We previously established a bioluminescent transgenic mouse model, sPSA-Luc, with luciferase gene expression restricted to the prostate under the control of the supra prostate-specific antigen (sPSA) promoter. We now assess the feasibility of generating bigenic mice, TRAMP-Luc, with the sPSA-Luc as the founder strain crossbred with TRAMP (transgenic adenocarcinoma mouse prostate) mice, to evaluate non-invasively the metastatic potential of prostate tumors.
TRAMP-Luc mice were obtained as [C57BL/6 TRAMP x FVB sPSA-Luc] F1 offspring. Tumor development in 10 TRAMP-Luc males was followed by bioluminescence imaging from 8 to 24 weeks of age. Immunohistochemical (IHC) staining for T antigen (Tg), androgen receptor (AR), luciferase and/or pathological analysis verified the tumor distribution in the imaged tissues including prostate gland, lymph node and bone.
Group I animals that presented with no grossly visible tumors showed prostate-confined bioluminescence with slightly increased signal intensity with age. Group II animals that developed large tumors displayed a widely distributed and biphasic bioluminescence pattern. The peak was reached between 10 and 14 weeks of age, then markedly decreased or even disappeared beyond week 16, except for one mouse that showed an increased bioluminescence signal at the jaw bone and hind limbs at week 22. These tumors were shown by IHC to contain Tg but lost AR and luciferase beyond week 16 in poorly differentiated prostate tumors.
A direct correlation between bioluminescence emission and AR expression was found in TRAMP-Luc tumor progression model. This model allows non-invasive imaging of prostate cancer metastases to bone and soft tissues.
"Assessment of tumor development and bone degeneration is important to characterize the interaction between tumor cells and the bone microenvironment as well as to evaluate the response of tissue to treatments. A variety of imaging techniques such as magnetic resonance imaging (MRI) , micro-positron emission tomography (PET) [4,5], micro-computed tomography (microCT) , and optical imaging including bioluminescence and fluorescence imaging      have been developed to investigate cancer growth and metastasis in small animals for such purposes. Although each modality Bone 56 (2013) 454–460 ⁎ Corresponding author at: Department of Nanomedicine and Biomedical Engineering, "
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is the most common primary tumor and the second leading cause of cancer-related deaths in men in the United States. Prostate cancer bone metastases are characterized by abnormal bone remodeling processes and result in a variety of skeletal morbidities. Prevention of skeletal complications is a crucial element in prostate cancer management. This study investigated prostate cancer-induced alterations in the molecular composition and morphological structure of metastasis-bearing bones in a mouse model of prostate cancer using Raman spectroscopy and micro-computed tomography (microCT). LNCaP C4-2B prostate cancer cells were injected into the right tibiae of 5-week old male SCID mice. Upon sacrifice at 8 weeks post tumor inoculation, two out of the ten tumor-bearing tibiae showed only osteoblastic lesions in the radiographs, 4 osteolytic lesions only and 4 mixed with osteoblastic and osteolytic lesions. . Carbonate substitution was significantly increased while there was a marked reduction in the level of collagen mineralization, mineral crystallinity, and carbonate:matrix ratio in the cortex of the intact tumor-bearing tibiae compared to contralateral controls. MicroCT analysis revealed a significant reduction in bone volume/total volume, trabecular number and trabecular thickness, as well as significant increase in bone surface/volume ratio in tibiae with osteolytic lesions, suggesting active bone remodeling and bone loss. None of the changes in bone compositional properties were correlated with lesion area from radiographs or the changes in bone architecture from microCT. This study indicates that LNCaP C4-2B prostate cancer metastases alter bone tissue composition independent of changes in architecture, and altered bone quality may be an important contributor to fracture risk in these patients. Raman spectroscopy may provide a new avenue of investigation into interactions between tumor and bone microenvironment.
Bone 07/2013; 56(2). DOI:10.1016/j.bone.2013.07.006 · 3.97 Impact Factor
"By 28 weeks of age, all mice had lung or lymph node metastasis. While it is possible for TRAMP mice to develop bone metastases, it is rare [68,69]. The low frequency of bone metastasis observed across diverse mouse models of prostate cancer such as these further underscores the importance of developing an in vivo system that can be readily utilized to elucidate the mechanisms involved in human prostate cancer metastasis to the bone. "
[Show abstract][Hide abstract] ABSTRACT: Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies.
Andreas G. Wibmer, Irene A. Burger, Evis Sala, Hedvig Hricak, Wolfgang A. Weber, Hebert Alberto Vargas,
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