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In their efforts to understand cancer, investigators often compare the proteomic profiles of tumor cells with those of healthy cells. Although these efforts have led to advances in cancer detection and prognosis, they have done little to directly facilitate cancer prevention. In this issue of JPR (DOI 10.1021/pr800501j), Ranju Ralhan, K. W. Michael Siu, and colleagues at York University (Canada) and the All India Institute of Medical Sciences describe their efforts to identify and understand proteomic biomarkers in precancerous lesions. “If we can identify the biomarkers that detect disease in the early stages, we have a better chance to treat the disease before it becomes a problem,” Ralhan says. The researchers focused their efforts on oral cancers, which Ralhan says are very common in South and Southeast Asia because of the prevalence of tobacco use and the human papilloma virus. Despite advances in the treatment paradigms for oral cancer, the 5 year survival rates for infected people in these regions have not significantly improved, she says. The investigators homogenized tissues in and around oral premalignant lesions (OPLs) as well as tissues from healthy individuals and labeled the proteins with isobaric tagging for relative and absolute quantitation (iTRAQ) reagents. As Ralhan explains, the team wanted to include nearby cell types in the OPL samples to better understand the contributions of tissues surrounding the lesions to cancer development. “The early events in tumor development are spontaneous and link inflammation with development of microscopic intraepithelial lesions that are affected by the interactions between epithelial cells and tissue stromal components,” she says. “The tumor cells and stromal components secrete growth factors, chemokines, and enzymes into the microenvironment that contribute to the ensuing tissue remodeling, cytoskeletal reorganization, rapid cell proliferation, and ultimatelypromote tumor growth,” she adds. However, the role of the tissue mi-
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cellular signaling, proliferation, and gene expression. Perhaps more important, the researchers noted an overlap between the proteins upregulated in OPLs and those identified in an earlier study (Mol. Cell. Proteomics 2008, 7, 1162-1173). “This provides a very important link between chronic inflammation and premalignant lesions,” Ralhan says. “While it has been known that inflammation is linked to cancer, we have not known how. The next step will be to create cell lines that develop premalignant lesions to further understand the mechanisms behind these links using the cell cultures from oral premalignant lesions established by the group. “From a clinical perspective, we will have to develop immunoassays that will let us validate these biomarkers for use in medical tests,” adds Ralhan. This step will be critical, she says, because when cancers initially form in the oral cavity, extensive molecular and genetic alterations occur that are not picked up by histology. Ralhan describes the formation of these alterations as Ahh. Researchers are using multidimensional LC/MS/MS to field cancerization. identify markers of premalignant oral cancer (leukoplakia). The present work complements earlier efforts by the researchers to identify prognostic biomarkers in cancer tissues as well, Siu control sample. They also included says. “In another paper, we describe proteins that were known to be inthe identification of biomarkers volved in tumorigenesis. The differlinked to what happened to patients ential expressions were confirmed at who developed oral cancer,” he exthe protein and RNA levels with implains (J. Proteome Res. 2008, 7 (5), munohistochemical, western blot, 2078-2087). “We looked at tissue and RT-PCR analyses. samples from the patients and retroOf the 439 nonredundant proteins spectively analyzed the patients’ prothey identified, the researchers found gression for 42 months following diag17 that met their criteria for further nosis, finding strong links between analysis; the three candidates that certain biomarkers and patient surperformed the best in subsequent vival.” statistical analyses were stratifin, By identifying biomarkers at all YWHAZ, and hnRNPK. These proteins stages of oral cancer development, were up-regulated 2-4-fold in the the researchers are developing a proOPLs compared with normal tissues, teomic profile that characterizes the as were two other proteins they anadisease from its earliest precancerous lyzed, prothymosin alpha and moments to malignancy and its ultiS100A7, which had links to tumormate impact on patient survival. “Uligenesis. timately, we want this work to be Network analysis of the five protranslational so that it can be used to teins showed they were involved in improve patient care,” Siu says. “But one of two major networks. The first there is a long road between here network was related to inflammation, and there.” molecular transport, cancer, and cel—Randall C Willis lular movement; the second involved croenvironment in early premalignant stages of tumorigenesis is not well defined. To identify proteins differentially expressed in the OPL samples, the researchers analyzed the samples with multidimensional LC/MS/MS. The researchers chose to focus on proteins that were detected in more than half the OPLs and showed >50% change in expression relative to the
Journal of Proteome Research • Vol. 8, No. 1, 2009
JUPITERIMAGES
Identifying markers of premalignancy
10.1021/pr800930c
© 2009 American Chemical Society
