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dc.contributor.advisorMcKnight, C. Jamesen_US
dc.contributor.advisorBirge, Raymond B.en_US
dc.contributor.authorDevoe, Connor B.en_US
dc.date.accessioned2020-11-19T18:31:21Z
dc.date.available2020-11-19T18:31:21Z
dc.date.issued2020
dc.identifier.urihttps://hdl.handle.net/2144/41699
dc.description.abstractCell death occurs by multiple pathways, though perhaps the most well-studied is apoptosis. Apoptosis describes a regulated, or programmed, form of cell death. While other forms of cell death, such as ischemic necrosis, occur via ATP-independent mechanisms, apoptosis is an ATP-dependent process that is reliant on intracellular enzymes known as “caspases”. Caspase-dependent cell death has been described as “death by a thousand cuts” as these proteases have a vast array of downstream targets which ultimately lead to chromatin condensation, extensive membrane blebbing and the formation of apoptotic bodies which are tagged for engulfment by professional and non-professional phagocytes. While the machinery for cell death is expressed in all living cells, inhibitory proteins have been shown to exert control over apoptosis, particularly the B-cell lymphoma-2 (Bcl-2) protein and its family members. Bcl-2 itself is anti-apoptotic, alongside others such as Bcl-XL, Mcl-2 and Bcl-w. Others, such as BAK and BAX are pro-apoptotic and considered essential mediators of the mitochondrial outer membrane permeabilization characteristic of intrinsic apoptotic signaling. The highest level of control, however, appears to be exerted by the so-called “BH3-only” proteins, such as BAD and BID, which disrupt Bcl-2-mediated antagonism of BAK/BAX and directly stimulate BAK/BAX activity. The balance of these proteins was described in the “Rheostat Model”, proposed in the 1990s by Stanley Korsmeyer and colleagues. The idea that oncogenic overexpression of anti-apoptotic proteins (i.e. the BCL-2 family) play an integral role in the survival and growth of tumors is a long-standing and well-supported hypothesis. Compared to necrotic cell death, apoptosis is considered relatively “silent” to the immune system, as it does not generate a large-scale inflammatory response. Engulfment of apoptotic cells by phagocytic cells is also known as “efferocytosis”, and results in the release of anti-inflammatory cytokines. One molecule integral in mediating efferocytosis is phosphatidylserine (PS), a signaling lipid externalized on the cell membrane in apoptotic cells. PS interacts with PS receptors to mediate resolution of inflammation through triggering the release of anti-inflammatory cytokines and directly preventing pro-inflammatory cytokine release. Physiologically, this is a desirable process. Dysregulation of efferocytosis can lead to chronic inflammatory conditions, such as systemic lupus erythematosus. Recently, however, evidence has emerged supporting a role of apoptosis in signaling proliferation of neighboring cells in the tumor microenvironment. This stems from an understanding of apoptotic signaling in healthy tissues, such as wound regeneration, and the analogy of tumors as “wounds that do not heal”. Work by Andreas Bergmann and colleagues has demonstrated this apoptosis-induced proliferation (AiP) in Drosophila and described how this could translate to higher organisms including mammals. Cells neighboring a site of injury where apoptosis is occurring in massive amounts may undergo compensatory proliferation. In the tumor microenvironment, where apoptosis is occurring, efferocytosis and AiP may work in concert to suppress an appropriate immune response and promote proliferation of neighboring cells. AiP may be further implicated in tumorigenesis and recurrence after treatment with apoptosis inducing chemotherapeutics. Sustained compensatory proliferation signaling may provide an explanation for this paradoxical phenomenon.en_US
dc.language.isoen_US
dc.subjectMedicineen_US
dc.titleApoptotic cell death promotes an immune evasion phenotype in tumor cellsen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2020-11-19T17:02:11Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.orcid0000-0003-0760-9196


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