Archive for ‘Cancer’

November 13, 2011

Learning why BRCA1 mutations lead to breast cancer

BRCA1 is a gene whose name is among the most familiar to the general public of all genes – for the unfortunate reason that mutations of BRCA1 are associated with significantly increased hereditary risk for breast cancer (as the name suggests). Strangely, however, it’s still not known exactly how mutations of BRCA1 confer this greater risk for cancer. But recent research has narrowed down the possibilities.

The protein that the gene codes for, BRCA1, is a fairly long chain of 1863 amino acids. BRCA1 is known to be involved in repair of damaged DNA. If BRCA1 is defective (due to a gene mutation), the failure to properly repair DNA (which can become damaged for many possible reasons) can lead to a cell becoming cancerous.

Previous research has identified around 1500 different mutations of BRCA1 associated with cancer risk. But most of these mutations directly affect the amino acids of only two different regions of BRCA1. Every protein has an amine group at one end of its chain and a carboxyl group at the other end. One of the two regions in which mutations lead to cancer is at the amino end and is called the “RING domain”. The other region, near the carboxyl end, is called BRCT (BRCA1 carboxyl-terminal tandem repeats).

The RING domain is known to have a role in the process that attaches a marker called ubiquitin to a protein in order to identify the protein as ready for recycling. The BRCT region is associated with the process of protein phosphorylation, which is a key element of chemical signaling within cells. What hasn’t been known is what aspects of DNA repair are disrupted by defects in one or both of these regions.

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November 10, 2011

Controlling cancer cells by weakening their defense against reactive oxygen species

Reactive oxygen species (ROS, sometimes loosely referred to as “free radicals”) are generally harmful to cells. Persistent high levels of ROS may damage cells and, eventually, cause cancer. But ROS are also harmful to cancer cells – which, therefore, often develop means of defending themselves against ROS.

Shielding Cancer Cells from Damage

By activating an enzyme involved in the breakdown of glucose, researchers were able to slow the growth of lung cancer cells and increase the harm inflicted by reactive oxygen species (ROS)—byproducts of normal metabolism that can cause damage to the cell in high concentrations. The findings, published Thursday (November 3) in Science Express, could one day be used to make cancer cells more susceptible to cancer treatments and minimize tumor growth.

It’s long been known that cancer cells often have an alternate form of the enzyme pyruvate kinase M1 (PKM1) – PKM2. The new research shows why this is: cancer cells can control the activity of PKM2, which is not possible with PKM1, and this control helps them defend against ROS. Cancer cells need such a defense, because their metabolism differs from normal cell metabolism and is more active, tending to result in higher ROS levels.

The way this works is that both PKM1 and PKM2 play an important role in the glycolysis process, which metabolizes glucose. Glutathione is an antioxidant molecule that can help neutralize ROS. But it also participates in glycolysis, which diverts it from acting as an antioxidant. Cancer cells favor PKM2 over PKM1, because they can lower its level of activity, and therefore leave more glutathione available for antioxidant work.

The researchers equipped cancer cells with a mutant form of PKM2 that, like PKM1, the cells could not control. Such cells were found to sustain more damage from ROS. And when altered cells were implanted in mice, they grew smaller tumors than unmodified cancer cells.

There are fairly obvious ways that these findings may help develop better cancer therapies.

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September 28, 2011

Blood Pressure Drugs May Lengthen Lives of Some Cancer Patients

It appears that a certain class of drugs (beta-blockers) used to control high blood pressure may also be helpful for people with some cancers, at least by slowing the progression of the disease.

How does this happen? It seems that earlier studies had shown that a couple of stress hormones – epinephrine and norepinephrine – bind to certain tumor cell receptors. When that happens, the cell is stimulated to produce vascular endothelial growth factor and two immune system interleukins. The result is an enhancement of blood supply to the tumor, thus promoting growth and metastasis.

But beta-blockers block the receptors, and hence inhibit effects of the hormones. Theoretically this should inhibit tumor development. In order to test this hypothesis, a large database of Danish cancer patient records was examined. It was found that melanoma patients who were also taking beta-blockers had their chances of surviving a specified number of years improved by 13%. Not a lot, but a benefit nevertheless. And the value of reducing effects from stress hormones was demonstrated. Perhaps other drugs may have larger effects. Lowering stress levels may help too.

Blood Pressure Drugs May Lengthen Lives of Melanoma Patients – Ohio State University

Beta-blocker drugs, commonly used to treat high blood pressure, may also play a major role in slowing the progression of certain serious cancers, based on a new study.

A review of thousands of medical records in the Danish Cancer Registry showed that patients with the skin cancer melanoma, and who also were taking a specific beta-blocker, had much lower mortality rates than did patients not taking the drug.

Further reading:

β-Blockers and Survival among Danish Patients with Malignant Melanoma: A Population-Based Cohort Study

September 24, 2011

Stems cells are potential source of cancer-fighting T cells

The human immune system is, in principle, capable of killing cancer cells all by itself, without need for any extra drugs or doses of radiation. But that supposes the immune system is able to distinguish cancer cells from healthy body cells, since it’s not a good thing when the immune system targets healthy cells.

Stems cells are potential source of cancer-fighting T cells

Adult stem cells from mice converted to antigen-specific T cells — the immune cells that fight cancer tumor cells — show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body’s immune system to fight cancer, according to Penn State College of Medicine researchers.

“Cancer immunotherapy is a promising method to treat cancer patients,” said Jianxsun Song, assistant professor of microbiology and immunology. “Tumors grow because patients lack the kind of antigen-specific T cells needed to kill the cancer. An approach called adoptive T cell immunotherapy generates the T cells outside the body, which are then used inside the body to target cancer cells.”

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September 15, 2011

Gene therapy kills breast cancer stem cells, boosts chemotherapy

Gene therapy has had a somewhat tortuous history – as well as some fairly recent successes. The key issue is being able to deliver appropriate genes to exactly the cells where they are needed.

The way this therapy works is somewhat complicated. The agent is targeted to cells, such as cancer cells, that overexpress a gene called claudin4, which encodes a cell membrane protein. Cancer therapies such as chemotherapy and radiation therapy work by causing apoptosis (programmed cell death). But some types of cancer overexpress genes for certain members of the Bcl-2 family of proteins, which inhibit apoptosis. Another protein, BIK counteracts the effects of these Bcl-2 proteins, but it falls short if they are overexpressed. However, BIKDD is a mutant form of BIK that is better at the same task. The experimental therapy delivers BIKDD genes to targeted cancer cells, and pre-clinical tests show that it improves the anti-cancer activity of the lapatinib chemotherapy drug.

Gene therapy kills breast cancer stem cells, boosts chemotherapy

Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

Further reading:

BikDD Eliminates Breast Cancer Initiating Cells and Synergizes with Lapatinib for Breast Cancer Treatment