MicroRNA and cancer

MicroRNAs are 18 to 25 nucleotide, noncoding RNA molecules that have been found to regulate a wide variety of cellular processes. Unusual levels of varions miRNAs have been shown to be diagnostic of pathology in a number of different cancers, such as chronic lymphocytic leukemia, lung cancer and pancreatic cancer.

The first microRNA was discovered in 1993, in C. elegans, but the term microRNA was not introduced until 2001. It took seven years for the second miRNA to be found, also in C. elegans, but many others then followed. Over 500 microRNAs have been identified in the human genome. Over a third of the human genome appears to be regulated by miRNAs orginally found is some mammal or another.

In some cases, changes to gene expression caused by miRNA seem to promote cancer. But in other cases, a miRNA may repress genes that promote cancer or its metastasis.

The p53 anti-cancer gene is affected by some miRNAs, but we will cover that in a separate note. Some miRNAs also seem to be related to cancer stem cells, which is a large topic that merits broader coverage. (See here, here.)

We've already looked at one example (here, and see below) where a gene associated with cancer can affect levels of some miRNAs. Unlike most other findings, this is a case where cancer-related pathology seems to affect miRNA expression levels, rather than the reverse.

One miRNA, in particular, stands out for the variety of genes it may affect. This miRNA is let-7, and it is known to be expressed in the later stages of animal development. Some estimates put the number of human genes affected by let-7 in the hundreds, though most of those may not be related to cancers. Ras is an important cancer-related protein that is suppressed by let-7 (See here, here.) (This report has more on let-7. See also here, here, here, here.)

The miRNA miR-21 has been associated with cancers of the colon, liver, and thyroid.

It's difficult to summarize the following research findings – they involve a variety of cancer types and many different miRNAs. Unusually high or low levels of some miRNAs seem to promote cancer in some cases, but suppress cancer in others. MiRNAs also work in a variety of different ways to affect gene expression and protein activity.

This diversity of effects due to miRNAs may well be the most interesting current finding to come out of research in this area.

Molecules may help predict survival in liver cancer (1/30/08)

In a long-term study of patients with liver cancer, it was found that those with the poorest survival history also had lower levels of 19 specific microRNAs in cancer cells compared to nearby noncancer cells than did patients with significantly better survival. This result is out of a total of 196 different microRNAs whose levels were measured.

Expression Patterns Of MicroRNAs Appear Altered In Colon Cancer, And Associated With Poor Outcomes (1/29/08)

In one cohort of 84 patients with colon cancer 37 different microRNAs were differently expressed in cancer cells compared with noncancer cells. 5 of these miRNAs could reliably discriminate between tumorous and nontumor tissue. The same 5 miRNAs had similar discriminatory powers in a different cohort of 113 patients. For the specific miRNA known as miR-21, high expression levels were associated with poor survival outcomes in both patient cohorts. (High levels of miR-21 are also associated with thyroid cancer, see here, and with liver cancer, see here.)

Two MicroRNAs Promote Spread Of Tumor Cells (1/28/08)

MicroRNAs have been shown in many studies to block translation of tumor suppressor genes. In this study, two specific miRNAs (out of 450 tested) have been shown to transform non-invasive human breast cancer cells into cells that rapidly metastasized in cell cultures and laboratory mice. One of the miRNAs, miR-373, was previously identified as a possible oncogene in testicular cancer. The other miRNA, miR-520c, hasn't previously been associated with cancer, but is similar to miR-373. Both miRNAs are found only in cancer cells. There is evidence that they downregulate the CD44 gene, and that in turn leads to metastasis of non-metastatic tumor cells. In human patients, metastatic cells are found to have higher levels of miR-373 and lower expression of CD44 than non-metastatic tumor cells.

Molecules Might Identify High-risk Acute-leukemia Patients (1/15/08)

In a study of leukemia cells from 122 patients with high- and intermediate-risk acute myeloid leukemia (AML) the same miRNAs could be found in both normal and leukemic cells, but there were differences in levels of various miRNAs present. Two specific miRNAs (miR-191 and miR-199a) were present at abnormally high levels that were clearly associated with patient survival. The same two miRNAs have been previously found to be associated with cancers of the lung, prostate, colon, stomach and breast. Another miRNA (miR-155) was associated with a gene mutation, and high levels of it have been reported in other cancers (see here, here) and to cause leukemia in mice.

