Competing financial interests
The authors declare no competing financial interests.
International Team Reports on Large-Scale Pancreatic Cancer Analysis
NEW YORK (GenomeWeb News) – A whole-exome sequencing and copy number variation study of pancreatic cancer published online today in Nature suggests that the disease sometimes involves alterations to genes and pathways best known for their role in axon guidance during embryonic development.
The work was conducted as part of the International Cancer Genome Consortium effort by researchers with the BCM Cancer Genome Project, the Australian Pancreatic Cancer Genome Initiative, and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study.
As they reported today, the investigators identified thousands of somatic mutations and copy number alterations in pancreatic ductal adenocarcinoma cancer, the most common form of pancreatic cancer. Some of the mutations affected known cancer genes and/or pathways implicated in pancreatic cancer in the past. Other genetic glitches pointed to processes not previously linked to the disease including mutations to axon guidance genes such as SLIT2, ROBO1, and ROBO2.
“This is a category of genes not previously linked to pancreatic cancer,” Baylor College of Medicine researcher William Fisher, a co-author on the new paper, said in a statement. “We are poised to jump on this gene list and do some exciting things.”
Pancreatic cancer is among the deadliest types of cancer, he and his colleagues explained, with a grim five-year survival rate of less than 5 percent. But despite its clinical importance, direct genomic studies of primary tumors had been stymied in the past due to difficulties obtaining large enough samples for such analyses.
“Genomic characterization of pancreatic ductal adenocarcinoma, which accounts for over 90 [percent] of pancreatic cancer, has so far focused on targeted polymerase chain reaction-based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines,” the study authors noted.
“A deeper understanding of the underlying molecular pathophysiology of the clinical disease is needed to advance the development of effective therapeutic and early detection strategies,” they added.
For the current study, researchers started with a set of tumor-normal samples from 142 individuals with stage I or stage II sporadic pancreatic ductal adenocarcinoma. Following a series of experiments to assess tumor cellularity and other features that can impact tumor analyses, they selected 99 patients whose samples were assessed in detail.
For whole-exome sequencing experiments, the investigators nabbed coding sequences from matched tumor and normal samples using either Agilent SureSelectII or Nimblegen capture kits before sequencing the exomes on SOLiD 4 or Illumina sequencing platforms. They also used Ion Torrent and Roche 454 platforms to validate apparent somatic mutations in the samples.
For its copy number analyses, meanwhile, the team tested the pancreatic cancer and normal tissue samples using Illumina HumanOmni1 Quad genotyping arrays.
When they sifted through data for the 99 most completely characterized pancreatic tumors, researchers uncovered 1,628 CNVs and roughly 2,000 non-silent, somatic coding mutations. More than 1,500 of the non-silent mutations were subsequently verified through additional sequencing experiments.
On average, each of the tumors contained 26 coding mutations. And despite the variability in mutations present from one tumor to the next, researchers identified 16 genes that were mutated in multiple tumor samples.
Some were well-known cancer players such as KRAS, which was mutated in more than 90 percent of the 142 pancreatic tumors considered initially. Several other genes belonged to cell cycle checkpoint, apoptosis, blood vessel formation, and cell signaling pathways, researchers reported, or to pathways involved in chromatin remodeling or DNA damage repair.
For example, some 8 percent of tumors contained mutations to ATM, a gene participating in a DNA damage repair pathway that includes the ovarian/breast cancer risk gene BRCA1.
Genes falling within axon guidance pathways turned up as well. That pattern was supported by the researchers analyses of data from published pancreatic cancer studies — including two studies based on mutagenesis screens in mouse models of the disease — and by their own gene expression experiments in mice.
The team also tracked down a few more pancreatic ductal adenocarcinoma cases involving mutations to axon guidance genes such as ROBO1, ROBO2, and SLIT2 through targeted testing on 30 more pancreatic cancer patients.
The findings are consistent with those found in some other cancer types, according to the study’s authors, who noted that there is evidence indicating that some axon guidance components feed into signaling pathways related to cancer development, such as the WNT signaling pathway. If so, they explained, it’s possible that mutations to axon guidance genes might influence the effectiveness of therapies targeting such downstream pathways or serve as potential treatment targets themselves.
Still, those involved in the study cautioned that more research is needed not only to explore such possibilities but also to distinguish between driver and passenger mutations in pancreatic cancer.
“The potential therapeutic strategies identified will … require testing in appropriate clinical trials that are specifically designed to target subsets of patients stratified according to well-defined molecular markers,” the study’s authors concluded.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette