{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/115877"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/115877","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Investigating the dependency of metabotropic glutamate receptor 1 signaling for sustaining rapid proliferation of hemangiosarcoma cells","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","abstract_has_math":false,"creators":["Masyr, Alison Renee"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"M.S.","degree_level":"Thesis","degree_discipline":"VMS-Veterinary Clinical Medcne","degree_department":null,"school":null,"contributors":["Fan, Timothy M","Gal, Arnon","Samuelson, Jonathan"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08","date_published":"2022-08","updated_at":"2026-07-22T22:24:55Z","subjects":["hemangiosarcoma","glutamine"],"languages":["en","eng"],"rights":["Copyright 2022 Alison Masyr"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/115877","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Fan, Timothy M","Gal, Arnon","Samuelson, Jonathan"]},{"key":"dc:creator","label":"Author","values":["Masyr, Alison Renee"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-08","2022-07-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["VMS-Veterinary Clinical Medcne"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.S."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["hemangiosarcoma","glutamine"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2022 Alison Masyr"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/115877"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","The student, Alison Masyr, accepted the attached license on 2022-06-23 at 19:11.","The student, Alison Masyr, submitted this Thesis for approval on 2022-06-23 at 19:35.","This Thesis was approved for publication on 2022-07-05 at 16:24.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18099 on 2022-11-16 at 10:17:23","Glutamine is an amino acid utilized by numerous types of cancer cells as an anaplerotic resource as it can be incorporated into several different biosynthetic pathways. Rapid glutamine utilization allows cancer cells to undergo brisk proliferation and eventual metastasis. Specifically, metabotropic glutamate receptor 1 (mGluR1) is a transmembrane protein overexpressed in several cancer types and heavily involved in tumorigenesis. Furthermore, proliferating endothelial cells express mGluR1 and rely on glutamine metabolism in both physiologic and pathophysiologic conditions. These pathophysiologic conditions include tumor-associated neovasculature and malignantly transformed endothelial cells (such as Kaposi’s sarcoma). Canine hemangiosarcoma (cHSA) is an aggressive malignancy that is believed to arise from hemangioblast bone marrow progenitor cells. The majority of canine splenic tumors are cHSA and despite the high incidence of this tumor, treatment advances have stagnated over the last several decades. Historically, treatment approaches have revolved around cytoreduction and cytotoxicity. The reliance on glutamine leaves cancer cells vulnerable to metabolic strategies that limit glutamine availability. Metabotropic glutamate receptor 1 antagonists, in particular, have been successful at reducing tumor and endothelial cell proliferation. Given the high demand for glutamine by tumor cells, tumor-associated neovasculature, and malignantly transformed endothelial cells, we hypothesize that glutamine metabolism will be implicated in cHSA proliferation. We anticipate that cHSA cells will express mGluR1 and that cHSA cells will experience a reduction in proliferation rate when exposed to mGluR1 inhibitors. RNA transcripts and protein levels of mGluR1 were evaluated in three cHSA cells lines. Metabotropic glutamate receptor 1 expression was demonstrated in cHSA tissues via immunohistochemistry (IHC). IC50 values for mGluR1 inhibitors BAY-36-7620 and riluzole were established in all cell lines. Ki-67 protein expression was used as a marker of cellular proliferation and was demonstrated in cHSA tissues via IHC. Confocal microscopy was utilized to assess alterations in Ki-67 expression following treatment with BAY-36-7620. Flow cytometry was used to evaluate changes cell cycle distribution and apoptotic cell fraction following treatment with BAY-36-7620. Canine hemangiosarcoma cell lines and tissues express mGluR1. The IC50 value of BAY-36-7620 in cHSA cells ranged from 29 to 54 μM. The IC50 value of riluzole in cHSA cells ranged from 22 to 40 μM. Ki-67 expression was documented in cHSA tissues. A correlation between Ki-67 and mGluR1 staining scores was not established. Treatment with BAY-36-7620 resulted in reduced Ki-67 expression and increased the fraction of cHSA cell in non-proliferative phases of the cell cycle. However, BAY-36-7620 treatment (10 μM) did not increase the proportion of apoptotic or dead cells. Metabotropic glutamate receptor 1 is expressed in cHSA and inhibition thereof can induce cytostasis. This non-cytotoxic driven approach may have therapeutic applications for cHSA and warrants further investigation of mGluR1 inhibition strategies for treatment of cHSA and other highly vascularized tumors."