Small Molecule Can Prevent Spread Of Breast Cancer, Study Suggests (1/9/08)

Three miRNAs have been found that prevent breast cancer metastasis by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate. Researchers found lower levels of a few miRNAs (miR-335, miR-126 and miR-206) in metastatic cells compared to non-metastatic tumor cells. Testing in mice showed that raising levels of these miRNAs inhibited metastasis. Further analysis showed that miR-126 influences the proliferation rate of metastatic cells, while miR-335 and miR-206 influence the cancer cells' ability to migrate into lungs or bone. miR-335 was found to inhibit expression of SOX4 and TNC genes, which affect cell migration.

More: here, here

Virus Discovered Using Same Tools As Host Cell (12/17/07)

A microRNA expressed in the genome of the Kaposi's Sarcoma Associated Herpesvirus (KSHV) appears to be very similar in stucture and function to a miRNA associated with lymphoma – miR-155, mentioned above. KSHV itself causes a rare skin cancer that disproportionately affects HIV-infected individuals. Both miR-155 and the KSHV miRNA regulate the same genes, including several associated with B cell function and cell cycle regulation. Hence KSHV may promote B cell tumors by repressing one or more of these genes, as miR-155 seems to do.

Scientists Identify And Repress Breast Cancer Stem Cells In Mouse Tissue (12/17/07)

Since 2001 stem-like cells that appear to initiate cancer development have been discovered in breast, lung, brain and colon tissues, as well as in the blood. A microRNA (let-7) has now been found that can help to identify such cancer stem cells in breast cancer tissue of mice. Further tests indicate that let-7 can attack and eliminate these cancer progenitors.

MicroRNA Regulates Cancer Stem Cells: Could Lead To Treating Cancer As A Whole (12/13/07)

Another study involving the interaction of miRNA let-7 and cancer stem cells was conducted independently and published just before the one described above. In this study, researchers found a way to grow large quantities of tumor stem cells by growing human breast cancer cells in immunosuppressed mice. They found that these stem cells contained low amounts of several miRNAs, compared to more mature tumor cells or stem cells that had differentiated in culture. When let-7 was activated in these cells, they lost their ability to self-renew and began to differentiate. They also became less able to form tumors in mice or to metastasize. It appears that let-7 did this by switching off two cancer-related genes: the oncogene Ras, and HMG2A (see here, here).

Silencing Small But Mighty Cancer Inhibitors (12/10/07)

As discussed here, the important transcription factor Myc, which is overexpressed in many cancers, can also stop the production of at least 13 microRNAs. Some of these miRNAs have an inhibiting effect on cancer. In some cases re-introducing repressed miRNAs into Myc-containing cancer cells suppressed tumor growth in mice. So repression of miRNAs may be another pathway through which overexpression of Myc promotes cancer. The research involved lymphoma cells in mice, and showed that Myc repressed the miRNAs by directly attaching to the DNA at the miRNA genes.

Scientists discover new role for miRNA in leukemia (12/10/07)

A microRNA has been found to play a new role in the development of cancer, in this case chronic myeloid leukemia (CML). The miRNA is miR-328, and normally it is able to directly bind to a certain protein, inhibiting the activity of that protein. But if levels of miR-328 become abnormally low, the protein prevents white blood cells maturing as they should. The result is the build-up of immature white blood cells and entrance to what is called the "blast-crisis" phase of the disease.

Cellular Pathway Identified That Makes Prostate Cancer Fatal (11/27/07)

Expression levels of microRNAs were measured in samples of prostate cancer cells. Five different miRNAs were found to have unusual expression levels. One of these, miR-125b, was found at high levels in both androgen-dependent and the more dangerous androgen-independent prostate cancer cells.

