NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
December 7, 2004 • Volume 1 / Number 47 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Tamoxifen's Risks Similar in African American and White Women

African American and white women who are treated with tamoxifen for breast cancer appear to have the same risks of contralateral breast cancer and thromboembolic events, according to a new study by Dr. Worta McCaskill-Stevens of NCI's Division of Cancer Prevention in the December 1 Journal of the National Cancer Institute .

Between 2 and 15 percent of women diagnosed with breast cancer will develop contralateral breast cancer - cancer in the opposite breast - depending on age and other factors. Tamoxifen has been shown to reduce the risk of contralateral breast cancer by 47 percent in women with early-stage primary breast cancer, but the trials demonstrating this were done largely in populations of white women, and little data exist on the drug's effects on African American women. Tamoxifen use is also associated with an increased risk of thromboembolic events, such as stroke, and the African American population has more risk factors - such as cardiovascular disease and diabetes - for these events compared with the white population.

Dr. McCaskill-Stevens and colleagues pooled data from 13 National Surgical Adjuvant Breast and Bowel Project clinical trials that had included more than 20,000 women. They found that in women from both ethnic groups who had estrogen-receptor-positive tumors, tamoxifen use was associated with a similar reduction in contralateral breast cancer and thromboembolic events.

"It is not unreasonable to extrapolate these findings to the prevention setting," the authors wrote. "Our data therefore provide further support for the need to assess an individual woman's health and personal history, not only her race and ethnicity, to determine the benefits and risks of tamoxifen as a chemopreventive agent."

Study Finds BCL6 Protein Inactivates p53 Tumor Suppressor

The BCL6 protein can turn off the expression of the p53 tumor suppressor in B-cells, according to a study published in the November 2 Nature . Normally, this inactivation of p53 allows B-cells to grow rapidly and produce numerous antibodies, but the findings also showed that if BCL6 is constantly expressed, the excess growth can lead to the development of B-cell lymphomas.

High levels of BCL6 are usually only expressed in B-cells in the germinal center, a lymphoid structure in which B-cells proliferate and produce antibodies. To produce a diverse set of antibodies, germinal center B-cells undergo a series of selective mutations to immunoglobulin, the protein that makes up antibodies. BCL6 expression is believed to be important for this process, but the precise mechanism has been unclear.

Ryan T. Phan and Dr. Riccardo Dalla-Favera at Columbia University found that BCL6 acts by suppressing the expression of the p53 protein. They observed that injecting increasing amounts of a vector expressing BCL6 resulted in a dose-dependent decrease in p53 expression. They also found that BCL6 binds to the DNA around the p53 gene, thus preventing transcription.

Numerous other proteins are regulated by p53, which controls cell growth and programmed cell death. By suppressing p53, BCL6 likely helps the B-cells tolerate DNA damage at a low level to allow for the crucial immunoglobulin mutations required to make antibodies. If BCL6 becomes too active, the authors note, then the loss of p53 function would stop all control over growth and death, leading to lymphomagenesis.

Cord Blood Stem Cells Studied in Adult Leukemia

Transplants of stem cells from newborn babies' umbilical cord blood could offer a viable treatment alternative for adults with leukemia who are unable to find well-matched bone marrow donors, according to two studies published in the November 25 New England Journal of Medicine (NEJM) .

In the first study, a research team led by Dr. Mary J. Laughlin of Case Comprehensive Cancer Center and University Hospitals of Cleveland Ireland Cancer Center analyzed treatment results in 600 adult leukemia patients, comparing outcomes in those who had HLA antigen-mismatched cord blood stem cell transplants with results in two groups that received bone marrow. One group received HLA antigen-mismatched bone marrow and another received marrow from perfectly matched donors.

While patients who received the matched bone marrow had the highest survival rate (33 percent), rates of survival were equal (22 percent) in the group that received cord blood transplants and the group that received mismatched marrow. "HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor," the researchers concluded.

A similar conclusion was reached by European investigators led by Dr. Vanderson Rocha of the Hospital Saint-Louis in Paris. The team looked at treatment outcomes in 682 adult leukemia patients who received stem cell transplants from unrelated donors - 98 cord blood transplants (92 mismatched) and 584 transplants of perfectly matched bone marrow. Finding comparable success rates in the two groups, researchers concluded, "Cord blood from an unrelated donor is an alternative source of hematopoietic stem cells for adults with acute leukemia who lack an HLA-matched bone marrow donor."

Experts have estimated that as many as 16,000 people diagnosed annually with leukemia need a bone marrow transplant but cannot get one because a close match is unavailable. Cord blood is readily available, but - as Dr. Robert Steinbrook pointed out in a commentary about cord blood banks that appears in the same issue of NEJM - has a much lower concentration of blood cell-forming stem cells compared with bone marrow. This article is also accompanied by an editorial by Dr. Miguel A. Sanz on the issue of cord blood for leukemia.

Gastric Cancer May Arise from Bone Marrow-Derived Cells

Researchers in the United States and Japan have found that gastric cancer can originate from bone marrow-derived cells (BMDCs). In a paper published in the November 26 Science, researchers investigated the possible role of BMDCs in carcinoma progression in mice chronically infected with Helicobacter species. They found that BMDCs recruited into the stomach due to persistent inflammation could subsequently undergo transformation and progress to epithelial cancer. This research was funded by grants from the NIH and Vanderbilt, as well as a VA merit award.

In cases of chronic inflammation, stem cells, such as the BMDCs, are recruited to the site of injury to replenish lost tissue. Stem cells' unique abilities, such as rapid proliferation and resistance to apoptosis, allow them to restore the tissue quickly, but also make them suitable targets for malignant transformation. Gastric cancer resulting from a chronic Helicobacter infection is a prime example, and malignant stem cells could be responsible.

The researchers tested this possibility by using radiation to deplete the bone marrow cells from mice and then transplanted specially marked BDMCs. They then examined for the presence of marked cells in the gastric lining after giving the mice various injuries. Acute Helicobacter infections or acute ulceritis did not lead to recruitment of BDMCs to repopulate the stomach. However, when they examined mice infected with Helicobacter for a year that had developed gastric cancer, they found that the malignant cells had arisen from the transplanted marrow cells.

"The concept that epithelial cancers can arise from BMDCs greatly alters our overall understanding of cancer initiation and progression," state the authors.