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Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy

PURPOSE: Orthotopic tumors more closely recapitulate human cancers than do ectopic models; however, precision targeting of such internal tumors for radiation therapy (RT) without inducing systemic toxicity remains a barrier. We developed an innovative murine orthotopic rectal tumor model where the i...

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Autores principales: Uccello, Taylor P., Kintzel, Sarah A., Mills, Bradley N., Murphy, Joseph D., Garrett-Larsen, Jesse, Battaglia, Nicholas G., Rodriguez, Carlos J., Drage, Michael G., Ye, Jian, Love, Tanzy M.T., Johnston, Carl J., Repasky, Elizabeth A., Qiu, Haoming, Linehan, David C., Lord, Edith M., Gerber, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749199/
https://www.ncbi.nlm.nih.gov/pubmed/35036637
http://dx.doi.org/10.1016/j.adro.2021.100867
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author Uccello, Taylor P.
Kintzel, Sarah A.
Mills, Bradley N.
Murphy, Joseph D.
Garrett-Larsen, Jesse
Battaglia, Nicholas G.
Rodriguez, Carlos J.
Drage, Michael G.
Ye, Jian
Love, Tanzy M.T.
Johnston, Carl J.
Repasky, Elizabeth A.
Qiu, Haoming
Linehan, David C.
Lord, Edith M.
Gerber, Scott A.
author_facet Uccello, Taylor P.
Kintzel, Sarah A.
Mills, Bradley N.
Murphy, Joseph D.
Garrett-Larsen, Jesse
Battaglia, Nicholas G.
Rodriguez, Carlos J.
Drage, Michael G.
Ye, Jian
Love, Tanzy M.T.
Johnston, Carl J.
Repasky, Elizabeth A.
Qiu, Haoming
Linehan, David C.
Lord, Edith M.
Gerber, Scott A.
author_sort Uccello, Taylor P.
collection PubMed
description PURPOSE: Orthotopic tumors more closely recapitulate human cancers than do ectopic models; however, precision targeting of such internal tumors for radiation therapy (RT) without inducing systemic toxicity remains a barrier. We developed an innovative murine orthotopic rectal tumor model where the insertion of clinical grade titanium fiducial clips on opposing sides of the rectal tumor allowed for targeted administration of short-course radiation therapy (SCRT). With this novel approach, clinically relevant RT regimens can be administered to orthotopic tumors to explore the biology and efficacy of radiation alone or as a combination therapy in a murine model that closely recapitulates human disease. METHODS AND MATERIALS: Murine Colon 38-luciferase tumor cells were injected into the rectal wall of syngeneic mice, and fiducial clips were applied to demarcate the tumor. An SCRT regimen consisting of 5 consecutive daily doses of 5 Gy delivered by an image-guided conformal small animal irradiator was administered 9 days after implantation. Tumor burden and survival were monitored along with histological and flow cytometric analyses on irradiated versus untreated tumors at various time points. RESULTS: SCRT administered to orthotopic rectal tumors resulted in a reduction in tumor burden and enhanced overall survival with no apparent signs of systemic toxicity. This treatment paradigm resulted in significant reductions in tumor cellularity and increases in fibrosis and hyaluronic acid production, recapitulating the SCRT-induced effects observed in human cancers. CONCLUSIONS: We have established a means to target murine orthotopic rectal tumors using fiducial markers with a fractionated and clinically relevant SCRT schedule that results in an RT response similar to what is observed in human rectal cancer. We also validated our model through examining various parameters associated with human cancer that are influenced by irradiation. This model can be used to further explore RT doses and scheduling, and to test combinatorial therapies.
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spelling pubmed-87491992022-01-13 Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy Uccello, Taylor P. Kintzel, Sarah A. Mills, Bradley N. Murphy, Joseph D. Garrett-Larsen, Jesse Battaglia, Nicholas G. Rodriguez, Carlos J. Drage, Michael G. Ye, Jian Love, Tanzy M.T. Johnston, Carl J. Repasky, Elizabeth A. Qiu, Haoming Linehan, David C. Lord, Edith M. Gerber, Scott A. Adv Radiat Oncol Scientific Article PURPOSE: Orthotopic tumors more closely recapitulate human cancers than do ectopic models; however, precision targeting of such internal tumors for radiation therapy (RT) without inducing systemic toxicity remains a barrier. We developed an innovative murine orthotopic rectal tumor model where the insertion of clinical grade titanium fiducial clips on opposing sides of the rectal tumor allowed for targeted administration of short-course radiation therapy (SCRT). With this novel approach, clinically relevant RT regimens can be administered to orthotopic tumors to explore the biology and efficacy of radiation alone or as a combination therapy in a murine model that closely recapitulates human disease. METHODS AND MATERIALS: Murine Colon 38-luciferase tumor cells were injected into the rectal wall of syngeneic mice, and fiducial clips were applied to demarcate the tumor. An SCRT regimen consisting of 5 consecutive daily doses of 5 Gy delivered by an image-guided conformal small animal irradiator was administered 9 days after implantation. Tumor burden and survival were monitored along with histological and flow cytometric analyses on irradiated versus untreated tumors at various time points. RESULTS: SCRT administered to orthotopic rectal tumors resulted in a reduction in tumor burden and enhanced overall survival with no apparent signs of systemic toxicity. This treatment paradigm resulted in significant reductions in tumor cellularity and increases in fibrosis and hyaluronic acid production, recapitulating the SCRT-induced effects observed in human cancers. CONCLUSIONS: We have established a means to target murine orthotopic rectal tumors using fiducial markers with a fractionated and clinically relevant SCRT schedule that results in an RT response similar to what is observed in human rectal cancer. We also validated our model through examining various parameters associated with human cancer that are influenced by irradiation. This model can be used to further explore RT doses and scheduling, and to test combinatorial therapies. Elsevier 2021-12-09 /pmc/articles/PMC8749199/ /pubmed/35036637 http://dx.doi.org/10.1016/j.adro.2021.100867 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Scientific Article
Uccello, Taylor P.
Kintzel, Sarah A.
Mills, Bradley N.
Murphy, Joseph D.
Garrett-Larsen, Jesse
Battaglia, Nicholas G.
Rodriguez, Carlos J.
Drage, Michael G.
Ye, Jian
Love, Tanzy M.T.
Johnston, Carl J.
Repasky, Elizabeth A.
Qiu, Haoming
Linehan, David C.
Lord, Edith M.
Gerber, Scott A.
Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title_full Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title_fullStr Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title_full_unstemmed Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title_short Development of an Orthotopic Murine Model of Rectal Cancer in Conjunction With Targeted Short-Course Radiation Therapy
title_sort development of an orthotopic murine model of rectal cancer in conjunction with targeted short-course radiation therapy
topic Scientific Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749199/
https://www.ncbi.nlm.nih.gov/pubmed/35036637
http://dx.doi.org/10.1016/j.adro.2021.100867
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