Colorectal Cancer Cell Biology and Its Clinical Implication
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Numerous approaches have been focused on developing new tools for the detection of colorectal cancer at an earlier stage, or extending a further insight of raidio-, and chemo-sensitivity, which gives a clue to increase therapeutic efficacy and/or predict response. We herein introduce our approaches and achieves so far.<BR>Early Detection of Colorectal Cancers<BR>Microarray technologies can be used for mutation detection in DNAs from cancer tissues, stools, and cancer cell lines. For early detection of colorectal cancers by mutational analysis, we have developed β3-catenin, x-ras, and BRAF oligonucleotide microarrays, and several microarrays to detect mutations in stool DNA are under developing. We also developed a new approach for a robust microsatellite instability (MSI) analysis. Five Bethesda microsatellite markers (BAT-25, BAT-26, D5S346, D2S123, and D17S250) for MSI have been tested by denaturing high-performance liquid chromatography (DHPLC) analysis. It took just 9 min per PCR product to determine MSI using this new protocol. Our microarrays and new MSI analysis mighty be useful for colorectal cancer diagnosis at an earlier stage.<BR>Chemoradiotherapy of Rectal Cancer<BR>It was recently reported that microarray gene expression profiling was capable of response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. It will be very helpful to predict the responsiveness of chemoradiotherapy by using microarray expression profiling. High sensitivity and specificity of response prediction was obtained in microarray analysis. We are also performing microarray analysis to predict responsiveness of rectal cancers in preoperative chemoradiotherapy.<BR>Chemotherapy of Advanced Colorectal Cancer<BR>5-Fluorouracil (5-FU) has been mainstay of chemotherapeutic option for patients with advanced colorectal cancer. However, 5-FU resistance becomes a problem for chemotherapy. Thymidylate synthase (TS) has been focused as an important molecule leading to 5-FU resistance. High TS protein or mRNA levels in tumors have tended to be associated with a worse response to 5-FU. Nevertheless, recent reports have shown the opposite i. e., level of TS protein in primary tumors does not aid in predicting outcome or response to 5-FU. Thus, it is now generally accepted that other, yet unknown mechanisms have to be involved in resistance to 5-FU-based chemotherapy. Because understanding of these unknown mechanisms by which tumors become resistant to 5-FU is an essential step towards predicting or overcoming that resistance, we have been screening new targets linked to 5-FU resistance by means of 2-DE-based proteomics. From this assessment, we were able to confirm not only that 5-FU resistance can be mediated by abnormal regulation of single protein such as mitochondrial F1F0-ATP synthase, metabotropic glutamate receptor 4, but also that various mechanisms are existed depending on type of colorectal cancer cell. Now our approaches are therefore, focusing on finding of the 'common' (or 'crossed') 5-FU resistance mechanism (s) applying for all types of colorectal cancer cells and it might be a basis to increase an efficacy of 5-FU-based chemotherapy.