A new target which may be used in the therapy of neuroblastoma was identified by Scientists from University of Liverpool. This study could accelerate the development of new drugs against neuroblastoma. Their finding was published in Cancer Research.

Neuroblastoma is the most common extracranial solid tumor in children and a cancer that has a high potential to metastasize. In 40% of high-risk neuroblastoma cases, amplification of the MYCN (MYCN-A) oncogene has been found as the oncogenic event responsible for aggressive progression and poor clinic outcome. The machanisms by which MYCN promotes tumorigenesis are complex and linked primarily to its transcriptions activity,upregulating the expression of a large variety of genes involved in proliferation, survival, differentiation, DNA repair, drug resistance, and survival.

In this study, researchers have shown that altered expression of sulfotransferases in human neuroblastoma cells with higher levels of Sulf-2 expression, a specific feature of MYCN-amplified cells(MYCN-A cells) that represent a particularly aggressive subclass. Sulf-2 overexpression in neuroblastoma cells lacking MYCN amplification (MYCN-NA cells) increased their in vitro survival. They also confirmed , in two different patient cohorts, the association in expression patterns of Sulf-2 and MYCN and determined that Sulf-2 overexpression predicted poor outcomes in a nonidependent manner with MYCN.

This finding defines Sulf-2 as a novel positive regulator of neuroblastoma pathogenicity that contributes to MYCN oncogenicity.

Reference:

Solari V, Borriello L, Turcatel G, et al. MYCN-Dependent Expression of Sulfatase-2 Regulates Neuroblastoma Cell Survival[J]. Cancer research, 2014, 74(21): 5999-6009.

Scientists from the University of Texas MD Anderson Cancer Center have demonstrated that histone protein could play its role through the protein reader called YEATS. YEATS could be absorbed to the tail of histone protein and plays important role in gene activating. This study was published in Cell.

The histone proteins are subjected to a number of posttranslational modifications(PTMs) that play a critical role in regulating chromatin dynamics and the accessibility of the underlying DNA in eukaryotes. The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the understanding of protein modules known to recognize histone methylation, our knowledge of the protein modules that can recognize histone acetylation is very limited.

In this study, researchers have reported the discovery of the YEAS domains as a novel family of histone acetylation readers. They found that YEATS domains of AF9 from diverse species all bind to acetylation (H3K9ac). ChIP-seq experiments revealed a strong colocalization of AF9 and H3K9 acetylation genome-wide, which is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L.

Their studies also identified the evolutionarily conserved YEATS domain as a novel acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control.

Reference:

Li Y, Wen H, Xi Y, et al. AF9 YEATS Domain Links Histone Acetylation to DOT1L-Mediated H3K79 Methylation[J]. Cell, 2014, 159(3): 558-571.

Scientists from University of Oxford have indicated that a new-found anti-cancer protein named ASPPS could control and reverse epithelial cells’ changes of shape and motion state. This finding would be very important in the study of wound healing, embryonic development, and cancer metastasis. This study was published in Nature Cell biology.

Epithelial to mesenchymal transition(EMT) and the reverse, mesenchymal to epithelial transition(MET), provide cellular plasticity during development, wound healing and cancer metastasis. EMT is associated with enhanced cell migration and invasion and requires a disruption of apical-basal polarity and loss of E-cadherin expression. MET is required for nephrogenesis, and defects in MET result in kidney fibrosis. In addition, ASPP2 was first identified as a tumor suppressor and an activator of the p53 family. Its downregulation is associated with metastasis of human breast cancer and head and neck cancer, and poor prognosis in diffuse large B-cell lymphomas.

In this study, researchers have identified ASSP2 as a molecular switch of MET and EMT.ASPP2 contributes to MET in mouse kidney in vivo. Mechnistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin’s N-terminal phosphorylation to stabilize the β-catenin-E-cadherin ternary complex. ASSP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASSP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients.

Therefore, ASPP2 is a key regular of epithelial plasticity that connects cell polarity to the suppression of WNT signaling, and tumor metastasis.

