The parable of the proteome: cancer biomarkers

The parable of the proteome: cancer biomarkers

358 News & Comment TRENDS in Cell Biology Vol.12 No.8 August 2002 Journal Club Putting a Nek into the cellular guillotine The French Revolution di...

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News & Comment

TRENDS in Cell Biology Vol.12 No.8 August 2002

Journal Club

Putting a Nek into the cellular guillotine The French Revolution didn’t have a monopoly on guillotines. Like a molecular ‘Madame Guillotine’, the severing factor Katanin brutally dismembers mitotic microtubules, and, in cells with cilia or flagella, it hacks off the flagellum in response to environmental stresses. In addition to this dual role of katanins, a recent genetic analysis [1] now has revealed a second link between flagellar severing and mitosis. The FA2 gene of Chlamydomonas was identified in a screen for mutants unable to sever flagella and encodes a kinase of the NIMA family. NIMA promotes the G2–M transition in fungi, and animal cell homologs called Nek proteins

play a variety of roles, including regulating centriole separation. Interestingly, fa2 mutant cells also show defects in cell-cycle progression. fa2 mutants enter and complete S phase just as fast as wild-type cells but show a delay in entering mitosis. Thus, fa2 mutants show a defect at the same stage of the cell cycle as NIMA mutants in fungi. Unlike NIMA, FA2 is not essential; however, the Chlamydomonas genome project has already revealed two other genes encoding Nek proteins, which might act redundantly to FA2. Why is FA2 involved in both deflagellation and mitosis? This kinase might simply regulate two disparate processes. Or perhaps deflagellation,

which usually precedes cell division, allows basal bodies to become centrioles. Deflagellation defects could thus impede mitosis. But since katanin acts in both processes, it is possible that the FA2 kinase is a cellular ‘Robespierre’ that controls katanin-based severing in the cell in general. Resolving these possibilities awaits future experiments. 1 Mahjoub, M.R. et al. (2002) The FA2 gene of Chlamydomonas encodes a NIMA family kinase with roles in cell cycle progression and microtubule severing during deflagellation. J. Cell Sci. 115, 1759–1768

Wallace F. Marshall [email protected]

The parable of the proteome: cancer biomarkers Ovarian cancer is the leading gynecologic malignancy resulting in death in the USA. It is estimated that 23 000 new cases will be diagnosed and 14 000 deaths will occur in 2002 [1]. Early symptoms of this disease are often overlooked, and no clear risk factors or early detection biomarkers are available. As a result, the majority of ovarian cancers are not detected until late stages, after the cancer has already metastasized from the ovary. Unfortunately, the five-year survival for late-stage ovarian cancer is less than 20%. By contrast, the five-year survival for patients diagnosed with stage I ovarian cancer can be as high as 95%. Thus, early detection, combined with current therapies, has the potential to greatly decrease the mortality and suffering associated with this disease. The application of emerging genomic and proteomic array technologies to the early detection of disease is generating an enormous volume of data. Recent developments in bioinformatics are providing researchers with the tools necessary for analyzing these results. Liotta and colleagues [2] have developed a method, which combines surface-enhanced laser desorption and ionization time-offlight (SELDI-TOF) mass spectroscopy and bioinformatics, for analyzing proteomic sera patterns. Using this method, they have

generated a proteomic ‘fingerprint’ capable of distinguishing the serum profiles of ovarian cancer patients from those of control women. A ‘training set’ SELDI-TOF mass spectra, consisting of sera analyses from 50 control patients and 50 ovarian cancer patients, was generated and analyzed. A proteomic pattern or ‘fingerprint’ for ovarian cancer was generated that consists of five distinguishing mass/charge spectra values. These investigators then used this discriminatory pattern to analyze 116 masked serum specimens and were able to correctly identify 50/50 ovarian cancer patients (100% sensitivity; including 18 stage I cases) and 63/66 (95% specificity) unaffected women. The discovery of this unique proteomic pattern in serum might provide a promising screening test for the early detection of ovarian cancer, which could ultimately contribute to a dramatic decrease in the mortality of this disease. But, who should be screened? Interestingly, the majority of control patients used in this study were from a high-risk population, in which the test yielded 95% specificity. What would the specificity of this test be in the general population? Future prospective studies will be required to better understand the frequency of false positives and also to

determine the appropriate clinical follow-up for patients with positive test results. Another major challenge introduced by this technology is whether the unknown peptide/protein pattern alone is sufficient for diagnosing ovarian cancer, or could this test be improved by identifying and validating the individual discriminatory peptides/proteins? One could argue that, if the ‘shadows’ of these proteins can be profiled reproducibly, then they should be clinically useful anonymously. One also could argue, however, that knowing the identity of the proteins that these profiles represent might reveal new insights into the biology of ovarian cancer, thereby creating new avenues for basic cell-biological and clinical research. This study represents just one example of the rapid clinical application of recent advances in proteomic technology and the challenge that this pace implies for cancer cell biologists. 1 Jemel, A. et al. (2002) Cancer statistics, 2002. CA Cancer J. Clin. 52, 23–47 2 Petricoin, E.F. et al. (2002) Use of proteomic patterns in serum to identify ovarian cancer. Lancet 359, 572–577

Jacqueline M. Lafky Nita J. Maihle [email protected]

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