A mouse model of prostate cancer bone metastasis in a syngeneic immunocompetent host.
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ABSTRACT:
SUBMITTER: Simons BW
PROVIDER: S-EPMC6901336 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Over 70% to 85% of men with advanced prostate cancer (PCa) develop bone metastases characterized by severe bone pain and increased likelihood of bone fracture. These clinical features result in decreased quality of life and act as a predictor of higher mortality. Mechanistically, the skeletal pathologies such as osteolytic lesions and abnormal osteoblastic activity drive these symptoms. The role of immune cells in bone cancer pain remains understudied, here we sought to recapitulate this symptomology in a murine model. METHODS:The prostate cancer bone metastasis-induced pain model (CIBP) was established by transplanting a mouse prostate cancer cell line into the femur of immunocompetent mice. Pain development, gait dynamics, and the changes in emotional activities like depression and anxiety were evaluated. Animal tissues including femurs, dorsal root ganglion (DRG), and spinal cord were collected at killing and microcomputed tomography (?CT), histology/immunohistochemistry, and quantitative immunofluorescent analysis were performed. RESULTS:Mice receiving prostate cancer cells showed a significantly lower threshold for paw withdrawal responses induced by mechanical stimulation compared with their control counterparts. Zero maze and DigiGait analyses indicated reduced and aberrant movement associated emotional activity compared with sham control at 8-weeks postinjection. The ?CT analysis showed osteolytic and osteoblastic changes and a 50% reduction of the trabecular volumes within the prostate cancer group. Neurologically we demonstrated, increased calcitonin gene-related peptide (CGRP) and neuronal p75NTR immune-reactivities in both the projected terminals of the superficial dorsal horn and partial afferent neurons in DRG at L2 to L4 level in tumor-bearing mice. Furthermore, our data show elevated nerve growth factor (NGF) and TrkA immunoreactivities in the same segment of the superficial dorsal horn that were, however, not colocalized with CGRP and p75NTR . CONCLUSIONS:This study describes a novel immunocompetent model of CIBP and demonstrates the contribution of NGF and p75NTR to chronic pain in bone metastasis.
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Project description:Many cancers metastasize to the bones, particularly in cases of breast and prostate cancers. Due to the "vicious cycle" of cancer cells inducing bone resorption, which promotes further tumor growth, they are difficult to treat and may lead to extreme pain. These factors increase the urgency for emerging therapeutics that target bone metastases more specifically and effectively. Animal studies are essential to the development of any therapeutics, but also require robust animal models of human diseases. Robust animal models are often challenging to develop in the case of bone metastasis studies. Previous methods to induce bone metastasis include intracardiac, intravenous, subcutaneous via mammary fat pad, and intraosseous cancer cell injections, but these methods all have limitations. By contrast, the caudal artery route of injection offers more robust bone metastasis, while also resulting in a lower rate of vital organ metastases than that of other routes of tumor implantation. A syngeneic animal model of bone metastasis is necessary in many cancer studies, because it allows the use of immunocompetent animals, which more accurately mimic cancer development observed in immunocompetent humans. Here we present a detailed method to generate robust and easily monitored 4T1-CLL1 syngeneic bone metastases with over 95% occurrence in BALB/c mice, within two weeks. This method can potentially increase consistency between animals in bone cancer metastasis studies and reduce the number of animals needed for studying bone metastases in mice.
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Project description:We collected clinical data from 308 prostate cancer (PCa) patients to investigate the clinical characteristics and independent risk factors of bone metastasis (BM) and to establish a prediction model for BM of PCa and determine the necessity of bone scans. Univariate and multivariate analyses were performed based on age, biopsy Gleason score (BGS), clinical tumor stage (cTx), total prostate specific antigen (tPSA), free prostate specific antigen (fPSA), fPSA/tPSA, prostate volume, alkaline phosphatase (ALP), serum calcium and serum phosphorus. Moreover, 80 of the 308 PCa patients had a PI-RADS v2 score and were analysed retrospectively. The univariate analysis showed that the BGS, cTx, tPSA, fPSA, prostate volume and ALP were significant. The multivariate logistic regression analysis showed significant differences among the BGS, cTx, tPSA and ALP. Four cases should be highly suspected with BM: (i) cTl-cT2, BGS ≤7, ALP >120 U/L and tPSA >90.64 ng/ml; (ii) cTl-cT2, BGS ≥8, and ALP >120 U/L; (iii) cT3-cT4, BGS ≤7, and ALP >120 U/L; and (iv) cT3-cT4 and BGS ≥8. After the PI-RADS v2 score was included in the model, the AUC of the prediction model rose from 0.884 (95% CI: 0.813-0.996) to 0.934 (95% CI: 0.883-0.986). This model may help determine the necessity of bone scans to diagnose BM for PCa patients.
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Project description:We developed a sensitive real-time polymerase chain reaction (QPCR) assay that allows us to track early lodging/homing events in vivo. We used this technology to develop a metastasis assay of human prostate cancer (PCa) growth in severe combined immunodeficient mice. For this purpose, marked human PCa cell lines were implanted subcutaneously or in the prostate (orthotopically) of severe combined immunodeficient mice as models of primary tumors. Mice were then sacrificed at various time points, and distant tissues were investigated for the presence of metastatic cells. At 3 weeks, a number of tissues were recovered and evaluated by QPCR for the presence of metastatic cells. The data demonstrate that several PCa cell lines are able to spread from the primary lesion and take up residence in distant sites. If the primary tumors were resected at 3 weeks, in several cases, metastatic lesions were identified over the course of 9 months. We propose that this new model may be particularly useful in exploring the molecular events in early metastasis, identifying the metastatic niche, and studying issues pertaining to dormancy.
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Project description:The study aimed to determine mechanisms of macrophage promotion of anti-androgen resistance of prostate cancer bone disease. For this purpose, we developed a novel prostate cancer bone metastasis mouse model, MycCaP-Bo, via multiple rounds of in vivo selection of bone homing cells following intra-cardiac inoculation of a murine prostate cancer cell line, MycCaP cells. Cancer cells were purified from bone metastasis using fluoresent accelerated-cell sorting (FACS) based on their iRFP expression. Cancer cells were purified from treatment- naïve tumours, resistant tumours and resistant tumours with short-term depletion of macrophages. RNA was extracted from purified cancer cells and profiled using next-generation sequencing.
2023-01-29 | GSE156427 | GEO
Project description:BACKGROUND:Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. METHODS:Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6?J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with ?-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry. RESULTS:The number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P?<?0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P?=?0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P?<?0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P?=?0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P?<?0.05, P?<?0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression. CONCLUSIONS:This model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.
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