The identification of specific protein markers for colorectal cancer would provide the basis for early diagnosis and detection, as well as clues for understanding the molecular mechanisms governing cancer progression. In this report, we describe the proteomic analysis of the samples of colorectal cancer corresponding to seven patients. We have used the highly sensitive two-dimensional differential gel electrophoresis (2-D DIGE) coupled with mass spectrometry (MS) for the identification of proteins differentially expressed in tumoral and neighboring normal mucosa. We have detected differences in abundance of 52 proteins with statistical variance of the tumor versus normal spot volume ratio within the 95th confidence level (Student's t-test; p < 0.05). Forty-one out of 52 analyzed proteins were unambiguously identified by matrix-assisted laser desorption/ionization-time of flight MS coupled with database interrogation as being differentially expressed in colorectal cancer. An ontology analysis of these proteins revealed that they were mainly involved in regulation of transcription (synovial sarcoma X5 protein, metastasis-associated protein 1), cellular reorganization and cytoskeleton (cytokeratins, vimentin, beta actin), cell communication and signal transduction (annexins IV and V, relaxin, APC), and protein synthesis and folding (heat shock protein 60, calreticulin, cathepsin D, RSP4) among others. Preliminary studies demonstrated that the differentially expressed proteins found by 2-D DIGE could be confirmed and validated by immunoblotting and immunohistochemistry analyses in those few cases where antibodies were available. We believe that the incorporation of more samples and new datasets will permit the definition of a collection of proteins with a potential interest as biomarkers for colorectal cancer.

Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938-47. Ó2014 AACR.

Ewing's sarcoma family tumors (EFT) are characterized by specific chromosomal translocations, which lead to EWS/ETS transcription factors. Elucidation of EWS/ETS target gene networks within the context of other signaling pathways, together with the identification of the initiating cell, and the development of genetically engineered mice will hopefully lead to biology-based therapeutic strategies for these tumors.