Reference:

Wang Y, Bu F, Royer C, et al. ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1[J]. Nature cell biology, 2014.

Scientists have developed a way to identify important cancer mutations. This approach can mode the effects that cancer mutations have on the intricate patterns of communication between groups of proteins involved in cell signaling. Using this tool, researchers can get a better understanding of how mutations can alter signaling networks.

To find meaning in the rising oceans of genomic data, scientists, from the new Laboratory of Systems Pharmacology, have created multidimensional models and applied them to the genome-wide studies. The models show that specific mutations somehow alter the social networks of proteins in cells. From this they can deduce which mutations among the numerous mutations present in cancer cells might actually play a role in driving disease.

Find driver mutations

Many of the most widely studied cancer genes, such as P53 and Ras, were discovered after decades of work by many groups. But today, in the era of high throughput genomics, there are thousands of times more data than previously existed, showing that the sheer volume of catalogued cancer mutations is vast.

Not all mutations actually influence tumor behavior. In order to distinguish the drivers, researchers use a kind of “polling” strategy in which the most common mutations–deduced as the significant ones–can be identified. Only the most promising candidates are then subjected to the detailed analysis in the fields of cancer biomarker and molecular diagnostics.

For every common mutation, there are approximately four rare ones, so, based on numbers, rare mutations might be much more significant than previously suspected. Some researchers consider a large universe of rare mutations to be dark matter. a study, published in the journal Nature Genetics ,shows that all this dark matter actually matters.

The researchers found that mutations are not really the blunt force that they expected. An altered protein cause a subtle, almost surgically precise, altering of the communication pathway, rather than knocking out an entire branch of a network or inserting an entirely new character.

From the perspective of the mutation, it is hard to be so precise, but cancer can’t be too disruptive, or else it might die. This subtle altering of networks achieves that objective. Drug companies can exploit this and possibly develop more targeted therapies.

Reference:

A multiscale statistical mechanical framework integrates biophysical and genomic data to assemble cancer networks. Nature Genetics, 2014

A study, led by the UK Early Cancer Detection Consortium, reports that more than 800 markers in the blood of cancer patients that could help lead to a single blood test for early detection of many types of cancer in future.

This is the first time that cancer-specific blood markers have been comprehensively reviewed and identified for further clinical development. To find these markers, researchers analyzed 19,000 scientific papers and found the most promising molecular candidates.

The aim of this research is to develop a screening test from a single blood sample for multiple cancer types. Considering that all cancers produce markers in the blood, scientists believe it could be feasible to develop a general screening test for many different forms of the disease. After decades of study, they make it.

The innovative and promising approach, although in its early stages, can spot cancers earlier, offering options for curative treatment. Diagnosing cancer at an early stage generally means more effective treatment and that translates into better survival. The goal over the next 20 years is that three in four cancer patients will survive at least ten years after their diagnosis.

A researcher, engaged in this Study, said: “This is a new approach to early detection and the first time such a systematic review has been done. A single blood-based screening test would be a game changer for early detection of cancer which could help make it a curable disease for many more patients. We believe that we’ve identified all the relevant biomarkers; the next step is working out which ones work the best for spotting cancers.”

In the UK, cancer is most often detected after patients present symptoms to their doctor, with a small proportion being detected through any of the three national screening programmes for breast, bowel, and cervical cancer. This study could open the way for less invasive, new screening tests that could detect more cancers, possibly including some rare types, at an early stage when they are more likely to be treatable.

Reference:

A novel approach toward development of a rapid blood test for breast cancer. Clin Breast Cancer. 2003 Aug;4(3):203-9.

Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001216.

A new study, published in the journal Cancer Epidemiology, Biomarkers & Prevention, claims genomic sequencing could be useful for identifying women who are most likely to benefit from screening, and it could render an effective approach for women to decrease their risk of breast cancer.

Among American women, breast cancer is the second leading cause of death. This year see that about 232,000 women are diagnosed with invasive breast cancer, along with 40,000 lethal cases.

