G, A10283G, T11233C, and C11503T. Our report
supports the notion that mtDNA polymorphisms establish a
specific genetic background for breast cancer development
and that mtDNA analysis may help in selection of cohorts
that should undergo intensive screening and early detection
programs

Development and testing of hyperbaric atomic force microscopy (AFM) and fluorescence microscopy for biological applications

by Dominic D'Agostino

A commercially available atomic force microscopy and fluorescence microscope were installed and tested inside a... more A commercially available atomic force microscopy and fluorescence microscope were installed and tested inside a custom-designed hyperbaric chamber to provide the capability to study the effects of hyperbaric gases on biological preparations, including cellular mechanism of oxidative stress. In this report, we list details of installing and testing atomic force microscopy and fluorescence microscopy inside a hyperbaric chamber. The pressure vessel was designed to accommodate a variety of imaging equipment and ensures full functionality at ambient and hyperbaric conditions (≤85 psi). Electrical, gas and fluid lines were installed to enable remote operation of instrumentation under hyperbaric conditions, and to maintain viable biological samples with gas-equilibrated superfusate and/or drugs. Systems were installed for vibration isolation and temperature regulation to maintain atomic force microscopy performance during compression and decompression. Results of atomic force microscopy testing demonstrate sub-nanometre resolution at hyperbaric pressure in dry scans and fluid scans, in both contact mode and tapping mode. Noise levels were less when measurements were taken under hyperbaric pressure with air, helium (He) and nitrogen (N(2) ). Atomic force microscopy and fluorescence microscopy measurements were made on a variety of living cell cultures exposed to hyperbaric gases (He, N(2) , O(2) , air). In summary, atomic force microscopy and fluorescence microscopy were installed and tested for use at hyperbaric pressures and enables the study of cellular and molecular effects of hyperbaric gases and pressure per se in biological preparations.

Dynamic Mitochondrial Networks in Cancer

by Jalees Rehman

Published on the Scientific American Blog

Research projects evolve in a fortuitous manner, often guided by a convergence of novel observations, intuition,... more Research projects evolve in a fortuitous manner, often guided by a convergence of novel observations, intuition, helpful colleagues and unique personal circumstances. It is precisely this constellation that prompted two cardiologists to study the mitochondrial networks in lung cancer cells.

In 2008, my colleague and friend Stephen Archer, a Professor of Medicine at the University of Chicago, asked me whether I would be interested in studying the role of mitochondrial networks in lung cancer cells. My first response was the question “Do mitochondria really form networks?”, because at that time the expression “mitochondria” evoked images of scattered oval-like organelles, a textbook image of electron microscopy.......

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres

by Andrew Beggs

Genomics and breast cancer: the different levels of inherited susceptibility

by Andrew Beggs

The genomics of colorectal cancer: state of the art

by Andrew Beggs

The DCC gene and colorectal cancer: the story is more complex

by Andrew Beggs

Down-regulation of serum/glucocorticoid regulated kinase 1 in colorectal tumours is largely independent of promoter hypermethylation

by Andrew Beggs

Hypericum perforatum Extracts and Hypericin Treatment of a Mouse Mammary Cancer Cell Line Induces Growth Inhibition in a Dose Dependent Manner

by Ravi Dinakar

For free pdf paper visit:

http://www.jes2s.com/pdfs/Jan2012/Hypericum%20perforatum%20Extracts%20and%20Hypericin%20Treatment%20of%20a%20Mouse%20Mammary%20Cancer%20Cell%20Line%20Induces%20Growth%20Inhibition%20in%20a%20Dose%20Dependent%20Manner.pdf

Authors:

Ashley Ferguson1*, Caitlin Morris1*, and Jackie Curley2
Student1, Teacher2: The Loudoun County Academy of Science, Sterling VA
*these authors contributed equally.
*correspondence: ashleyferguson7@aol.com; camorris94@gmail.com

