Study Provides New Insights into Tumor Cell Survival

A new study from NCI researchers has provided the first evidence that a specific transcription factor, C/EBPβ, is required for the transformation of macrophages into tumor cells, as well as the identification of a C/EBPβ-regulated gene that allows these cells to elude cell death and proliferate despite the absence of exogenous growth factors. The study, by Dr. Peter F. Johnson and colleagues, was published in the April 2004 Molecular and Cellular Biology.

The researchers infected bone marrow cells from mice lacking C/EBPβ with a transforming virus that carried the Myc and Raf oncogenes. This virus has been shown to produce myeloid tumor cells that are "self sufficient," no longer requiring external growth factors to proliferate. In this study, however, the authors showed that macrophage transformation is dependent on C/EBPβ. Further investigation using microarray analysis indicated that C/EBPβ activated the insulin-like growth factor I (IGF-I) gene, thus triggering a signaling pathway that is essential for tumor cell survival and proliferation.

Tumor cells' ability to avoid cell death is considered a central component of cancer development, the authors write. As a result, finding ways to interrupt the molecular pathways to tumor cell immortality, such as by inhibiting the activity of implicated transcription factors or the genes that they target, "has emerged as a promising strategy for cancer intervention."

A preliminary analysis, the authors noted, indicated that other transcription factors also are likely to play a role in IGF-I expression. The combination of their findings with future studies that further elucidate the mechanisms by which IGF-I is regulated, the authors concluded, "may facilitate the development of anticancer strategies based on inhibiting IGF-I production."

Evidence Shows Dynamic Nature of Steroid Receptor-Mediated Transcription

Dr. Gordon Hager and scientists in his laboratory have developed evidence that challenges the 30-year-old paradigm of how our cells respond to hormones. The classic view is that nuclear receptors such as the glucocorticoid receptor (GR) bind statically to chromatin - a complex of DNA and histone proteins in the cell nucleus - and nucleate large transcription complexes, which in turn mediate the transcription of genes that the receptor controls.

In a report published in the April 23 issue of Molecular Cell, Dr. Akhilesh Nagaich and colleagues in the Hager lab demonstrate that, contrary to widely held belief, the interaction of receptors such as GR with chromatin is highly dynamic and periodic; the interaction may last on the order of seconds rather than minutes or hours.

The researchers applied a technique called ultraviolet (UV) laser crosslinking to their novel in vitro chromatin model system, which closely approximates the in vivo state of a natural promoter. The UV laser crosslinking allowed the researchers to make fast measurements of GR binding and dissociation from the chromatin. They show the receptor first binds cooperatively to promoter DNA during chromatin remodeling, then is actively ejected from the template as the remodeling reaction proceeds.

Transcriptional regulation by nuclear receptors is now a major focus of pharmaceutical drug screening. The new results point to ligand-modified receptor interactions with chromatin remodeling systems as a new target for drug discovery.

Higher NHL Risk Among Asthmatics Linked to Pesticide Use

NCI researchers have found a higher risk of non-Hodgkin's lymphoma (NHL) among asthmatics who have been exposed to common agricultural pesticides than among individuals without asthma.

To conduct the study, published online April 12 in the International Journal of Cancer, Dr. Won Jin Lee, of NCI's Occupational and Environmental Epidemiology Branch, and colleagues pooled data from two population-based, case-controlled NHL studies conducted in three Midwestern states. They looked at cases of NHL diagnosed between 1980 and 1983 among white males over age 30 from Iowa and Minnesota, and NHL cases diagnosed between 1983 and 1986 among white men and women over age 21 in Nebraska. They compared the resulting 872 NHL case histories with 2,336 healthy controls from the same geographic areas and interviewed either the subjects or their next-of-kin to collect information on use of and exposure to pesticides and other known or suspected risk factors for NHL.

"We found that farmers with potential exposure to pesticides and a history of asthma tended to have higher relative risks for NHL than pesticide-exposed farmers not reporting asthma," the researchers observed. One possible explanation, they said, is that immunologic changes sparked by asthma may inhibit the immune system's ability to respond to potentially carcinogenic elements in specific pesticides. "Considering the widespread use of pesticides and the relatively high prevalence of asthma," the authors concluded, "further studies, particularly with carefully defined asthma diagnoses and biomarkers … are needed to confirm these findings and clarify the mechanisms involved."

UTF Adjuvant Chemo for Lung Adenocarcinoma Improves Patient Survival

Adjuvant chemotherapy with uracil-tegafur (UTF) improves survival among patients with completely resected stage I lung adenocarcinoma, according to the results of a new study from Japan. In the study, published in the April 22 New England Journal of Medicine, 979 patients aged 45 to 75 with stage I lung adenocarcinoma were randomized to surgery alone followed by observation, the standard therapy, or surgery plus UTF twice daily for 2 years. The UTF group, reported study authors Dr. Harubumi Kato and colleagues, had a statistically significant 5-year overall survival rate of 88 percent, compared with 85 percent for the standard therapy group.

There were few severe adverse reactions associated with UTF, with 10 patients (2 percent) developing a grade 3 adverse reaction. The authors reported that in patients with tumors 2 cm or less, the survival rate was 91 percent. Therefore, they recommended that patients with small tumors be excluded from adjuvant trials unless a subgroup with a poor prognosis is identified. "Our study indicated that patients with completely resected stage I disease, especially T2 N0 adenocarcinoma, will benefit from adjuvant chemotherapy with uracil-tegafur," the authors noted.

UTF has not been approved in the United States "and has been used in relatively few clinical trials in this country, despite widespread approval elsewhere," wrote Dr. Robert Diasio of the Comprehensive Cancer Center at the University of Alabama at Birmingham in an accompanying editorial. But given the "compelling evidence" of its effectiveness among patients with adenocarcinoma of the lung in the study by Kato and colleagues, he argued, newer forms of this class of drugs, fluoropyrimidines, may prove to have an even greater effect on survival.