Earlier research reports:

• MicroRNA Convicted Of Triggering Metastasis (9/26/07) – More: here – breast cancer, miR-10b
  
  
• Molecule Blocks Gene, Sheds Light On Liver Cancer (8/1/07) – liver cancer, miR-21
  
  
• New Genetic Marker Characterizes Aggressiveness Of Cancer Cells (6/25/07) – various cancers, let-7
  
  
• Tiny Genes May Increase Cancer Susceptibility, Scientists Find (5/23/07)
  
  
• Newly Identified Mechanism For Silencing Genes Points To Possible Anti-cancer Strategies (5/16/07)
  
  
• Pancreatic Cancer Markers Identified, May Predict Survival (5/1/07) – pancreatic cancer
  
  
• Biomarker Discovery Bodes Well For Better Cancer Diagnostics, Pharmacologist Says (5/1/07) – pancreatic cancer
  
  
• MicroRNAs Can Be Tumor Suppressors (4/25/07) – various cancers, let-7
  
  
• Leukemia Drug Turns Mini-molecules Up, Cancer Genes Down (3/2/07) – leukemia, miR-15b, miR-16-1, let-7
  
  
• MicroRNA Helps Prevent Tumors (2/22/07) – various cancers, let-7
  
  
• Micro Molecules Can Identify Pancreatic Cancer (1/10/07) – pancreatic cancer
  
  
• Pair Of MicroRNA Molecules Controls Major Oncogene In Most Common Leukemia (12/15/06) – leukemia, miR-29, miR-181 – more on miR-29 here
  
  
• MiRNA Fingerprint Identified In Platelet Formation (3/16/06) – leukemia
  
  
• Role Of MicroRNA Identified In Thyroid Cancer (12/23/05) – thyroid cancer, miR-21, miR-146, miR-181a, miR-221, miR-222
  
  
• Unusual RNAs Linked To Chronic Leukemia, May Help Treat It (9/18/05) – leukemia, miR-15, miR-16
  
  
• Yale Scientists Find MicroRNA Regulates Ras Cancer Gene (3/25/05) – lung cancer and others, let-7
  
  
• Small Molecule May Help Pinpoint Some Cancers (3/9/05) – lymphoma, miR-155
  

Tags: cancer, microRNA, cancer stem cell

Histone deacetylase enzymes

You don't often hear histone deacetylase (HDAC) enzymes being discussed in ordinary conversation at cocktail parties or around the water cooler – unless perchance you stumble into a conversation among biomedical researchers.

But that might change a bit sometime in the not too distant future. HDAC and HDAC inhibitors are increasingly one of the "hot" topics in cancer research, and their importannce is now leaking out into a variety of disparate areas of biomedicine. There are even connections with other trendy topics, such as the SIR2 "longevity gene" and the NF-κB transcription factors.

Perhaps I should back up a moment and say a few words about histones and histone deacetylases. As you know, DNA generally does not float around all by itself inside a cell. With about 3 billion base pairs, human DNA, simply in order to fit into a cell in an orderly way, needs to be kept most of the time in a very compact form within the 23 chromosome pairs. The material making up chromosomes is called chromatin, which is made up of protein complexes called nucleosomes, around which the DNA is wound. Each nucleosome in turn is made up mostly of a core containing 8 histone proteins of several different types.

This arrangement has important implications for gene expression, because genes that occur in a portion of DNA that is wrapped tightly around a nucleosome are not readily available for translation into messenger RNA, which determines when and how proteins corresponding to the gene can be constructed. However, when an acetyl group is attached to one or more histones of a nucleosome, the DNA becomes less tightly bound, so that its genes can be more easily expressed.

Conversely, removing acetyl groups that may be attached to histones of the nucleosome largely inhibits access to the genes, effectively "silencing" them. A histone deacetylase is an enzyme that removes acetyl groups, so it is a mechanism for silencing groups of genes. About 11 HDACs (depending on how one counts) are known in higher eukaryotic cells.

This gene silencing is anything but a trivial function. For example, the proteins Sirtuin and Sir2 (Sirt1 in mammals), variations of which are found in most eukaryotic cells and are known to be involved with aging, are HDACs. On the other hand, cancer tumors frequently take advantage of HDACs to silence genes that would otherwise promote cancer cell death.

Because of the role of HDACs in cancer, an inhibitor of an HDAC is a potential anti-cancer drug. As we will see, there are a number of these now in clinical trials to fight various cancers – and one has even been approved by the FDA for use (Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA)).

For a great source of technical information on HDACs, especially in relation to cancer, check here.

Following are some research announcements pertaining to HDACs. They are mostly recent, and have been appearing at an increasing rate. Note how some of the most recent ones are in areas well outside of oncology.