Early detecting for the disease would be helpful in reducing patient’s death rate, but screening approaches like mammography can sometimes produce inconsistent results.

Mammography , as the most common screening method for breast cancer, is not without its risk. It may produce false-positive results, meaning a woman may be subject to further treatment for no reason. On the other hand, it also show false-negative results, meaning a woman whose has breast cancer may fail to undergo treatment because her results appear normal.

More effective screening approaches are expected to discriminate between women who are high-risk or not. Genomic sequencing is more effective for disease prevention, in which specific genes linked to the disease are identified through searching small sections of DNA. Scientists found that the lifetime risk for the entire female population stood at 0.35, significantly higher than the 0.07 variance, via using such tool and 86 breast cancer gene variants.

These findings indicate that genomic sequencing has the potential to effectively predict a woman’s risk of breast cancer. It’s expected that preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected.

Reference:

The Role of Genome Sequencing in Personalized Breast Cancer Prevention. Cancer Epidemiol Biomarkers Prev. 2014 Oct 23

Wen Pan and colleagues have demonstrated that CSBF/C10orf99 inhibits colon cancer cell growth through inducing G1 arrest as a novel potential cytokine.

Cytokines are usually small secreted proteins with optimal activity at quite low concentrations and their functions are dependent on the binding of specific receptors. In the present study, they identified a novel potential cytokine CSBF/C10orf99 using immunogenomics. CSBF/C10orf99 is a classical secreted protein with a regular N-terminal signal peptide of 24 amino acids. SUSD2 is indispensable for the growth inhibitory effect of CSBF/C10orf99 on colon cancer cells and recombinant sSUSD2-Fc can block its function. CSBF/C10orf99 displays a bell-shaped activity curve and its optimal effect is about 10 ng/ml, which is in accordance with the characteristics of cytokines.

To our knowledge, this is the first systemic study of CSBF/C10orf99. The expressional and functional characteristics of CSBF/C10orf99 indicate it may be a tumor suppressor. Its gene is located on chromosome 10q23.1 beside the genomic region of tumor suppressor PTEN (10q23.3). Inactivation of TSGs through promoter methylation, gene mutation, or loss of heterozygosity is important for carcinogenesis. In human colon cancer cell lines, the expression of CSBF/C10orf99 cannot be restored by Aza or combined with TSA, which indicates that it is not regulated by promoter methylation. The mechanism underlying the down-regulation of CSBF/C10orf99 remains to be studied further. Possible roles for genetic and/or other epigenetic controls must be considered. The promoter of SUSD2 contains non-typical CpG islands, but it can be restored by Aza or combined with TSA, indicating that promoter methylation manipulates its expression directly or transcription factors regulating its expression are epigenetically regulated.

Intriguingly, higher expression of CSBF/C10orf99 and SUSD2 has also been detected in a few colon cancer samples (7/42 and 4/42), which is similar to the increased expression of tumor suppressor p16 in many malignant tumors. There are some possible mechanisms to elucidate why p16 overexpression occurs. On one hand, partial loss of p16 function due to missense mutations can be compensated by elevated expression as observed in some tumor specimens. On the other hand, in the presence of wild-type p16, other molecular events, such as over-expression of CDC6 and cyclin D1, or deregulation of Rb in tumor cells and cancer tissues have the potential to positively feedback p16 expression. Given these available mechanisms and our results, there might be some mutations of CSBF/C10orf99 and SUSD2, or other downstream molecules changing in the mentioned samples.

This study shows that CSBF/C10orf99 inhibits G1-S phase transition through down-regulating cyclin D and CDK6. G1-S phase transition is known to be a major checkpoint for cell cycle progression. It is necessary to identify the intracellular interacting proteins of SUSD2 and elucidate its mechanism on the modulation of cyclin D and CDK6 in the future study, which will be helpful to understand the pathogenesis of colon cancer.

