中華民國解剖學學會AN

  Advances in stem cell research have given rise to organoid technology for generation of in vitro self-assembling three-dimensional cellular structures that stably retain key characteristics of the respective organs, can be generated either from adult tissue stem cells or induced pluripotent stem cells (iPSCs) of patients. In fact, cancer patient-derived organoids (PDOs) that have been shown to recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. The finding suggests cancer PDOs may be ideal platforms to not only be used to understand cancer mechanisms but also to identify and assess the efficacy of drugs for patients.

  Although the five-year survival rate of colorectal cancer (CRC) is significantly high with localized stage (90%), only 38% of the patients are diagnosed at this stage. Therefore, finding high risk factors of CRC could prevent the disease at the early stage. Obesity and high-fat diet consumption are risk factors of CRC. In detail, oleic acids (OA) were found to accumulate in the adipose tissues of obese patients as well as being the most common long chain fatty acid in dietary lipid. The role of OA in colorectal cancer development is still controversary. in order to dissect how long chain fatty acid can contribute to malignant transformation of Kras-mutant colonic epithelia, organoids, derived from Lgr5+-EGFP mice (normal colon control), Lgr5+-EGFP-creER;LSL-KrasG12D mice (colonic epithelium harbored KrasG12D mutation) and AOM/DSS-induced CRC mice (cancerous colon control) were generated. We discovered that oleic acid can promote the malignant transformation of Kras-mutant colonic organoids through NFATc-relating pathway. The expansion of tumorigenic stem cells via induction of abnormal Paneth cell, possibly contribute to the potential of cancer-toward metaplasia in Kras-mutant organoids when exposing to high levels of oleic acid.

  Clinically, addition of oxaliplatin to adjuvant 5-FU, such as FOLFOX (leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin), has significantly improved the disease-free survival in advanced colorectal cancer (CRC) patients, and serves as the first line adjuvant chemotherapy. However, more than 40% of patients remains refractory to oxaliplatin-based treatment. It is urgent to be able to predict the responsiveness toward oxaliplatin and to improve the efficacy in the resistant patients. Initially, we have established organoid lines from the biopsies of CRC patients, and performed drug sensitivity against oxaliplatin using patients-derived organoids. Notably, oxaliplatin sensitivity assessed in PDO lines in vitro was correlated to oxaliplatin sensitivity in PDO-xenografted tumors in vivo. In summary, our findings suggest organoid technologies can possibly be used to dissect role of metabolic reprogramming in development of CRC and PDOs are useful in informing decision-making on chemotherapy and in designing personalized chemotherapy for CRC patients.