Future Therapies For Stroke May Block Cell Death (6/14/07)

Substantial neurological damage occurs in strokes and neurodegenerative diseases like ALS, Parkinson's, and Huntington's. Researchers suspect that there are neuroprotective proteins whose expression could be increased to limit cell death if an inhibitor for the appropriate HDAC can be found.

At Penn, 'tantalizing' finds in cell research (6/14/07)

There are various neurodegenerative diseases which involve damaged or misfolded proteins that are toxic to cells. There is a mechanism called autophagy that is capable of disposing of such proteins, but it does not work fast enough in the presence of disease. Researchers have found that HDAC6 can facilitate autophagy and mitigate disease in a fruit fly model.

Gene Switched Off In Cancer Can Be Turned On, Researchers Discover (6/12/07)

A gene whose protein controls cell growth, called Brahma or BRM, is silent but not missing or mutated in some cancer cells. It is turned off in about 15 percent of tumors studied, including cells from lung, esophageal, ovarian, bladder, colon and breast cancers. HDAC inhibitors were found that could undo the silencing of the gene.

Cancer Drug Enhances Long-term Memory (6/6/07)

In a study with mice, researchers have shown that HDAC inhibitors together with a protein called CBP can enhance memory and actually strengthen neural connections in the hippocampus. CBP is known to relax chromatin, making gene expression easier in affected portions of DNA. Presumably the HDAC inhibitors prevent undoing the effect of CBP. Use of HDAC inhibitors alone did not have an effect on memory. If this effect exists in humans, CBP and HDAC inhibitors could be a therapy for people with Alzheimer's and Huntington's diseases and Rubenstein-Taybi syndrome.

Vorinostat Shows Anti-cancer Activity In Recurrent Gliomas (6/5/07)

Vorinostat is the first FDA approved oral anti-cancer agent that is an HDAC inhibitor. It has been shown to be effective as a treatment for cutaneous T cell lymphoma. This study indicates it also shows activity in patients with recurrent glioblastoma multiforme.

Eat Your Broccoli: Study Finds Strong Anti-Cancer Properties In Cruciferous Veggies (5/18/07)

Cruciferous vegetables such as broccoli, bok choy, and brussels sprouts contain significant amounts of sulforaphane, which has noteworthy anti-cancer properties. This research suggests that cruciferous vegetables have HDAC inhibiting effects, which might explain their anti-cancer properties.

Healthy Muscles: Scientists Identify Pathway That Promotes Muscle Cell Survival In Mice (5/1/07)

Mice genetically engineered with a defective protein called cAMP responsive element binding protein (CREB) have poorly developed muscles. This appears to be related to lack of inhibition of a specific HDAC enzyme when CREB is defective. Investigation revealed that production of an enzyme called salt-inducible kinase-1 (SIK1) is also inhibited in the presence of defective CREB. SIK1 was found to phosphorylate the HDAC protein, which inhibits its histone deacetylation capability. Further experimentation showed that raised SIK1 levels or use of other inhibitors of the HDAC enzyme also restored muscle cell health in the mice with defective CREB. The findings may lead to treatments for diseases that affect cell survival, such as muscular dystrophy, neurodegenerative diseases, and congestive heart failure.

Novel Drug Shows Potential For Treating Leukemia (4/21/07)

HDAC inhibitors, when used in combination with an experimental proteasome inhibitor drug, NPI-0052, were more effective at inhibiting the main enzymatic activity of the proteasome than NPI-0052 alone. Either alone or in combination NPI-0052 was much more effective than bortezomib (marketed as Velcade), the only FDA-approved proteasome inhibitor. Proteasomes clean out mutated or damaged proteins within cells, but in cancer cells this allows unwanted cell growth and reproduction. Proteasome inhibitors block this process, resulting in apoptosis of the malignant cells. Although bortezomib is effective for treating multiple myeloma and mantle cell lymphoma, it is ineffective by itself against leukemia, so NPI-0052 may be a good alternative.

Scientists Induce Cell Death In Leukemia (4/17/07)

The proteasome inhibitor bortezomib when used in combination with either of two HDAC inhibitors (romidepsin and belinostat) was shown in preclinical tests to be very lethal to cultures of human chronic lymphocytic leukemia cells. Other preclinical and clinical data suggest similar synergistic effects of bortezomib in additional cancer cell types.

