[ Back to EurekAlert! ] Public release date: 11-Nov-2008
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Journal of the National Cancer Institute

Also in the Nov. 11 JNCI

Overexpression of OLC1 Gene Associated with Smoking-Related Lung Cancer

The Overexpressed in Lung Cancer 1 (OLC1) gene is expressed at high levels in the majority of lung cancers, more often in samples from smokers than nonsmokers, and its expression is increased in cells treated with cigarette smoke.

Smoking increases the risk of lung cancer, but the mechanisms by which smoke triggers tumor formation are unknown. In earlier experiments, Shujun Cheng, M.D., of the Peking Union Medical College and the Chinese Academy of Medical Sciences in Beijing and colleagues identified 50 genes that were overexpressed in squamous cell carcinoma samples compared with normal lung epithelium.

In the current study, Cheng and colleagues tested the 50 genes for their ability to transform tissue culture cells. They examined the expression and gene amplification pattern of OLC1 in human tumor samples. They also tested the effects of overexpression of OLC1 in tissue culture and in a mouse model of lung cancer.

OLC1 overexpression transformed human fibroblast cells in culture and induced tumor formation in mice. The protein was overexpressed in the majority of human lung cancer samples tested, and the gene was amplified in the majority of lung tumor samples tested. High OLC1 protein expression was associated with smoking history in patient tissue samples. Exposure of cells in vitro to cigarette smoke increased OLC1 protein expression. Reduced expression of OLC1 in tissue culture cells increased cell death and decreased their ability to form colonies.

"Altogether, this study provides strong evidence supporting an important role for the novel gene OLC1 in the carcinogenesis of the human lung. The results indicate that cigarette smoke-induced overexpression of OLC1 may be involved at an early stage of human lung carcinogenesis," the authors write.

In an accompanying editorial, Frederic Kaye, M.D., of the National Cancer Institute and National Naval Medical Center in Bethesda, Md., acknowledges that the association of a previously uncharacterized gene with carcinogenesis provides exciting opportunities for research––and possibly for new treatments in the future. He cautions, however, that the new data on OLC1, also known as Ist1, should be considered preliminary. Researchers have criteria for which genes can be called oncogenes, including the existence of loss-of-function or gain-of-function mutations in human tumors. Therefore, he concluded, "we may need to reserve judgment on candidate cancer genes identified largely by functional data, such as Ist1/OLC1, until stronger supporting evidence for tumor-specific activation by gene amplification becomes available."

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Isolated Breast Cancer Cells in Sentinel Lymph Node Associated with Non-Sentinel Lymph Node Metastases

Women who are found to have isolated breast cancer cells upon sentinel lymph node biopsy have a risk of having metastases in other lymph nodes.

Numerous studies have examined the risk of metastatic tumors in other lymph nodes associated with isolated tumor cells in a sentinel lymph node. However, the results from those studies have been inconsistent, and no standard recommendations regarding the use of axillary lymph node dissection have been made.

To better understand the relationship between isolated tumor cells in the sentinel lymph node and the likelihood of disease spread to other lymph nodes, Paul van Diest, M.D., Ph.D., of the University Medical Center Utrecht in The Netherlands and colleagues reviewed 29 published studies that included 836 patients.

The overall pooled risk estimate was 12.3 percent. The pooled risk was marginally higher than the risk of a false-negative sentinel lymph node biopsy but marginally lower than the risk of non-sentinel lymph node metastases in patients with micrometastases, who are currently eligible for axillary lymph node dissection. Not all of the original studies provided information on the size of the non-sentinel lymph node tumors, but in 10 studies that classified the non-sentinel lymph node metastases according to size, 36 of the 56 women (64 percent) with isolated tumor cells had macrometastases, greater than 2 mm in diameter.

"In conclusion, results on isolated tumor cells in the sentinel lymph node are somewhat controversial, and there is still doubt about the need for axillary lymph node dissection after finding isolated tumor cells in the sentinel lymph node," the authors write. A wait-and-see approach may be appropriate for some women, while axillary lymph node dissection may be appropriate for women if they are unsure about whether to undergo adjuvant systemic therapy.

Contact: Paul van Diest, P.J.vandiest@umcutrecht.nl, + 31887556565


Downstream RAS Signaling Protein May Be Lung Cancer Target

Blocking expression of a protein involved in RAS signaling, called seven-in-absentia homolog 2 (SIAH-2), in lung cancer cells increased cell death and decreased the tumorigenicity of the cells.

The RAS signaling pathway drives cell proliferation and is often mutated in human cancers. However, drugs that directly target the RAS protein, or cell surface receptors such as the epidermal growth factor receptor that signal through RAS, have demonstrated limited efficacy in treating human disease.

To determine whether blocking a downstream component of the RAS signaling pathway could reduce tumor cell growth, Amy Tang, Ph.D., of the Mayo Clinic Cancer Center in Rochester, Minn., and colleagues inhibited SIAH-2 in lung cancer cells and tested their ability to grow in culture and in mice.

Cells that lacked SIAH-2 expression showed reduced signaling in the proliferation-stimulating MAP kinase pathway and had reduced growth relative to control cells. Moreover, the SIAH-2-deficient cells had a higher rate of programmed cell death in vitro compared with control cells and were unable to form tumors in mice.

