The role of neuropilin-1 and semaphorin 3A in glioblastoma progression and dispersal
Başlık çevirisi mevcut değil.
- Tez No: 400445
- Danışmanlar: DANIEL G. JAY
- Tez Türü: Doktora
- Konular: Biyomühendislik, Radyoloji ve Nükleer Tıp, Radyasyon Onkolojisi, Bioengineering, Radiology and Nuclear Medicine, Radiation Oncology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2008
- Dil: İngilizce
- Üniversite: Tufts Unıversıty
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Biyomedikal Bilimler ve Mühendislik Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
Özet yok.
Özet (Çeviri)
Glioblastoma multiforme (GBM) is the most common and aggressive type ofgliomas with a mean survival of 1 year after diagnosis. A major obstacle in treatingGBMs is the extensive tumor cell infiltration into the surrounding brain. Therefore,understanding the mechanisms that contribute to GBM cell dispersal is crucial fordeveloping effective therapies. The first and the major part of this thesis work addressedthe role of Neuropilin-1 in GBM dispersal. A functional proteomic screen performed inour laboratory identified Neuropilin-1 as a mediator of cancer cell invasion. Neuropilin-1was originally known as a neuronal receptor for Semaphorin3A (Sema3A), a secretedchemorepellent that facilitates axon guidance during neural development. My thesis workdemonstrated a novel role for this ligand-receptor pair in GBM dispersal. Usingfluorophore-assisted light inactivation, I showed that Neuropilin-1 is required for GBMcell migration. I also showed that GBM cells secrete their own Sema3A, which acts as anautocrine chemorepellent for Neuropilin-1 expressing tumor cells. Downregulation ofSema3A by RNA interference decreases migration and three-dimensional dispersal oftumor cells away from a spheroid suggesting that endogenous chemorepulsive signals ofSema3A facilitate GBM dispersal. My studies also revealed that Sema3A facilitatesdispersal by decreasing cell-substrate adhesion in a Neuropilin-1 dependent manner,thereby allowing for efficient release from focal adhesions. In addition, I showed thatSema3A and Neuropilin-1 are overexpressed in human GBMs compared to nonneoplasticbrain attesting to their pathological relevance. These findings implicateSema3A as an autocrine signal for Neuropilin-1 to promote GBM dispersal and suggestthat targeting Sema3A-Neuropilin-1 signaling may limit the infiltration of GBMs.The second part of my thesis focused on another feature of GBMs: tumorhypoxia. The presence of hypoxic zones surrounded by a dense layer of cells,pseudopalisades, is a distinguishing feature of GBMs and is associated with poorprognosis. These hypoxic regions are physically and functionally coupled to robusttumor angiogenesis, which is also a hallmark of GBMs. I showed that Sema3Aexpression is lower in the hypoxic, pseudopalisade-enriched regions compared tonormoxic regions within GBMs. Importantly, the receptor for Sema3A, Neuropilin-1,also functions as a receptor for the most well-known pro-angiogenic factor, vascularendothelial growth factor (VEGF). In the second part of my thesis work, I showed thatthe angiogenesis mediated by Neuropilin-1 might be controlled by the opposite regulationof its pro- and anti-angiogenic ligands, VEGF165 and Sema3A, respectively. Therefore,the competition between the two Neuropilin-1 ligands, VEGF and Sema3A, could affectangiogenesis and ultimately influence GBM progression. Lastly, I introduced a new set offunction blocking anti-Nrp-1 recombinant antibodies that are generated by phage display.These antibodies will serve as potential tools to target Neuropilin-1 mediated processes inGBMs.Together, these studies provide insight into the role of Neuropilin-1 and Sema3Ain GBM progression and dispersal. They implicate this receptor-ligand pair as a potentialtarget for drug therapy to treat GBM.
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