Treatment Extends Survival In Mouse Model Of Spinal Muscular Atrophy (2/23/07)

Spinal muscular atrophy (SMA) is the most common severe hereditary neurological disease of childhood and is usually fatal. SMA is caused by mutations in a gene called SMN1. A related gene called SMN2 can sometimes produce the SMN protein, but in very small amounts. A drug called trichostatin A (TSA) is a potent HDAC inhibitor that is an antifungal antibiotic and has been found capable of increasing SMN protein production from the SMN2 gene in a mouse model and in cells from SMA patients. Improved survival was observed in the mouse model of SMA.

Two Drugs May Stabilize Plaques In Atherosclerosis (11/15/06)

An anti-fungal drug and an anti-cancer drug – TSA and SAHA (see references elsewhere in this report) – have been reported to decrease cholesterol deposits in the walls of arteries. In this case, the drugs appear to have an anti-inflammatory mechanism. The two compounds decreased inflammatory proteins produced by macrophages taken from normal mice. Such inflammatory proteins can make atherosclerotic plaque unstable. After the macrophages were treated with either TSA or SAHA, dramatic decreases were measured in LDL and total cholesterol in the macrophages. In addition, the drugs prevented macrophages from turning into foam cells inside arterial walls,

Researchers Make Advances In Attacking Leukemia Cells (10/21/05)

This somewhat older research demonstrated that in leukemia cells, HDAC inhibitors also induce changes in a master regulatory protein known as NF-κB, which is involved in regulation of inflammation, cell survival and many other functions. It was found that NF-κB inhibitors dramatically increased the lethality of HDAC inhibitors in various leukemia cell types. Such inhibitors are the subject of great interest as potential anti-inflammatory agents for use in various disorders, such as arthritis and inflammatory bowel disease. The research suggests they may also be valuable in enhancing the antileukemic efficacy of HDAC inhibitors, which have already shown antileukemic activity on their own.

MIT Researchers Uncover New Information About Anti-Aging Gene (2/18/00)

This is old and now well-known research by Leonard Guarente and associates, showing that an anti-aging gene, called Silent Information Regulator (SIR2), is an enzyme – specifically an HDAC enzyme. As such, SIR2 can silence genes in whole sections of a genome. As cells age, problems such as genome instability and inappropriate gene expression surface as genes that had always been turned off sometimes get turned on. SIR2 may forestall such age-related problems, which can lead to cell death. The research team found that yeast cells with an extra copy of SIR2 live longer, while yeast cells without SIR2 have a shorter lifespan. The connection with metabolism (and hence caloric restriction) may stem from a co-enzyme, called nicotinamide adenine dinucleotide (NAD), that is related to metabolism and is required for SIR2 to be activated.

Tags: histone deacetylase, cancer, inflammation, molecular biology, gene expression.

News dump: inflammation

I've already done one news dump on the subject of inflammation (here), and there's been a lot of interesting stuff since then. This is just the first installment of new stuff, in reverse chronological order.

Schizophrenia may be linked to inflammation: study (3/21/07)

Many patients with schizophrenia also have autoimmune diseases. Using a technique called whole genome association researchers have located a gene variant common to many schizophrenics. The variant is located close to genes that produce receptors for two cytokines, which are immune system signals whose production is a first step in causing inflammation. Although the result is intriguing, the evidence for a relation to inflammation is still circumstantial.

Why Aerobic Exercise Is Good For The Heart (3/21/07)

The biological mechanisms connecting exercise and cardiovascular health are not fully understood. This study shows how exercise decreases inflammation, which reduces the risk of atherosclerosis, which in turn causes most cases of heart disease. Blood samples were taken from experimental volunteers before and after aerobic exercise. The samples were stimulated with an infectious agent and then analyzed for levels of tumor necrosis factor (TNF), an initial step in the inflammatory cascade. Substantially lower levels of TNF were found after aerobic training

Inflammation May Play Role In Metastasis Of Prostate Cancer (3/19/07)

This research strongly suggests that inflammation associated with the progression of tumors plays a key role in the metastasis of prostate cancer. It appears that inflammation in the tumor may lead to production of a cytokine called RANK. This eventually results in turning down the expression of a gene called Maspin, which has well-established anti-metastatic activity in breast and prostate cancers.