Reference

Wen Pan, Yingying Cheng,etc. CSBF/C10orf99, a novel potential cytokine, inhibits colon cancer cell growth through inducing G1 arrest, Scientific Reports, 4, Article number: 6812 ︳doi:10.1038/srep06812

It is reported in this week’s Nature that scientists have successfully grown miniature stomachs in the lab from human stem cells, guiding them through the stages of development seen in an embryo. The lumps of living tissue, which are no bigger than a sesame seed, have a gland structure that is similar to human stomachs and can even harbour gut bacteria.

The study offers a window to how cells in human embryos morph into organs. Scientists say that these ‘gastric organoids’ could also be used to understand diseases such as cancer, and to test the stomach’s response to drugs.

In this study, the key to turning pluripotent stem cells into stomach cells was a pathway of interactions that acts as a switch between growing tissues in the intestine and in the antrum, a part of the stomach near its outlet to the small intestine.

When the stem cells were around three days old, researchers added a cocktail of proteins including Noggin, which suppresses that pathway, and timed doses of retinoic acid, a compound in vitamin A. After nine days, the cells were left to grow in a protein bath.

At 34 days though the resulting organoids were only a few millimetres in diameter and had no blood cells, immune cells, nor the ability to process food or secrete bile, they are remarkably similar to an actual stomach.

The researchers say that they can grow the stomach organoids from both embryonic stem cells and skin cells induced to pluripotency. Jason Mills, a gastrointestinal pathologist at Washington University School of Medicine in St. Louis, envisions growing thousands of such organoids, each from a different person’s cells, and infecting them with a pathogen to study the role of individual genetics.

Scientists from Queen’s University Belfast have reported a breakthrough on experimental physics, this finding demonstrates the mechanism in the process of killing cancer cells during chemotherapy. This study was published in Science.

The investigation of ultrafast processes in atoms received a major stimulus with the introduction of attosecond pulses in the extreme ultraviolet spectral region. In this study, researchers report the application of isolated attosecond pulses to prompt ionization of the amino acid phenylalanine and the subsequent detection of ultrafast dynamics on a sub-4.5-femtosecond temporal scale, which is shorter than the vibrational response of the molecule. They also present experimental evidence of ultrafast charge dynamics in the amino acid pheylanlanine after prompt ionization induced by isolated attosecond pulses.

The application of attosecond techniques to molecules offers the possibility of investigating primary relaxation processes, which invole electronic and nuclear degrees of freedom and their coupling.

The researchers hope to develop new chemotherapy for cancer treatment on the basis of this finding.

Reference:

Calegari F, Ayuso D, Trabattoni A, et al. Ultrafast electron dynamics in phenylalanine initiated by attosecond pulses[J]. Science, 2014, 346(6207): 336-339.

A study from University of California, Berkeley has indicated that the cytokine therapy could increase the capability of NK cell to kill MHC classⅠtumor cells. Their finding supports that cytokine therapy may be used in the treatment of patients whose tumor cells are lack of MHC class I molecules. This study was published on The Journal of Clinical Investigation.

Cytokines are powerful modulators of the immune system. Studies in mice have shown that cytokines can enhance the immune response to tumors and opened the possibility of using them as immunotherapeutic agents. Various cytokines have been evaluated as potential anticancer drugs, however , most cytokine trials have shown relatively low efficacy.

In this study, researchers have identified that the outcome of cytokine treatment of tumor-bearing mice largely depends on the level of expression of MHC classⅠmolecules on tumor cells, and is associated with the anergic state that NK cells acquire within such tumors. For the first time, they demonstrated that NK cell anergy is caused by impaired signal transduction and that activating cytokines can restore the full functionality of NK cells.

Their results indicate that such cytokine therapies would be optimized by stratification of patients. Further, the study suggests that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.

Reference:

Ardolino M, Azimi C S, Iannello A, et al. Cytokine therapy reverses NK cell anergy in MHC-deficient tumors[J]. The Journal of clinical investigation, 2014, 124(124 (11)): 0-0.