Hypericum perforatum, commonly known as St. John’s
Wort, has been found to exhibit many medicinal, especiallymore Hypericum perforatum, commonly known as St. John’s
Wort, has been found to exhibit many medicinal, especially
anti-depressant, properties. Hypericin is thought to be the
main chemical constituent responsible for H. perforatum’s
medicinal properties. We report here the ability of H.
perforatum and hypericin to inhibit the growth of mouse
mammary cancer CRL2539 cells. H. perforatum, at
concentrations of 0.4% and 0.8%, significantly (P<0.05)
inhibited cell growth in a concentration dependent manner.
Hypericin (purity 80-90%) at a concentration of 0.001%
also significantly inhibited cell growth but not to the extent
which the H. perforatum extracts did. In addition, H.
perforatum at a concentration of 0.8% inhibited cell growth
significantly more than H. perforatum at a concentration
of 0.4%. Our study shows a promising therapeutic strategy
in using the whole H. perforatum extract as its own form
of treatment to effectively slow the growth rate of cancer
cells, and potentially overcome the negative side effects
associated with current forms of cancer treatment.

Survivin is Essential for Efficient Cell Mobility and Proliferation in U87 and C6 Glioma Cells

by Ravi Dinakar

For FREE full pdf visit:

http://www.jes2s.com/pdfs/Jan2012/Survivin%20is%20Essential%20for%20Efficient%20Cell%20Mobility%20and%20Proliferation%20in%20U87%20and%20C6%20Glioma%20Cells.pdf

Authors:

Miguel Santiago Montana1* and Christine Marshall-Walker2
Student1, Teacher2: Phillips Academy Andover, 180 Main Street Andover, MA 01810
*Correspondence: m.montana@umiami.edu

Published in The Journal of Experimental Secondary Science (www.jes2s.com)

The BIRC5 gene, which codes for Survivin and is a member
of the Inhibitor of Apoptosis family, is activated in... more The BIRC5 gene, which codes for Survivin and is a member
of the Inhibitor of Apoptosis family, is activated in most
cancer cells including gliomas. The BIRC5 gene’s role in
cancer motility is not well understood. From the functions
of similar genes, like those in its family, it was hypothesized
that the gene would play an important role in cancer
motility as well as cancer proliferation1. The BIRC5 gene’s
importance in migration and proliferation was studied in
rat C6 and human U87 glioma cells. The gene’s importance
in migration was assessed by observing the migration
behaviors of four groups of cells: an experimental group
that was transfected with BIRC5 siRNA and permitted to
grow for one day after transfection, another experimental
group that was permitted to grow for two days after
transfection, and two corresponding control groups that
did not undergo RNAi of BIRC5 and were permitted to
grow for one and two days. The control groups exhibited
near-equal levels of migration when a migration assay was
performed. Both groups that underwent RNAi of BIRC5
showed impaired migratory ability. When proliferation
was analyzed for the same groups, the cells that underwent
RNAi showed diminished ability to reproduce and survive,
especially when they were plated at lower densities. These
results suggest Survivin is a promising drug target in the
control of glioma cell motility and proliferation.

The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity

by Victoria James

Super competition as a possible mechanism to pioneer precancerous fields

by Eduardo Moreno Lampaya

Is cell competition relevant to cancer?

by Eduardo Moreno Lampaya

Keratins in oral cancer: Necessity of mass spectrometry for validation of antibody based identifications

