Huda I Atiya1, Anna Dvorkin-Gheva2, John Hassell2, Shrusti Patel1, Rachel L Parker1, Adam Hartstone-Rose3, Johnie Hodge1, Daping Fan1, Ann F Ramsdell4,5,6. 1. Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, U.S.A. 2. Department of Biochemistry and Biomedical Science, McMaster University, Hamilton, ON, Canada. 3. Department of Biological Sciences, North Carolina State University, Raleigh, NC, U.S.A. 4. Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, U.S.A. ann.ramsdell@uscmed.sc.edu. 5. Program in Women's and Gender Studies, College of Arts and Sciences, University of South Carolina, Columbia, SC, U.S.A. 6. Department of Regenerative Medicine and Cell Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, U.S.A.
Abstract
BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development. Copyright
BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. MATERIALS AND METHODS:Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development. Copyright
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