Researchers Identify Molecular Basis Of Inflammatory Bowel Disease (3/15/07)

The category of inflammatory bowel diseases includes Crohn's disease and ulcerative colitis. A likely molecular basis for such diseases has been identified in a mouse model. It appears that there is an underproduction of the signaling molecule NF-kB, which helps cells cope with stress, in the intestinal epithelium. With insufficient NF-kB, epithelial cells are more likely to die, and as a result bacteria can penetrate the epithelium. This results in activation of the intestinal immune system, producing a strong immune response and inflammation. The inflammation leads to death of more epithelial cells due to lack of NF-kB, perpetuating the cycle.

Obstructive Sleep Apnea Patients Show Silent Brain Infarction Lesions (3/15/07)

Patients with sleep apnea often have high levels in their blood of inflammatory markers. Cardiovascular disease is commonly characterized by ongoing inflammatory responses that can enhance blood platelet activation and increase the risk of silent brain infarction (stroke). Treatment of patients with obstructive sleep apnea using devices to create positive airway pressure led to lower blood levels of C-reactive protein and levels of two markers of platelet activation, suggesting that the apnea played a causal role in inflammation.

Belly Fat May Drive Inflammatory Processes Associated With Disease (3/14/07)

This research strongly suggests that visceral fat present in significant amounts surrounding organs in the midsection of the body may be a major source of inflammatory molecules. The resulting inflammation is suspected to play an important role in diseases such as insulin resistance, hypertension, type 2 diabetes, and atherosclerosis, and possibly Alzheimer's, cancer, and general aging. The study was done by analyzing blood taken from the portal vein (which drains organs surrounded by visceral fat) during gastric bypass surgery. Elevated levels of the inflammatory cytokine IL-6 were found, along with higher levels of C-reactive protein.

C-Reactive Protein Liver Protein Induces Hypertension, Researchers Find (2/22/07)

Researchers claim to have found that C-reactive protein is not merely a marker of the risk of hypertension, it actually induces hypertension. Using a mouse model having an engineered gene for CRP that was regulated by another gene responsive to carbohydrate in the diet, the researchers determined that raising CRP levels increased blood pressure, while lowering CRP levels lowered blood pressure. (It has been known for some time that high CRP levels are correlated with risk of hypertension and atherosclerosis.) Further investigation showed that the experimental mice were highly sensitive to the blood pressure regulating protein angiotensin II, and this was due to alterations in key proteins in the vascular wall that are involved with angiotensin II. The mechanism involves a lack of nitric oxide in the artery wall, and a connection was found between nitric oxide and proteins responsible for angiotensin II activity. Remaining to be shown is whether the same mechanism operates in humans.

Inflammatory Genes Linked To Salt-sensitive Hypertension (12/30/06)

A team of researchers is investigating interrelations among genetic variations, stress, inflammation, and hypertension. One hypothesis is that sodium handling goes awry because of mutations in genes for the inflammation-related proteins IL-6, IL-6 receptor, cytokine signal transducer, and C-reactive protein. Stress is involved because of a suspicion that the connection between stress, inflammation and hypertension is the kidneys’ ability to release sodium. When stress activates the sympathetic nervous system, the body increases production of IL-6, which ultimately leads to production of other inflammatory factors such as CRP. Stress also prompts the body to hold onto sodium to help temporarily raise blood pressure in order to deal with the situation.

Tags: inflammation, immune system, cancer, hypertension, obesity, C-reactive protein, cardiovascular disease, diabetes, insulin resistance

News dump: the Wnt signaling pathway

Here's one of the interesting things about biology: sometimes small number of genes, present in a large number of animal species, can affect a very diverse range of biological processes – including a number we'd like to have better control over.

In this case, we're concerned with a family of about 19 related genes, called Wnt. Genes of this family code for proteins that are important in embryonic development. They also play an important role in the regeneration of body parts, in those species where such regeneration has been known to be possible – and perhaps someday even in humans.

Here are some recent news releases on the topic, most recent first.

