UF study shows how cigarette smoke blocks cell repair
| August 2006
By Melanie Fridl Ross
GAINESVILLE, Fla. - Cigarette smoke can turn normal breast cells cancerous by blocking their ability to repair themselves, eventually triggering tumor development, University of Florida scientists report.
While some cells nonetheless rally and are able to fix their damaged DNA, many others become unable to access their own cellular first aid kit, according to findings from a UF study published today (Aug. 21) in the journal Oncogene. If they survive long enough to divide and multiply, they pass along their mutations, acquiring malignant properties.
Past research has been controversial. Tobacco smoke contains dozens of cancer-causing chemicals, but until more recently many studies found only weak correlations between smoking and breast cancer risk, or none at all. Those findings are increasingly being challenged by newer studies that are focusing on more than just single chemical components of tobacco, as past research often has done. In the UF study, researchers instead used a tar that contains all of the 4,000 chemicals found in cigarette smoke.
"Our study suggests the mechanism by which this may be happening," said Satya Narayan, Ph.D., an associate professor of anatomy and cell biology at UF's College of Medicine. "This is basically the important finding in our case: We are now describing how cigarette smoke condensate, which is a surrogate for cigarette smoke, can cause DNA damage and can block the DNA repair of a cell or compromise the DNA repair capacity of a cell. That can be detrimental for the cell and can lead to transformation or carcinogenesis."
In their study, funded by the National Institutes of Health and the Miami-based Flight Attendant Medical Research Institute, UF researchers exposed normal breast epithelial cells to cigarette smoke condensate-a tar derived from a machine that literally "smokes" a cigarette in the laboratory-and found the cells acquired mutations characteristic of malignant cells.
The scientists say DNA repair appears to be compromised when chemical components of smoke activate a key gene. That gene interacts with an enzyme that plays a crucial role in repairing damaged DNA, preventing it from doing its job. The cell, despite its mutated form, can then multiply wildly.
A cell with damaged DNA has one of two fates, said Narayan, also a member of the UF Shands Cancer Center.
"Its DNA repair machinery can be enhanced and it can fix the damaged DNA and restore genomic stability, or if the DNA repair machinery becomes compromised within the cell, then it can lead to an accumulation of mutations because the DNA is not fixed before the cell begins to divide," he said. "The mutation then becomes a permanent part of the genome and causes genomic instability, and genomic instability can bring about several cellular dysfunctions, and one of them can lead to tumor formation."
Other UF research led by Xingming Deng, M.D., Ph.D., and published last month in the Journal of Biological Chemistry revealed that nicotine activates a protein in cancer cells that helps them live long, spread to new sites and grow resistant to chemotherapy.
Narayan's team has previously studied cells that were exposed to the chemicals found in cigarette smoke yet did not die. In general, about two-thirds of these cells will be growth-retarded, and some actually acquire cancer-like characteristics, he said.
"Some of these cells that survive are really acquiring true mutagenic characteristics," Narayan said. "A defect in only one cell is important for growth of a full-blown tumor. You don't need 1,000 or 1 million cells to be affected. Only a single cell which may have genomic instability due to compromised DNA repair capacity of the cell can be sufficient for a tumor to develop. That has to be considered also when we do these kinds of studies."
Narayan said the next step will be to find ways to manipulate cells' capacity for DNA repair and to prevent tumor formation.
Meanwhile, he cautions people to avoid smoking, especially teenagers. A study last year found teenage smokers are at especially high risk of breast cancer development later in life, he said.
"Teenagers should realize they are inhaling 4,000 chemicals, and these chemicals can do so much harm in the body, not only posing a breast cancer risk but for so many other things," Narayan said. "The consequence of these chemicals is not apparent in one day or two days or in months; it takes years and years for cancers to develop. Once the gene is damaged and sitting there it's going to provide some harmful effect later on."
Jose Russo, M.D., a researcher at the Fox Chase Cancer Center in Philadelphia who has studied how breast epithelial cells transform after exposure to the chemical benzo[a]pyrine, which is found in tobacco smoke, called the UF findings very interesting.