"These findings suggest that anti-SIAH-2 molecules may have potential to become a new anticancer agent," the authors conclude.

Contact: Russell J. Vanderboom, Ph.D., vanderboom.russell@mayo.edu, (507) 538-8008


Expression of Lysophosphatidic Acid Receptors Stimulate Tumor Growth and Aggressiveness in Ovarian Cancer Cells

Ovarian cancer cells that express lysophosphatidic acid (LPA) receptor 2 or 3 form larger and more aggressive tumors in xenograft mouse models than controls cells that do not express the receptors.

LPA is a glycolipid that stimulates DNA synthesis, proliferation, survival, migration, and cytokine production in cells when it binds to cell-surface receptors called LPA1, LPA2, or LPA3. Previous studies indicated that LPA is present at high levels in ascites fluid in ovarian cancer patients, and the receptors are expressed in several malignancies, including ovarian cancers.

To determine if LPA and its receptors directly contribute to the oncogenic phenotype in ovarian tumors, Gordon Mills, M.D., Ph.D., of the University of Texas M. D. Anderson Cancer Center in Houston and colleagues engineered human ovarian cancer cells to overexpress each of the receptors or to prohibit their expression. The researchers assayed cell behavior in vitro and by injecting them into mice.

Ovarian cancer cells that expressed the LPA receptors gave rise to larger tumors and produced a larger volume of ascites than cells that did not express the receptors. Additionally, the LPA receptor-expressing cells invaded the peritoneal cavity in more than 75 percent of the animals. Injection of ovarian cancer cells expressing any one of the three LPA receptors into mice led to metastatic tumors. However, the cells that expressed LPA2 or LPA3 metastasized to a wider array of tissues than did the cells expressing LPA1.

"These results provide direct evidence that LPA receptor expression and LPA signaling regulate the behavior and aggressiveness of ovarian cancer cells," the authors write. "Therefore, the overexpression of the LPA2 or LPA3 receptor observed in ovarian cancer likely plays a role in the development and/or progression of this disease."

Contact: Scott Merville, SMerville@mdanderson.org, (713) 792-0661


Breast Cancer Incidence Among Premenopausal U.S. Women

African-American women under the age of 40 have a higher risk of breast cancer than do white women of a similar age. White women aged 40 and older, however, have a higher incidence than black women aged 40 and older.

The incidence of postmenopausal breast cancer is associated with screening and hormone therapy. The mechanisms that influence the incidence of breast cancer in premenopausal women are less well understood.

To get a better understanding of disease trends in younger women, Louise Brinton, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues analyzed the incidence of breast cancer among 387,231 women diagnosed between 1992 and 2004 who were included in the Surveillance, Epidemiology, and End Results (SEER) database.

The investigators found that the incidence rate of breast cancer was 16.8 per 100,000 for black women under the age of 40, compared with 15.1 per 100,000 for white women under the age of 40. The black-white incidence rate ratio was highest for women under the age of 30, with black women having a 52 percent higher incidence than white women. During the study years, only white women over the age of 40 had a statistically significant increase in the incidence of invasive breast cancer

"Continued surveillance of trends is needed, particularly for molecular subtypes that preferentially occur among young women," the authors conclude.

Contact: National Cancer Institute, office of media relations, ncipressofficers@mail.nih.gov, (301) 496-6641


Human Papillomavirus Not Associated with Majority of Squamous Cell Carcinomas in European Fanconi Anemia Patients

Squamous cell carcinomas (SCCs) in Fanconi anemia patients genetically resemble sporadic SCC and do not appear to be frequently associated with human papillomavirus (HPV) DNA as reported previously.

Fanconi anemia patients are at increased risk of SCC of the head and neck and anogenital regions. A previous study of SCC in mostly U.S. Fanconi anemia patients showed that 84 percent of the cancers had detectable DNA levels for HPV, a virus known to cause cervical cancer as well as head and neck cancer.

To determine whether HPV is associated with SCC in an independent group of mostly European Fanconi anemia patients, Ruud Brakenhoff, Ph.D., of the VU University Medical Center in Amsterdam and colleagues tested 21 SCC samples from 19 Fanconi anemia patients for evidence of HPV DNA. The investigators also examined the pattern of genetic changes, which is characteristic for squamous cancers caused by HPV, in the tumor samples as an additional surrogate marker for HPV infection.

Only 2 (10 percent) of the tumors showed evidence of HPV DNA. Additionally, the pattern of genetic changes in HPV DNA–negative tumors closely resembled the pattern of genetic changes commonly found in sporadic head and neck SCC associated with alcohol consumption and smoking, which supports the absence of HPV DNA in these cancers.

"Our data show that HPV does not play a major role in squamous cell carcinogenesis in this cohort of Fanconi anemia patients, and that the Fanconi anemia SCCs are geneti¬cally similar to sporadic SCCs despite having a different etiology," the authors write. The investigators hypothesize that the difference seen between this series and the previous study of SCC in Fanconi anemia is due to geographic differences in the prevalence of HPV infection.

Contact: Marcia Sanderse, Marcia.Sanderse@vumc.nl, +0031 20 444 3444 or +0031 20 444 4444

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Also in November 11 JNCI:

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