Amber E de Groot1,2, Kayla V Myers1,2, Timothy E G Krueger1,2,3, Ashley L Kiemen4, Natalia H Nagy1, Alexandria Brame1, Vicente E Torres1, Zhongyuan Zhang1, Levent Trabzonlu5, W Nathaniel Brennen1,3, Denis Wirtz4,6, Angelo M De Marzo1,3,6, Sarah R Amend1,3, Kenneth J Pienta1,2,3. 1. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 2. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 3. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 4. Department of Chemical and Biomolecular Engineering, Johns Hopkins Whiting School of Engineering, Baltimore, Maryland, USA. 5. Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, Illinois, USA. 6. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Abstract
BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the tumor microenvironment (TME) in prostate cancer. Commonly used orthotopic models do not accurately reflect the complete TME of a human patient or the natural initiation and progression of a tumor. Therefore, genetically engineered mouse models are essential for studying the TME as well as advancing TAM-targeted therapies. Two common transgenic (TG) models of prostate cancer are Hi-Myc and transgenic adenocarcinoma of the mouse prostate (TRAMP), but the TME and TAM characteristics of these models have not been well characterized. METHODS: To advance the Hi-Myc and TRAMP models as tools for TAM studies, macrophage infiltration and characteristics were assessed using histopathologic, flow cytometric, and expression analyses in these models at various timepoints during tumor development and progression. RESULTS: In both Hi-Myc and TRAMP models, macrophages adopt a more pro-tumor phenotype in higher histological grade tumors and in older prostate tissue. However, the Hi-Myc and TRAMP prostates differ in their macrophage density, with Hi-Myc tumors exhibiting increased macrophage density and TRAMP tumors exhibiting decreased macrophage density compared to age-matched wild type mice. CONCLUSIONS: The macrophage density and the adenocarcinoma cancer subtype of Hi-Myc appear to better mirror patient tumors, suggesting that the Hi-Myc model is the more appropriate in vivo TG model for studying TAMs and TME-targeted therapies.
BACKGROUND: Tumor-associated macrophages (TAMs) are critical components of the tumor microenvironment (TME) in prostate cancer. Commonly used orthotopic models do not accurately reflect the complete TME of a human patient or the natural initiation and progression of a tumor. Therefore, genetically engineered mouse models are essential for studying the TME as well as advancing TAM-targeted therapies. Two common transgenic (TG) models of prostate cancer are Hi-Myc and transgenic adenocarcinoma of the mouse prostate (TRAMP), but the TME and TAM characteristics of these models have not been well characterized. METHODS: To advance the Hi-Myc and TRAMP models as tools for TAM studies, macrophage infiltration and characteristics were assessed using histopathologic, flow cytometric, and expression analyses in these models at various timepoints during tumor development and progression. RESULTS: In both Hi-Myc and TRAMP models, macrophages adopt a more pro-tumor phenotype in higher histological grade tumors and in older prostate tissue. However, the Hi-Myc and TRAMP prostates differ in their macrophage density, with Hi-Myc tumors exhibiting increased macrophage density and TRAMP tumors exhibiting decreased macrophage density compared to age-matched wild type mice. CONCLUSIONS: The macrophage density and the adenocarcinoma cancer subtype of Hi-Myc appear to better mirror patient tumors, suggesting that the Hi-Myc model is the more appropriate in vivo TG model for studying TAMs and TME-targeted therapies.
Authors: E D Kwon; A A Hurwitz; B A Foster; C Madias; A L Feldhaus; N M Greenberg; M B Burg; J P Allison Journal: Proc Natl Acad Sci U S A Date: 1997-07-22 Impact factor: 11.205
Authors: N M Greenberg; F DeMayo; M J Finegold; D Medina; W D Tilley; J O Aspinall; G R Cunha; A A Donjacour; R J Matusik; J M Rosen Journal: Proc Natl Acad Sci U S A Date: 1995-04-11 Impact factor: 11.205
Authors: Katharine Ellwood-Yen; Thomas G Graeber; John Wongvipat; M Luisa Iruela-Arispe; JianFeng Zhang; Robert Matusik; George V Thomas; Charles L Sawyers Journal: Cancer Cell Date: 2003-09 Impact factor: 31.743