Modeling Medulloblastoma With Genetically Engineered Mice
Modeling Medulloblastoma With Genetically Engineered Mice
Medulloblastoma is a malignant tumor that arises in the cerebellum in children, presumably by transformation of granule neuron precursor cells. In vivo models of medulloblastoma in genetically engineered mice have shown that activation of signal transduction pathways that stimulate proliferation and inhibit differentiation of neural progenitor cells during cerebellar development initiate medulloblastoma formation. Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3kinase (PI3K) signaling pathway by insulin-like growth factorII, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shhmediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma. By revealing which cell signaling proteins can initiate medulloblastoma formation, mouse models have enabled investigators to identify molecular targets for designing new therapies. Small-molecule inhibitors of the Shh/Patched and PI3K pathways are potential chemotherapeutic agents for patients with medulloblastoma.
Over the past several decades, rapid expansion in our understanding of the molecular biology of cancer has dispelled any hope that this disease might be explained by mutations in a small number of genes. On the contrary, cancer cells have many mutant genes and dysfunctional proteins. Although this fact may pique the interest of basic scientists who challenge themselves by solving complex problems, it makes it difficult for clinical scientists to select targets for new cancer therapies. Therefore, we look to animal models of human cancer to help identify key proteins that are physiologically relevant to tumor formation. In this review, I will discuss how scientists are using genetically engineered mice to decipher, at the molecular level, the origins of the pediatric brain tumor, medulloblastoma, and how mouse models are used to design novel therapeutic strategies.
Medulloblastoma is the most common solid tumor afflicting children, and the need for improved treatments for patients with this disease is pressing. Current treatment regimens, which combine surgery with craniospinal radiation and multiagent chemotherapy, offer 5-year survival rates of 75% and result in cures in half of newly diagnosed patients.42 Nevertheless, long-term survivors experience skeletal growth retardation, endocrine dysfunction, and progressive cognitive impairment.43,57 They are also at increased risk for psychiatric disturbances and social difficulties.52 These devastating side effects are attributed to collateral damage to the developing nervous system by anticancer agents, particularly radiation, rather than to the disease itself. Thus, the central practical objective of modern medulloblastoma research is to find ways of increasing treatment specificity for cancer cells and thereby to minimize damage to the developing brain.
What can experiments in mice tell us about human cancer? First, the mouse models discussed in this review have made it possible to determine which cell signaling pathways are required to initiate formation of the tumor and which ones are needed to maintain its growth. Knowing which signaling pathways are activated in mouse tumors can reveal molecular targets for therapeutic intervention in humans, in addition to providing insights into tumor origins. Second, mouse toma, models of human cancer are valuable experimental systems for preclinical testing of novel therapies. Their utility includes testing new chemotherapy drugs and novel uses of existing drugs or combined regimens. Third, mouse models generate an abundant supply of tumor specimens for molecular analysis. This is particularly important for comparatively uncommon types of tumors like medulloblastomas. Finally, mouse models are facilitating the development of sensitive and noninvasive imaging modalities.
Medulloblastoma is a malignant tumor that arises in the cerebellum in children, presumably by transformation of granule neuron precursor cells. In vivo models of medulloblastoma in genetically engineered mice have shown that activation of signal transduction pathways that stimulate proliferation and inhibit differentiation of neural progenitor cells during cerebellar development initiate medulloblastoma formation. Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3kinase (PI3K) signaling pathway by insulin-like growth factorII, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shhmediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma. By revealing which cell signaling proteins can initiate medulloblastoma formation, mouse models have enabled investigators to identify molecular targets for designing new therapies. Small-molecule inhibitors of the Shh/Patched and PI3K pathways are potential chemotherapeutic agents for patients with medulloblastoma.
Over the past several decades, rapid expansion in our understanding of the molecular biology of cancer has dispelled any hope that this disease might be explained by mutations in a small number of genes. On the contrary, cancer cells have many mutant genes and dysfunctional proteins. Although this fact may pique the interest of basic scientists who challenge themselves by solving complex problems, it makes it difficult for clinical scientists to select targets for new cancer therapies. Therefore, we look to animal models of human cancer to help identify key proteins that are physiologically relevant to tumor formation. In this review, I will discuss how scientists are using genetically engineered mice to decipher, at the molecular level, the origins of the pediatric brain tumor, medulloblastoma, and how mouse models are used to design novel therapeutic strategies.
Medulloblastoma is the most common solid tumor afflicting children, and the need for improved treatments for patients with this disease is pressing. Current treatment regimens, which combine surgery with craniospinal radiation and multiagent chemotherapy, offer 5-year survival rates of 75% and result in cures in half of newly diagnosed patients.42 Nevertheless, long-term survivors experience skeletal growth retardation, endocrine dysfunction, and progressive cognitive impairment.43,57 They are also at increased risk for psychiatric disturbances and social difficulties.52 These devastating side effects are attributed to collateral damage to the developing nervous system by anticancer agents, particularly radiation, rather than to the disease itself. Thus, the central practical objective of modern medulloblastoma research is to find ways of increasing treatment specificity for cancer cells and thereby to minimize damage to the developing brain.
What can experiments in mice tell us about human cancer? First, the mouse models discussed in this review have made it possible to determine which cell signaling pathways are required to initiate formation of the tumor and which ones are needed to maintain its growth. Knowing which signaling pathways are activated in mouse tumors can reveal molecular targets for therapeutic intervention in humans, in addition to providing insights into tumor origins. Second, mouse toma, models of human cancer are valuable experimental systems for preclinical testing of novel therapies. Their utility includes testing new chemotherapy drugs and novel uses of existing drugs or combined regimens. Third, mouse models generate an abundant supply of tumor specimens for molecular analysis. This is particularly important for comparatively uncommon types of tumors like medulloblastomas. Finally, mouse models are facilitating the development of sensitive and noninvasive imaging modalities.
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