Hypoxia signaling in cancer development

Division Of Basic Sciences - Nci

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Abstract

We have successfully generated two murine models for the study of the two most well-known hypoxia signaling associated tumor syndromes: VHL disease and Pacak-Zhuang syndrome. These models provided a good opportunity to investigate the mechanisms of abnormal hypoxia signaling in tumorigenesis and development of these tumor syndromes. In VHL model, which recapitulates the human autosomal dominant inheritance and second hit of the VHL gene in tumorigenesis, we have found developmentally arrested hemangioblast cells leading to the development of retinal hemangioblastomas. In addition, the affected VHL mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histological analyses showed hemangioblastoma-like lesions characterized by tortuous, dilated vasculature surrounded by tumorlet cells and isolated foamy stromal cells which are typically associated with hemangioblastomas. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. VHL deletion was detected in tumorlet cells by microdissection. This is the first phenotypic recapitulation of VHL-associated retinal hemangioblastomas in a transgenic mouse model. This model may be useful for further study of tumor hypoxia pathogenesis and for testing VHL disease and its sporadic counter-part tumor treatments. We have also successfully developed the murine models carrying the same point mutation in HIF2A found in our index patients with Pacak-Zhuang syndrome. This model has recapitulated the phenotype of this syndrome. In this model we have found the classic constellation of the syndrome including polycythemia, the biochemical noradrenergic phenotype of the paraganglioma, and elevated somatostatin. Further, in this mouse model, we identified vascular malformations and congenital vascular anomalies that we were then able to confirm in the patients with the syndrome. This finding has added a new feature to the syndrome and also furthered our understanding of the HIF2A effect on vascular development. Further, this model of Pacak-Zhuang syndrome has been critical in identifying basic mechanism associated with developmental effect in this tumor syndrome, which further supports the early developmental impact of hypoxia signaling seen in VHL disease. For example, the unusual anatomic location of the tumors in Pacak-Zhuang syndrome reflect the cells arrested in early development during migration due to HIF2 gene mutation. All of the syndrome patients develop paraganglioma, not pheochromocytoma, and somatostatinoma in duodenal ampulla area instead of pancreatic islet tumor. These observations and studies in the mouse model explain the patient phenotype and molecular pathogenesis of their tumors associated with HIF2 effect on cell during development. The same effect can also explain the vascular malformations observed in the syndrome, which are the result of a failure of vascular regression and pruning during the development. With this model, we have a great opportunity to study the development of these malformations and tumors. Our studies on hypoxia signaling can provide insight into the development of glioma, which is well-known to have extensive hypoxia activation in tumor cells. A unique gene mutation associated with glioma is the IDH1/R132H mutation. It causes pseudo-hypoxia signaling due to the insufficiency of the TCA cycle. These IDH1 mutations are often coupled with P53 mutations in astrocytoma. To investigate the role of hypoxia signaling and the IDH1 and P53 mutations in gliomagenesis, we have made progress toward establishing a model of these tumors from induced pluripotent stem cells (iPS) from the peripheral mononuclear cells (PBMC) of Li-Fraumeni patients. These cells carry germline P53 mutations (P53.C141Y) with an introduced tetracycline-regulated (tet-on) expression system of IDH1R132H. We differentiated these cells to neuroprogenitor cells and injected them into the murine brain as a xenograft. We are following these mice for the development of IDH1+/P53+ gliomas derived from these injected iPS cells. In addition to the above studies, we have also made progress to develop small molecular compounds, immunotherapeutic agents, and CAR-T cell against targets in hypoxia signaling pathway for gliomas therapy.