Rare Mutation Causes Early Heart Disease And Metabolic Syndrome (3/14/07)

A very rare mutation of the LRP6 gene, whose protein affects the Wnt signaling pathway, has been found to cause high rates of early-onset coronary artery disease in a family that carries the mutation. Family members having the mutation were also at greater risk for other components of metabolic syndrome, as well as osteoporosis.

How Does A Zebrafish Grow A New Tail? The Answer May Help Treat Human Injuries (12/28/06)

Signaling pathways involving various Wnt proteins and Beta-catenin have been shown to control the regeneration of the fins of zebrafish. Some Wnt/Beta-catenin signals promote fin regeneration. A different pathway involving Wnt5b inhibits regeneration so it doesn't get out of hand. But a mutant form of Wnt5b speeds up regeneration, while an excess of Wnt8 also increases cell proliferation.

Researchers Discover Initial Steps In Development Of Taste (12/6/06)

Researchers have shown that Wnt signaling pathways regulates the development of taste buds in mice. They have also determined that Wnt proteins are required for hooking up the wiring of taste signals to the brain.

Control Mechanism For Biological Pattern Formation Decoded (11/30/06)

Using a mathematical model based on protein reactions and diffusions, researchers have been able to explain the dynamics and parameters of hair formation in mice, based on Wnt signaling.

Scientists Regenerate Wing In Chick Embryo (11/19/06)

This research provides direct evidence that limb regeneration in (some) vertebrates is affected by the Wnt signaling system. By activating Wnt signaling scientists were able to stimulate wing regeneration in chick embryos (where it does not normally occur), and by deactivating Wnt signaling in frogs, zebrafish, and salamanders it was possible to prevent regeneration of missing legs and tails.

Adult Stem Cells May Be Just Remnants Of Evolution (11/2/05)

At least some adult stem cells could be the mere remnants of former embryonal differentiation processes. In this research mesenchymal stem cells of mice we stimulated by Wnt signaling, but their transformation into muscle cells was not complete.

Wnt Signaling Controls The Fate Of Stem Cells In Adult Brains (10/31/05)

The Wnt3 protein affects whether neural stem cells in mice, upon division, continue as stem cell, become neurons, or become support cells, such as astrocytes or oligodendrocytes.

Prostate Cancer Uses Wnt Signaling Proteins To Promote Growth Of Bone Tumors (9/7/05)

Some Wnt proteins play a central role in regulating normal skeletal development in an embryo, but they may also be hijacked by prostate cancer cells to spread the cancer into bone tissue.

Mice With Hyperactive Gene Eat All They Want, But Have Half The Body Fat Of Normal Mice (6/30/04)

When the protein Wnt10b is present in artificially high amounts in fat tissue of experimental mice, the mice appear to be able to eat as much as they like without an increase in body fat.

Tags: Wnt signaling, regenerative medicine

News dump: inflammation

I've been collecting news stories on a variety of interesting topics, but don't quite have the time to discuss all of them right away. So what I'll do is put up the list with short summaries. And hope to come back with more details later. It's sort of like spring cleaning time.

First up: inflammation. It's one of the still not well understood "features" of our complex immune system.

Inflammation and cancer

February 20, 2007 – Antibody signal may redirect inflammation to fuel cancer

The body's normally protective inflammation response can drive some precancerous tissues to become fully malignant. The inflammation apparently stimulates B cells to send signals that trigger progams for stimulating cancerous cell growth and increased blood supply to tumors.

January 25, 2007 – Molecular Link Between Inflammation And Cancer Discovered

There is much evidence that chronic inflammation can promote cancer, but the cause of this relationship is poorly understood. New research shows a linkage, involving the protein called p100, between cellular pathways for response to infection and cellular growth.

December 21, 2006 – What Cures Your Aches Might Prevent Cancer: Seeking To Prevent Cancer Using Anti-inflammatory Medication

Some of the same biological processes that cause inflammation may also be involved in developing cancer. This suggests investigating whether drugs that prevent inflammation also serve to lessen the risk of cancer. Attention is focused on nonsteroidal anti-inflammatory drugs like aspirin.

April 4, 2006 – Inflammation and Drugs to Control this Activity Studied in a Variety of Tumor Sites

Several studies presented at the 97th Annual Meeting of the American Association for Cancer Research show a relationship between chronic inflammation and cancer. The COX-2 enzyme, produced as part of the inflammatory response, seems to be associated with development of some types of cancer. Drugs that inhibit COX-2 (nonsteroidal anti-inflammatory drugs) may also inhibit cancer.

