To better understand the signaling pathways active in sarcomas , researchers at Moffitt Cancer Center used state-of-the-art massspectrometry-based proteomics to characterize a family of proteinenzymes that act as "on" or "off" switches important in the biologyof cancer . The tyrosine kinases they identified, the researchers said, couldact as "drivers" for the growth and survival of sarcomas. Sarcomas are relatively rare forms of cancer. In contrast tocarcinomas, which arise from epithelial cells (in breast, colon and lung cancers , for example), sarcomas are tumors derived from bone, fat, muscleor vascular tissues. |
"Sarcomas are rare, diverse malignancies that arise from connectivetissues," said study lead author Eric B. Haura, M.D., programleader for Experimental Therapeutics. "We hypothesized that wecould identify important proteins that drive the growth andsurvival of these poorly understood sarcomas using an approach tocharacterize signaling proteins using mass spectrometry." According to Haura, whose lab focuses on signaling pathways incancer and understanding the role of kinases, proteinphosphorylation plays a significant role in a wide range ofcellular processes and is commonly disrupted in diseases such ascancer. The study approach is novel by engaging proteomics, anemerging and increasingly powerful approach to study proteins indisease in a more global and unbiased manner.
In this study, the Moffitt researchers identified 1,936 uniquetyrosine phosphorylated peptides corresponding to 844 uniquephospho-tyrosine proteins and found 39 tyrosine kinases in sarcomacells. Of the 99 tyrosine kinases present in the human genome, theresearch team identified peptides corresponding to nearly 40percent of the tyrosine kinome. "Tyrosine kinases play an important role in controlling thehallmarks of cancer, and they have a proven track record asdruggable targets for cancer treatment. Our goal was to produce a'landscape' of tyrosine phosphorylated proteins and tyrosinekinases prioritized for subsequent functional validation," Haurasaid.
"In our study, we identified numerous tyrosine kinases thatcan be important for cellular signaling in human sarcomas thatcould drive the natural progression of sarcoma and, therefore,could be targeted by small molecule inhibitors aimed at alteringsarcoma progression." Questions remain, however, about which, if any, of the 40 tyrosinekinases the researchers identified in sarcoma tumor cell lines actto regulate sarcoma tumor cell growth and tumor survival. "The answers to this question can help prioritize which potentialtargets to examine further, including advancement into trials ofpatients with advanced sarcoma," explained Haura. "As a first step,we screened sarcoma cell lines against a number of inhibitorsselected, all based on the tyrosine kinases we identified, andidentified some active drugs." While the researchers found kinases in sarcoma cells that deservedfurther study, they also concluded that the sarcoma cells testedexpressed multiple tyrosine kinases. That great number may limitthe effectiveness of targeted agents. "We think this approach could hold promise in profiling tumorsdirectly from patients and can complement existing genetic data onsarcomas.
Our results show this is feasible in tumor tissues, andwe hope to advance this further by directly studying additionaltumors from sarcoma patients." Additional References Citations.
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