30 June 2006

Cancer: The Biological Clock, Apoptosis, and Gene Amplification

Understanding cancer, and how to defeat it, is one of the main goals of western medical research. As people living in western nations live longer lives, they are more likely to confront cancer at some point. Cancer and ageing are closely linked.

This Biocom newsrelease discusses the relationship between the body's biological clock, and cancer:

"The notion that the clock regulates DNA-damage input and that mutation can affect the clock as well as the cell cycle is novel," says Jay Dunlap, professor and chair of genetics at DMS. "It suggests a fundamental connection among circadian timing, cell cycle progress, and potentially the origins of some cancers."

....Recent evidence in mammalian cells shows that other cell cycle regulators physically interact with clock proteins. Loss of at least one clock protein (mammalian period-2) is known to increase cancer susceptibility. The coordination of the clock and cell division through cell cycle checkpoints, supports the clock's "integral role in basic cell biology," conclude the researchers." Their work can help advance understanding of cancer origins as well as the timing of anti-cancer treatment.
Much more at source article.

When DNA damage occurs that could lead to cancerous transformation, cells usually detect the DNA damage, and trigger apoptosis, programmed cell death. Cancerous cells have evolved ways to prevent apoptosis, and their own programmed destruction. This Biocom newsrelease provides more details of how malignant cells obstruct apoptotic cascades, and how science might devise drugs to make cancer cells more vulnerable to treatment:

Researchers at The University of Texas M. D. Anderson Cancer Center have significantly refined the scientific understanding of how a cell begins the process of self-destruction - an advance they say may help in the design of more targeted cancer therapies.

In the June 30 issue of the journal Cell, the research team found that a natural "brake" exists in a cell to prevent it from undergoing apoptosis, or programmed cell death, and they say that optimal anti-cancer therapies should take a two-pronged approach to overriding this brake in order to force a tumor cell to die. Very few drugs do this now, they say.

The discovery "demonstrates that apoptosis is more complicated than had been believed, and consequently harder to achieve," says the study's lead author, Dean G. Tang, Ph.D., associate professor in the Department of Carcinogenesis in the Science Park Research Division of M. D. Anderson in Smithville, Texas.

Apoptosis can occur when a cell has reached its lifespan, and so is "programmed" to die, or is initiated when a cell is damaged beyond repair or infected by a virus. Apoptosis is rare in cancer because tumor cells have adapted biological pathways to circumvent cell death, so many anti-cancer therapies focus on inducing apoptosis in these cells, Tang says.

...."Many cancer drugs focus on pushing the mitochondria to release CC [cytochrome c], and not on reducing the nucleotide pool, and our new model suggests that decreasing this pool is essential to produce sensitivity in cancer cells to apoptosis," Tang says.

Cancers that quickly become resistant to therapy, such as melanoma and ovarian tumors, do so because they have found ways to prevent mitochondria from releasing a lot of CC, he says. Tumor cells also don't want to decrease their nucleotide pool, because they need ATP for continued functioning, he says.

"An optimal cancer therapy should combine both strategies," Tang says. "They should maximize release of CC and maximize the decrease of nucleotide levels."

Some chemotherapy drugs, like paclitaxel, cisplatin and etoposide, appear, coincidentally and perhaps inadvertently, to do both, and are very effective for specific cancers, he says. "But based on these new findings, we now have a new theoretical approach that can be used to help in the design of more targeted chemotherapy drugs," Tang says. "This will change the way that scientists now think about the role of nucleotides in cancer therapy."
Much more detail at source.

Here is another interesting finding about the molecular onset of cancer, from researchers at Georgia Tech:

Gene amplification plays an important role in causing cancers via activation of oncogenes. If scientists can determine the rules as to which segments of genetic material become amplified and how, oncologists and drug researchers may be able to interrupt that process and prevent the formation and growth of some tumors. Using yeast as a model organism, researchers at the Georgia Institute of Technology have discovered that the location of a hairpin-capped break relative to the end of the chromosome will determine the fate of the amplification event

Gene amplification is the increase in copy number of a particular piece of DNA and
is a hallmark of tumor cells. Double minutes are extrachromosomal segments of amplified DNA. Homogeneously staining regions are amplified intrachromosomal segments forming large genomic regions. Some strategies of pharmaceutical research in cancer prevention and treatment could involve curbing cancer development via restricting gene amplification. The first step towards achieving this is to discover the rules that govern whether an amplification event is a double minute or a homogenously-staining region.

It’s known that regions of chromosomes that are prone to amplification have
palindromic sequences of DNA, which are weak places where the chromosome can break. These palindromic sequences can be naturally found in human genome. The distribution of such sequences can vary from one individual to another. Researchers at the Georgia Institute of Technology have discovered that a particular type of DNA break, a hairpin-capped double strand break, induced by these palindromic sequences, is a precursor to amplification.

“We have a developed a system in yeast which would mimic the situation in human cancer cells wherein oncogenes might be located next to palindromic sequences. Using this system we have discovered the rules that determine how double minutes or homogeneously staining regions can be generated,” said Kirill Lobachev, assistant professor in Georgia Tech’s School of Biology.

....The findings can help researchers understand the cause of cancer in diseased individuals and also to potentially identify individuals who might be prone for cancer.
More information and links at the source.

The initiation and maintenance of cancer cells and tumours are complex. Only by understanding how to work within this cellular/molecular complexity will researchers devise better cancer therapies.

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