March 29, 2006 – Studies link cancer, inflammatory disease

The tumor necrosis factor (TNF) protein, which is involved in an inflammatory response, normally promotes death of damaged or infected cells, but overproduction can lead to automimmune diseases like rheumatoid arthritis. TNF may also stimulate production of the epidermal growth factor (EGF) protein, which may lead to tumor growth. So drugs that inhibit excessive TNF production may help inhibit cancer.

Inflammation and cardiovascular disease

March 4, 2007 – Treatment For Gum Disease Could Also Help The Heart

Periodontitis is a common inflammatory disease of the gums, caused by bacterial infection of gum tissue. This clinical trial is the first to demonstrate that relief of inflammation in the mouth, through intensive treatment of periodontitis, results in improved function of the arteries. The mechanism by which periodontitis affects endothelial function in the body is still uncertain. The periodontitis might trigger a low grade inflammatory response throughout the body that has a detrimental effect on the vascular wall.

February 22, 2007 – C-Reactive Protein Liver Protein Induces Hypertension, Researchers Find

Research with genetically engineered mice has shown that artificially elevated levels of C-reactive protein (CRP), normally a marker of inflammation, lead directly to higher blood pressures. It was found that the initiating mechanism is a lack of the nitric oxide in the artery wall. The lack of nitric oxide affected proteins responsible for activity of angiotensin II, which regulates blood pressure via arterial constriction.

December 30, 2006 – Inflammatory Genes Linked To Salt-sensitive Hypertension

Inflammation, a part of the immune response implicated in diseases such as cancer, Alzheimer’s and diabetes, may also help translate stress into high blood pressure. When stress activates the sympathetic nervous system, the body increases production of interleukin 6, a pro-inflammatory factor, which ultimately leads to production of other inflammatory factors such as C reactive protein. There is evidence suggesting that in salt-sensitive hypertension there are increased levels of inflammation factors such as interleukin 6 and C-reactive protein.

May 5, 2006 – Periodontitis May Increase C-reactive Protein Levels In Pregnancy

Pregnant women with periodontitis had 65 percent higher C-reactive protein (CRP) levels compared to periodontally healthy women. CRP levels are a marker of systemic inflammation and are associated with periodontal disease. CRP could amplify the inflammatory response. Alternatively, periodontal disease and CRP may share a common risk factor for predisposing individuals to a hyperinflammatory response.

Inflammation and obesity

February 19, 2007 – Obesity Finding: Chemical Pathway Causes Mice To Overeat And Gain Weight

"Knockout" mice bred to lack what is known as an E3 receptor cannot process prostaglandin E2, which is normally produced in the context of inflammation. Such mice, apparently as a consequence, do not develop a fever response. They also tend to overeat and accumulate body fat. It may be that an inability to respond to inflammation inhibits mechanisms which would otherwise control overeating.

April 10, 2006 – Research Provides Clues To Obesity's Cause And Hints Of New Approach For Curbing Appetite

New research suggests obesity is due at least in part to an attraction between leptin, the hormone that signals the brain when to stop eating, and C-reactive protein, which has been associated with heart disease. CRP not only binds to leptin but it impairs leptin's role in controlling appetite. Since fat cells produce CRP, these results may help explain why obese people have so much trouble controlling appetite and losing weight.

March 10, 2006 – Research Shows Fat Fuels Inflammation Killer

The protein sE-selectin is produced in response to inflammation in the walls of arteries. It is measured in greater amounts in people who have higher levels of body fat, indicating a higher level of inflammation in their arteries. It is known that such inflammation can directly trigger thrombosis, heart disease, strokes and diabetes.

September 16, 2005 – First Link Found Between Obesity, Inflammation And Vascular Disease

This research shows that human fat cells produce C-reactive protein (CRP), which is linked to both inflammation and an increased risk of heart disease and stroke. It would explain why higher levels of CRP are measured in overweight individuals, and why such individuals have a higher risk of cardiovascular problems. This study is the first to show how body fat participates in the inflammatory process that leads to cardiovascular disease.

Tags: inflammation, immune system, cancer, hypertension, obesity, C-reactive protein, cardiovascular disease