Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma
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The Ohio State University / OhioLINK
2010
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1285015046 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu12850150462021-08-03T06:00:46Z Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma Martin, Chelsea Kathleen Biomedical Research Oncology Veterinary Services oral squamous cell carcinoma head and neck cancer feline bone invasion meloxicam zoledronic acid <p>Bone invasion negatively effects prognosis for patients with oral squamous cell carcinoma (OSCC). Despite the clinical significance, mechanisms responsible for OSCC invasion into bone are not fully understood. There is limited availability of experimental models which recapitulate the bone invasive behavior of OSCC in which to study disease pathogenesis and treatment. The purpose of this body of work was to develop and characterize models of bone invasive OSCC, to investigate the factors responsible for osteoclastic bone resorption, and to evaluate treatment strategies designed to inhibit bone resorption and tumor growth. </p><p> The first objective was to characterize a naturally occurring model of bone invasive OSCC in domestic cats, and to determine if expression of parathyroid hormone-related protein (PTHrP) is associated with osteolytic behavior. Bone invasive feline OSCC was characterized by osteoclastic bone resorption and PTHrP expression and nuclear localization was increased in osteolytic tumors; supporting a relationship between PTHrP expression and bone-invasive behavior. </p><p> The second objective was to investigate the mechanisms responsible for OSCC-associated bone resorption in relevant in vitro and in vivo models of bone invasive OSCC. In bone invasive OSCC cells, PTHrP expression was associated with ability to stimulate in vitro and in vivo bone resorption, in addition to stimulation of receptor activator of nuclear factor κB ligand (RANKL) expression and inhibition of osteoprotegerin (OPG) in murine preosteoblasts. In vitro bone culture released factors which stimulated tumor cell proliferation and PTHrP expression in feline and human OSCC cells, suggesting the existence of a vicious cycle between OSCC growth and osteoclastic bone resorption. </p><p> The final two objectives were to evaluate the effectiveness of targeting osteoclastic bone resorption in a novel, bioluminescent orthotopic model of maxillary invasive OSCC. Zoledronic acid (ZOL, an aminobisphosphonate osteoclast inhibitor) reduced tumor growth and bone resorption associated with xenograft growth. OSCC cells expressed cyclooxygenase-2 (COX-2), and COX-2 expression was stimulated by factors in bone conditioned medium. A preferential cyxlooxygenase-2 inhibitor (meloxicam) was more effective than ZOL at reducing xenograft growth but did not have a significant effect on bone resorption. The combination of meloxicam and ZOL was well tolerated but did not stimulate additional tumor suppression or inhibition of bone loss compared to meloxicam or ZOL monotherapy. </p><p> These studies support the role of OSCC-expression of PTHrP and COX-2 in the pathogenesis of bone invasive OSCC, and support the presence of a vicious cycle between OSCC growth and bone resorption. Additionally, valuable experimental models of maxillary invasive OSCC were developed for the advancement of OSCC mechanistic and preclinical research.</p> 2010-11-02 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1285015046 http://rave.ohiolink.edu/etdc/view?acc_num=osu1285015046 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research Oncology Veterinary Services oral squamous cell carcinoma head and neck cancer feline bone invasion meloxicam zoledronic acid |
| spellingShingle |
Biomedical Research Oncology Veterinary Services oral squamous cell carcinoma head and neck cancer feline bone invasion meloxicam zoledronic acid Martin, Chelsea Kathleen Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| author |
Martin, Chelsea Kathleen |
| author_facet |
Martin, Chelsea Kathleen |
| author_sort |
Martin, Chelsea Kathleen |
| title |
Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| title_short |
Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| title_full |
Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| title_fullStr |
Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| title_full_unstemmed |
Mechanisms and Treatment of Bone Resorption in Models of Oral Squamous Cell Carcinoma |
| title_sort |
mechanisms and treatment of bone resorption in models of oral squamous cell carcinoma |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1285015046 |
| work_keys_str_mv |
AT martinchelseakathleen mechanismsandtreatmentofboneresorptioninmodelsoforalsquamouscellcarcinoma |
| _version_ |
1719429401813188608 |