"We found significant alteration in many of the chromosomes in these cells induced by the effect of benzo[a]pyrine," Russo said. "We were the first ones to demonstrate in normal-like epithelial cells this compound produced a transformation. Cigarette smoke condensate contains more than one compound, so the UF experiment is more similar to the way any human being would be exposed to the carcinogens. It mimics the human situation more closely."
Healing potential discovered in everyday human brain cells
By John Pastor
GAINESVILLE, Fla. - University of Florida researchers have shown ordinary human brain cells may share the prized qualities of self-renewal and adaptability normally associated with stem cells.
Writing online today (Aug. 16) in Development, scientists from UF's McKnight Brain Institute describe how they used mature human brain cells taken from epilepsy patients to generate new brain tissue in mice.
Furthermore, they can coax these pedestrian human cells to produce large amounts of new brain cells in culture, with one cell theoretically able to begin a cycle of cell division that does not stop until the cells number about 10 to the 16th power.
"We can theoretically take a single brain cell out of a human being and - with just this one cell - generate enough brain cells to replace every cell of the donor's brain and conceivably those of 50 million other people," said Dennis Steindler, Ph.D., executive director of UF's McKnight Brain Institute. "This is a completely new source of human brain cells that can potentially be used to fight Parkinson's disease, Alzheimer's disease, stroke and a host of other brain disorders. It would probably only take months to get enough material for a human transplant operation."
The findings document for the first time the ability of common human brain cells to morph into different cell types, a previously unknown characteristic, and are the result of the research team's long-term investigations of adult human stem cells and rodent embryonic stem cells.
Last year, the researchers published details about how they used stem-like brain cells from rodents to duplicate neurogenesis - the process of generating new brain cells - in a dish. The latest findings go further, showing common human brain cells can generate different cell types in cell cultures. In addition, when researchers transplanted these human cells into mice, the cells effectively incorporated in a variety of brain regions.
The human cells were acquired from patients who had undergone surgical treatment for epilepsy and were extracted from support tissue within the gray matter, which is not known for harboring stem cells.
When the donor cells were subjected to a bath of growth agents within cell cultures, a type of cell emerged that behaves like something called a neural progenitor - a cell that is a bit further along in development than a stem cell but shares a stem cell's vaunted ability to divide and transform into different types of brain cells.
Even when the cells from the epilepsy patients were transplanted into mice, bypassing any growth enhancements, they were able to take cues from their surroundings and produce new neurons.
"It was a long and difficult process, but we were able to induce what are basically support cells in the human brain to form beautiful new neurons in a dish," said Noah Walton, a graduate student in the neuroscience department at the UF College of Medicine. "But what we really needed is for these support cells to turn into neurons in the brain, and we found we could get them to do it. Something in the environment in the rodent brain is sufficient to get these cells to become neurons."
Scientists speculate a small amount of existing progenitors may be emerging from the gray matter of the brain and multiplying in torrents, or perhaps the aging clock of the mature cells actually turns backward when the donor cells are in a new environment, returning them to past lives as progenitors or as stem cells.
"It's been shown that the same sorts of tissue from the mouse brain can give rise to rapidly dividing cells, but this shows it is true with human cells," said Ben Barres, M.D., Ph.D., a professor of neurobiology at the Stanford University School of Medicine who was not involved in the research. "That these cells were able to integrate into tissue in an animal model and actually survive - it was extremely important to show that. Now the question is what will these cells do in a human brain? Will they be able to survive for the long term and rebuild circuitry? This work is a first step toward that end."
In addition to using the cells in treatments to repair or replace damaged brain tissue, the ability to massively expand cell populations could prove useful in efforts to test the safety and efficacy of new drugs. It is also possible to genetically modify the cells to produce neurotrophins - substances that help brain tissue survive, researchers said.
The research was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute of the National Institutes of Health. Steindler and co-senior author Bjorn Scheffler, M.D., a UF neuroscientist, are involved with RegenMed Inc., a biotechnology company that seeks to use stem cell technology to develop human therapeutics.