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Investigating the dependency of metabotropic glutamate receptor 1 signaling for sustaining rapid proliferation of hemangiosarcoma cells"]}]}],"canonical_facts":{"dc:contributor":["Fan, Timothy M","Gal, Arnon","Samuelson, Jonathan"],"dc:creator":["Masyr, Alison Renee"],"dc:date":["2022-08","2022-07-05"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-08-01","The student, Alison Masyr, accepted the attached license on 2022-06-23 at 19:11.","The student, Alison Masyr, submitted this Thesis for approval on 2022-06-23 at 19:35.","This Thesis was approved for publication on 2022-07-05 at 16:24.","DSpace SAF Submission Ingestion Package generated from Vireo submission #18099 on 2022-11-16 at 10:17:23","Glutamine is an amino acid utilized by numerous types of cancer cells as an anaplerotic resource as it can be incorporated into several different biosynthetic pathways. Rapid glutamine utilization allows cancer cells to undergo brisk proliferation and eventual metastasis. Specifically, metabotropic glutamate receptor 1 (mGluR1) is a transmembrane protein overexpressed in several cancer types and heavily involved in tumorigenesis. Furthermore, proliferating endothelial cells express mGluR1 and rely on glutamine metabolism in both physiologic and pathophysiologic conditions. These pathophysiologic conditions include tumor-associated neovasculature and malignantly transformed endothelial cells (such as Kaposi’s sarcoma). Canine hemangiosarcoma (cHSA) is an aggressive malignancy that is believed to arise from hemangioblast bone marrow progenitor cells. The majority of canine splenic tumors are cHSA and despite the high incidence of this tumor, treatment advances have stagnated over the last several decades. Historically, treatment approaches have revolved around cytoreduction and cytotoxicity. The reliance on glutamine leaves cancer cells vulnerable to metabolic strategies that limit glutamine availability. Metabotropic glutamate receptor 1 antagonists, in particular, have been successful at reducing tumor and endothelial cell proliferation. Given the high demand for glutamine by tumor cells, tumor-associated neovasculature, and malignantly transformed endothelial cells, we hypothesize that glutamine metabolism will be implicated in cHSA proliferation. We anticipate that cHSA cells will express mGluR1 and that cHSA cells will experience a reduction in proliferation rate when exposed to mGluR1 inhibitors. RNA transcripts and protein levels of mGluR1 were evaluated in three cHSA cells lines. Metabotropic glutamate receptor 1 expression was demonstrated in cHSA tissues via immunohistochemistry (IHC). IC50 values for mGluR1 inhibitors BAY-36-7620 and riluzole were established in all cell lines. Ki-67 protein expression was used as a marker of cellular proliferation and was demonstrated in cHSA tissues via IHC. Confocal microscopy was utilized to assess alterations in Ki-67 expression following treatment with BAY-36-7620. Flow cytometry was used to evaluate changes cell cycle distribution and apoptotic cell fraction following treatment with BAY-36-7620. Canine hemangiosarcoma cell lines and tissues express mGluR1. The IC50 value of BAY-36-7620 in cHSA cells ranged from 29 to 54 μM. The IC50 value of riluzole in cHSA cells ranged from 22 to 40 μM. Ki-67 expression was documented in cHSA tissues. A correlation between Ki-67 and mGluR1 staining scores was not established. Treatment with BAY-36-7620 resulted in reduced Ki-67 expression and increased the fraction of cHSA cell in non-proliferative phases of the cell cycle. However, BAY-36-7620 treatment (10 μM) did not increase the proportion of apoptotic or dead cells. Metabotropic glutamate receptor 1 is expressed in cHSA and inhibition thereof can induce cytostasis. This non-cytotoxic driven approach may have therapeutic applications for cHSA and warrants further investigation of mGluR1 inhibition strategies for treatment of cHSA and other highly vascularized tumors."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/115877"],"dc:language":["en","eng"],"dc:rights":["Copyright 2022 Alison Masyr"],"dc:subject":["hemangiosarcoma","glutamine"],"dc:title":["Investigating the dependency of metabotropic glutamate receptor 1 signaling for sustaining rapid proliferation of hemangiosarcoma cells"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["VMS-Veterinary Clinical Medcne"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["M.S."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:55Z"}