Though the sequence of the genome may be the same in every cell of the body, the spatial arrangement of chromosomes in the nucleus of a cell differs between cells from different tissues, according to a study by Drs. Luis Parada, Tom Misteli, and Philip McQueen at NCI and the National Institutes of Health (NIH). The findings, published in the June 21 issue of Genome Biology, also show a correlation between the likelihood of two chromosomes being positioned close to one another in a specific tissue and their involvement in cancer translocations.
Translocation, a chromosomal aberration often found in various cancers, occurs when a large section of DNA breaks off from one chromosome and fuses to another chromosome.
The scientists used high-resolution microscopy in conjunction with "chromosome painting" to visually map the spatial arrangement of six chromosomes in eight mouse tissue types. Using statistical methods and computer simulations, they verified that chromosomes were positioned differently relative to each other and to the center of the cell's nucleus in each tissue type. This is the first systematic study of the spatial organization of genomes in multiple tissues.
"While we have shown that a subset of mouse chromosomes exhibits differential nuclear positioning among tissues, we suspect that this tissue specificity is likely to occur in humans and that differential spatial organization is a general feature of most chromosomes," said Dr. Parada of NCI's Center for Cancer Research (CCR).
The researchers also saw that certain combinations of chromosomes clustered in different tissues, and they were able to link this to translocation frequency and cancer risk. For example, chromosomes 5 and 6 were often found to be in close proximity in liver cells, but not in lymphocytes; translocations between these two chromosomes are commonly observed in liver tumors, but not in lymphomas. Similar observations were made for other chromosomes in these tissues.
"The probability of two chromosomes undergoing translocation is related to the spatial proximity of these chromosomes," said Dr. Misteli of CCR. "We are now studying the positioning of chromosomes in intact normal and premalignant tissues to test whether three-dimensional spatial genome patterns can be used as diagnostic and predictive tools."
Researchers from the University of Washington School of Medicine have shown that women with ovarian cancer have symptoms that are distinct in severity and frequency from those reported by women in the general population. These findings provide physicians with new insight about symptoms that can be used to detect ovarian cancer - the fifth-leading cancer killer of women in the United States - early and accurately. The study was reported by Dr. Barbara A. Goff and colleagues in the June 9 Journal of the American Medical Association.
Ovarian cancer is generally considered asymptomatic until its late stage, at which point the 5-year survival rate drops dramatically - from the 70-90 percent seen with early detection, to between 20-30 percent. Previous studies had found a significant link between symptoms and early-stage ovarian cancer, but their reliability was limited. To confirm these earlier findings, Dr. Goff and colleagues surveyed 1,709 women attending primary care visits and compared their responses with those from 128 women who were preparing for surgery to remove an ovarian or pelvic mass.
The study results showed that the symptoms most reliably linked to malignant ovarian cancer were back pain, fatigue, bloating, constipation, abdominal pain, lack of appetite, and urinary urgency. These are common complaints among women, particularly during menses, but those who had malignant masses experienced them 20-30 times per month, with greater severity than the women with benign masses or without cancer. "Symptoms that are more severe, more frequent than expected, and of more recent onset warrant further diagnostic investigation," the researchers recommended.
Infertile women can be reassured that taking ovulation-stimulating drugs does not appear to put them at greater risk for developing ovarian cancer later in life. A retrospective cohort study of 12,193 women evaluated for infertility, reported in the June issue of Obstetrics & Gynecology, did not find a strong link between use of fertility drugs and an increased risk for ovarian cancer.
Infertility patients have a significantly higher risk of ovarian cancer compared to the general public. These higher risks are believed to be due to these women giving birth less often, because maternity is a recognized protective factor for ovarian cancer. As the use of infertility drugs has risen, several studies have suggested that ovulation-stimulating drugs may further increase risk. This theory is biologically plausible given that ovarian cancer has been linked in other studies to various factors associated with "incessant ovulation."
The study team at NCI's DCEG evaluated effects of the two drugs used most often to treat infertility - clomiphene citrate and gonadotropins - and the underlying conditions leading to treatment, such as anovulation, that need to be taken into account in evaluating drug effects.
"In comparison with other infertile patients, there was no evidence that use of either clomiphene or gonadotrophins had an adverse effect on ovarian cancer," reported lead investigator Dr. Louise Brinton of DCEG. Her group noted that there were slightly higher, but not statistically-significant, risks for the small group of women followed for 15 years or more, supporting the need for continued monitoring of possible long-term risks from use of infertility drugs.
NCI researchers have shown that the potent nonsteroidal anti-inflammatory drug celecoxib (Celebrex), when used with the relatively new CEA cancer vaccine, is effective in preventing colon tumors in the "MIN" mouse model that mirrors the pathology of the human disease familial adenomatous polyposis (FAP). The study, which represents the first compatibility test of this combined therapy, was led by Dr. John W. Greiner of NCI's Laboratory of Tumor Immunology and Biology, and was published in the May 15 issue of Cancer Research.
The CEA vaccine targets a protein that is overexpressed in tumor cells. Researchers bred MIN mice with those that carried the human CEA gene, then fed the offspring food that contained celecoxib and administered the CEA vaccine to them. One control group of vaccinated mice received normal food and a second control group of unvaccinated mice received food with celecoxib.
The results were dramatic. Mice that received the combined celecoxib/CEA vaccine treatment showed 100 percent survival for the 18-month observation period (most of the normal mouse lifespan). In addition to long-term survival, mice that received the combination had 95 percent fewer tumors compared to controls.
Co-author Dr. Jeffrey Schlom explained the clinical significance of the study: "There is a dogma that vaccines can't be used with chemotherapy, and we're finding instances where they can be used with conventional drugs to treat neoplasia." He added that the authors are discussing clinical trials of the celecoxib/CEA vaccine model in humans with FAP pending studies to determine if there is any long-term toxicity due to the vaccine.
Results of a new study by Baylor College of Medicine researchers reveals that "cross talk" between the HER2 growth factor receptor and a key estrogen receptor (ER) coactivator may play an important role in resistance to adjuvant tamoxifen in women with ER-positive breast cancer. The study, published in the June 16 Journal of the National Cancer Institute, also found that use of gefitinib (Iressa), an epidermal growth factor receptor (EGFR) inhibitor, appears to impede this cross talk and restores tamoxifen's ability to block estrogen from fueling breast cancer cell proliferation.
In the study, Dr. Jiang Shou and colleagues treated a MCF-7 breast cancer cell line that expresses high levels of the ER coactivator AIB1 and a tamoxifen-resistant breast cancer cell line that overexpressed HER2 (MCF-7/HER2-18) with estrogen, tamoxifen, epidermal growth factor, or heregulin in the absence or presence of gefitinib. They discovered that, in order for tumor cells to remain resistant to tamoxifen (at which point the drug actually began to serve as an agonist, fueling tumor cell growth), bidirectional molecular interactions, or cross talk, between the ER and HER2 pathways was necessary. Use of gefitinib interfered with this cross talk, however, and in cell lines and a mouse model, restored tamoxifen's antitumor activity.
In a related editorial, Dr. Daniel Hayes of the University of Michigan Medical Center noted that questions remain about whether these results can be "extrapolated to other cell lines" or "to the vastly heterogenous clinical situation." He added, however, that the findings may aid efforts to determine which patients will benefit most from tamoxifen and which should be given aromatase inhibitors, another class of drugs used in the same clinical setting.