by Amit Fulzele

Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer

by Jalees Rehman

Published in the FASEB Journal

Mitochondria exist in dynamic networks that undergo fusion and fission. Mitochondrial fusion and fission are mediated... more Mitochondria exist in dynamic networks that undergo fusion and fission. Mitochondrial fusion and fission are mediated by several GTPases in the outer mitochondrial membrane, notably mitofusin-2 (Mfn-2), which promotes fusion, and dynamin-related protein (Drp-1), which promotes fission. We report that human lung cancer cell lines exhibit an imbalance of Drp-1/Mfn-2 expression, which promotes a state of mitochondrial fission. Lung tumor tissue samples from patients demonstrated a similar increase in Drp-1 and decrease in Mfn-2 when compared to adjacent healthy lung. Complementary approaches to restore mitochondrial network formation in lung cancer cells by overexpression of Mfn-2, Drp-1 inhibition, or Drp-1 knockdown resulted in a marked reduction of cancer cell proliferation and an increase in spontaneous apoptosis. The number of cancer cells in S phase decreased from 32.4 ± 0.6 to 6.4 ± 0.3% with Drp-1 inhibition (P<0.001). In a xenotransplantation model, Mfn-2 gene therapy or Drp-1 inhibition could regress tumor growth. The tumor volume decreased from 205.6 ± 59 to 70.6 ± 15 mm(3) (P<0.05) with Mfn-2 overexpression and from 186.0 ± 19 to 87.0 ± 6 mm(3) (P<0.01) with therapeutic Drp-1 inhibition. Impaired fusion and enhanced fission contribute fundamentally to the proliferation/apoptosis imbalance in cancer and constitute promising novel therapeutic targets.

Cancer Networks: A general theoretical and computational framework for understanding cancer

by Eric Werner

Published on arxiv.org Oct 26, 2011:
http://arxiv.org/abs/1110.5865

We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of... more We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of the architecture and function of developmental control networks which guide the formation of multicellular organisms. Cancer networks are special cases of developmental control networks. Cancer results from transformations of normal developmental networks. Our theory generates a natural classification of all possible cancers based on their network architecture. Each cancer network has a unique topology and semantics and developmental dynamics that result in distinct clinical tumor phenotypes. We apply this new theory with a series of proof of concept cases for all the basic cancer types. These cases have been computationally modeled, their behavior simulated and mathematically described using a multicellular systems biology approach. There are fascinating correspondences between the dynamic developmental phenotype of computationally modeled in silico cancers and natural in vivo cancers. The theory lays the foundation for a new research paradigm for understanding and investigating cancer. The theory of cancer networks implies that new diagnostic methods and new treatments to cure cancer will become possible.

Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility

by Mark Morris

Dewi Astuti & Mark R Morris, Wendy N Cooper,  Raymond H J Staals, Naomi C Wake,  Graham A Fews, Harmeet Gill,  Dean Gentle,  Salwati Shuib, Christopher J Ricketts, Trevor Cole,  Anthonie J van Essen, Richard A van Lingen,  Giovanni Neri,  John M Opitz, Patrick Rump, Irene Stolte-Dijkstra, Ferenc Müller, Ger J M Pruijn, Farida Latif & Eamonn R Maher

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated... more Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.

Microenvironmental regulation of stem cells in intestinal homeostasis and cancer

by Louis Vermeulen, MD PhD

Published in Nature, 2011

Nature. 2011 Jun 15;474(7351):318-26. doi: 10.1038/nature10212.

Medema JP, Vermeulen L.
more Nature. 2011 Jun 15;474(7351):318-26. doi: 10.1038/nature10212.

Medema JP, Vermeulen L.

Abstract
The identification of intestinal stem cells as well as their malignant counterparts, colon cancer stem cells, has undergone rapid development in recent years. Under physiological conditions, intestinal homeostasis is a carefully balanced and efficient interplay between stem cells, their progeny and the microenvironment. These interactions regulate the astonishingly rapid renewal of the intestinal epithelial layer, which consequently puts us at serious risk of developing cancer. Here we highlight the microenvironment-derived signals that regulate stem-cell fate and epithelial differentiation. As our understanding of normal intestinal crypt homeostasis grows, these developments may point towards new insights into the origin of cancer and the maintenance and regulation of cancer stem cells.

Luna, L., Aranda, C., Bosio, L. y M. Berón 2008. A case of multiple metastasis in late Holocene hunter-gatherers from argentine Pampean region. International Journal of Osteoarchaeology 18: 492-506.

by Leandro Luna