Detection of different tumor growth kinetics in single transgenic mice with oncogene‐induced mammary carcinomas by flat‐panel volume computed tomography

Abstract

Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm 3 ) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns. ' UICCKey words: flat-panel volume computed tomography; in vivo imaging; murine transgenic tumor models; tumor angiogenesis Accompanying the rapid progress in deciphering the human and mouse genome, many transgenic mouse models have been generated. Weissleder and Mahmood already assumed in 2001 that more than 25 million transgenic and knockout mice would be raised that year for experimental studies, accounting for over 90% of all mammals in research.1 These mouse models offer the opportunity to study gene functions in their biological context in a much more physiological way than any other approach. Especially cancer research benefits from the advantages of these transgenic mice in elucidating the role of a specific gene in tumor growth and spread as well as angiogenesis. One promising model in addressing such questions is the WAP-T transgenic mouse. [2][3][4] In these mice, the SV40 early gene region is induced specifically in differentiating mammary epithelial cells upon activation of the WAPpromoter during late pregnancy and lactation, and drives mammary carcinogenesis in mammary epithelial cells re-expressing the transgene after involution of the mammary glands. The SV40 early region mainly serves to functionally eliminate the p53 and pRb tumor suppressors by binding to the SV40 large T-antigen 5 and to change the specificity of the phosphatase PP2A 6 by its interaction with SV40 small T-antigen, thereby...

CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

“…In addition, tumor growth was monitored by palpation of the mammae after weaning. Results for tumor growth rates and vascularization in hemizygous WAP-T mice have been reported recently (Jannasch et al, 2009). In Figure 1a, representative fpVCT analyses of tumor growth and vascularization are depicted in two CEACAM1null/ WAP-T and WAP-T Â CEACAM1 endo þ mice with comparable tumor sizes (Figure 1a), respectively.…”

“…fpVCT imaging Mice were imaged with a non-clinical fpVCT prototype (GE Global Research, Niskayuna, NY, USA), using intravenously administered Isovist 300 (Bayer-Schering, Berlin, Germany) as contrasting media, as described in Jannasch et al (2009). Scanning started between 60 and 70 days after induction and was repeated regularly at various time points.…”

Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

“…Outgrowth of invasive carcinomas from MIN in WAP-T mice is a rare event that occurs in a stochastic manner ([61], and manuscript in preparation), and thus is the decisive progression step in malignant mammary carcinogenesis. Therefore, we focused our molecular analysis of tumors from WAP-T and WAP-mutCK1δ/WAP-T mice on two gene sets contained within the RT 2 “mouse wnt -signaling pathway” and “mouse DNA-repair pathways” profiler PCR arrays (see Materials and Methods).…”

“…Combined with the finding that both types of mice develop MIN to a rather similar extent, we conclude that MIN/DCIS in bi-transgenic mice have a lower probability to progress to invasive carcinoma. Progression of MIN to invasive carcinomas in WAP-T mice is an extremely rare event, considering that virtually all terminal end buds of all mammary glands develop MIN, while WAP-T mice on the average develop only 2–4 invasive mammary carcinomas ([61], and manuscript in preparation). The even further reduced probability for developing invasive carcinomas in WAP-mutCK1δ/WAP-T bi-transgenic mice thus indicates that CK1δ activity plays an important role in promoting transition of MIN to an invasive carcinoma.…”

Imaging aspects of the tumor stroma with therapeutic implications

“…Tumor progression as well as the development of tumor vasculature was followed in vivo in a transgenic mouse model for mammary carcinogenesis (WAP-T mice), using iodine containing contrast agent (Isovist 30 ™ ) and a blood pool agent (eXia 160 ™ ). The use of blood pool agent enhanced the spatial resolution due to prolonged half life in the blood and reduced extravasation from blood vessels (Gerstel, et al; Jannasch, et al, 2009). …”