Establishment Of PTEN With Multiple Gene Mutant Cancer Mice Model Following Small Molecular Inhibitor Drugs Target Cancer Stem Cells Therapy

The precise regulation and maintenance of balance between cell proliferation, differentiation and death in multicellular organisms are critical for tissue homeostasis. Their disorders would cause the pathogenesis of many diseases, especially cancers including leukemias. Acute Lymphoid leukemia (ALL) is characterized by differentiation block and uncontrolled proliferation of immature lymphoid cells. It is well documented that the HSC fate is decided by the molecular signals, Whereas, dyregulation of the molecular signals will induce the development of leukemia. Nevertheless, the role of these factors in the Pten-null&β-cat-active induction in T-ALL cells is not clear. To futher understand the molecular mechanism of cancer development of CSC, we establish a novel double mutant cancer mice model, whileas, use small molecular inhibitor drugs target leukemia CSC which may suggest that one novel target therapy on Pten-null&β-cat-active CSC. Here, we show that novel target therapy on double mutant mice model with small molecular inhibitor drugs regulate CSC formation.Part one:Pten-null&p-catetin activation will enhance T-ALL development Wnt/β-catenin play a crucial role in self-renewal of HSC to maintain hematopoiesis and lymphoid lineages throughout life. PTEN/PI3K/AKT signal pathway regulates proliferaion and apopotosis of HSC. Both of these signal pathway play important role in T cell differentiation, even modulating T-ALL development.Part two:combination therapy of small moleculara inhibitor can reduce the CSC in T-ALL mice modelCSC is a specific subset of cancer cells that could be resistance to wide range of recent clinical chemotherapy or radiotherapy.Novel small molecular inhibitor is able to selectively target CSC, inhibit the proliferation of CSC, promote the CSC apopotosis. As importantly, successful cancer therpay not only require shrink tumor size, but also less CSC to prevent relapse.Part three:Establish colon cancer mice model following cancer target therapy with cox-2inhibitor and5FUThe development of colon cancer is a complicate process. Loss of the tumor suppressor gene PTEN and mutation of APC gene will cooperatively trigger the tumor formation, ultimately induce maliganant tumor development. The colon cancer will constantly relapse post nomal chemotherapy. We establish a novel intesnial PTEN-null&apcmin double mutant mice which will develop colon cancer in a short time, continuely, we give cox-2inhibitor combine with5fu to observe how the target therapy works on our mice model.Consequently, Our works provided a new double mutant mice model which would develop tumor in a short time. These models successfully show line of evidence that mechanism of CSC formation in T-ALL development, and also partially contribute to study targetherapeutic agents-induced apoptosis in leukemic CSC..These novel findings would shed new insights for understanding the molecular mechanisms of the balance between differentiation and apoptosis in hematopoiesis and leukemogenesis.