© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 14, 1039,
July 18, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
Advancements in laboratory technologies, such as gene-expression microarrays and immunohistochemical methods, have resulted in a proliferation of potential biomarkers to assist in the early detection of cancer. To coordinate research efforts in biomarker development and to promote scientific rigor in their systematic evaluation and use as screening tools, Pepe et al. (p. 1054) present guidelines for clinical testing of biomarkers. They recommend five phases of research, encompassing a hierarchy of levels of evidence. They suggest key components of study design for each phase, and they note that the overall strategy is designed to provide a thorough, systematic, and efficient approach to the identification of biomarkers with strong potential for early detection of cancer.
Angiogenic Activity in Tumor Cell Subpopulations
Achilles et al. (p. 1075) investigated the angiogenic heterogeneity of tumors as a possible explanation of why certain tumors do not grow when transplanted into immunodeficient mice. They implanted human liposarcoma cells or tumor tissue subcutaneously in severe combined immunodeficient mice. The resultant tumors were either highly angiogenic and fast growing, weakly angiogenic and slow growing, or not angiogenic and stable. Most tumors retained the original phenotype. The investigators analyzed the tumor tissues for microvessel density, tumor cell proliferation in vivo, and cell apoptosis. Tumor volume correlated positively with microvessel density and inversely with tumor cell apoptosis but poorly with tumor cell proliferation. The authors conclude that an angiogenic tumor can contain subpopulations of cells with little or no angiogenic activity. They suggest that this is a novel explanation for dormant micrometastases, late recurrence, and changes in rate of tumor progression.
In an editorial, Fidler (p. 1040) remarks that the work of Achilles et al. supports two main principles: Neoplasms are heterogeneous and consist of cells with different biologic properties, and the outcome of cancer growth and spread depends on multiple interactions of tumor cells with host homeostatic factors.
Red Blood Cell Fatty Acids and Breast Cancer Risk
Studies of the association between dietary fat and breast cancer have produced equivocal results, which may stem from errors in measuring dietary intake or confounding by unknown factors. The fatty acid composition of erythrocyte (red blood cell) membranes is not only a biomarker of dietary fat intake but also reflects other aspects of diet, fatty acid metabolism, and hormonal factors that may affect risk. As part of a prospective study, Pala and colleagues (p. 1088) compared the fatty acid profiles of erythrocytes in blood samples drawn well before a breast cancer diagnosis from women with and without the disease. Their results suggest that high levels of monounsaturated fatty acids, partly the result of high levels of endogenous synthesis (via the key enzyme 
9-desaturase), are associated with increased breast cancer risk, whereas the membrane saturation index, mainly the result of low 9-desaturase activity, is inversely associated with that risk. Polyunsaturated fatty acids were also inversely associated with the risk, but no association between saturated fatty acids and breast cancer was observed. The authors recommend further investigation of the possible role of the 9-desaturase pathway in breast cancer.
Smoking, Epithelial Cell Proliferation, and Ki-67
Although the risk of lung cancer is higher for current smokers than for former smokers, the risk for former smokers remains high for many years. Because abnormal cell proliferation is a hallmark of tumorigenesis, Lee et al. (p. 1081) determined whether proliferation indices using a marker called Ki-67 in bronchial biopsy specimens could serve as an intermediate endpoint biomarker in lung cancer chemoprevention trials. The authors found a high correlation between the epithelial proliferation and metaplasia indices in both 120 current and 207 former smokers. In active smokers, proliferation indices were correlated with smoking intensity. In subjects who had quit smoking, the parabasal proliferative indices decreased rapidly within 1 year but remained detectable for more than 20 years, even in the absence of metaplasia. The authors conclude that epithelial cell proliferation measured by Ki-67 may provide a useful biomarker in the assessment of the response to chemopreventive interventions.
In an editorial, Szabo (p. 1042) discusses the basic requirements for successful chemoprevention trials and useful biomarkers by highlighting some of the benefits and problems associated with Ki-67 and lung epithelial proliferation.
Oncogenic Ras and Cancer Therapy
Ras is a proto-oncogene product that functions as a molecular switch, mainly controlling the differentiation or proliferation of cells. Each mammalian cell contains at least three distinct ras proto-oncogenes that encode closely related but distinct proteins. Activating mutations in these ras genes results in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Oncogenic mutations in the ras gene are present in approximately 30% of all human cancers. The ras-signaling pathway has attracted considerable attention as a target for anticancer therapy because of its important role in carcinogenesis. In this review, Adjei (p. 1062) discusses the physiologic and biochemical properties of the Ras proteins, their mechanism of cell signaling, and their relation to human cancer. He also discusses novel cancer therapeutic approaches based on the inhibition of Ras-mediated signaling.
Magnetic Resonance Imaging and Mammography
It is recommended that women with a hereditary risk of breast cancer be screened beginning at a younger age. However, the sensitivity of mammography for young women is reduced. Stoutjesdijk et al. (p. 1095) compared magnetic resonance imaging (MRI) with mammography in a retrospective cohort of 179 Dutch women from a single clinic to determine if the addition of MRI would benefit the early detection of breast cancer in young women with a hereditary risk of the disease. The authors found that the specificity was slightly higher for mammography than for MRI but that the sensitivity, predictive value of a positive report, and predictive value of a negative report were all higher for MRI than for mammography. The authors conclude that MRI was more accurate than mammography in annual breast cancer surveillance of women with a hereditary risk of breast cancer.
| ||||||||||||||||||||||||||||||||||||