Preclinical Mouse Models of Human Prostate Cancer and Their Utility in Drug Discovery

Park, Serk In; Kim, Jong Hun; McCauley, Laurie K.; Gallick, Gary E.

doi:10.1002/0471141755.ph1415s51

Cited by 72 publications

(81 citation statements)

References 49 publications

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“…al. (24) and visualized in as in (25). Briefly, 1 × 10 5 PC-3-luc cells were injected into the left heart ventricle of male nude mice (Harlan Laboratories).…”

Section: Methodsmentioning

confidence: 99%

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

et al. 2014

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The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies we demonstrate that the cell adhesion molecule ALCAM is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGFβ. Not only is this post-translational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveal that ALCAM expression and shedding is elevated in response to TGFβ signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (Caspase-3) and decreased proliferation (Ki-67). Together these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.

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“…al. (24) and visualized in as in (25). Briefly, 1 × 10 5 PC-3-luc cells were injected into the left heart ventricle of male nude mice (Harlan Laboratories).…”

Section: Methodsmentioning

confidence: 99%

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

et al. 2014

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“…Animals for imaging and biodistribution studies had tumor volumes between 100 – 350 mm 3 . The intracardiac dissemination model was generated using the previously described method (35). …”

Section: Methodsmentioning

confidence: 99%

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

et al. 2015

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The increased proteolytic activity of membrane-bound and secreted proteases on the surface of cancer cells and in the transformed stroma is a common characteristic of aggressive metastatic prostate cancer. We describe here the development of an active site-specific probe for detecting a secreted peritumoral protease expressed by cancer cells and the surrounding tumor microenvironment. Using a human fragment antigen binding phage display library, we identified a human antibody termed U33 that selectively inhibited the active form of the protease urokinase plasminogen activator (uPA, PLAU). In the full-length immunoglobulin form, U33 IgG labeled with near-infrared fluorophores or radionuclides allowed us to non-invasively detect active uPA in prostate cancer xenograft models using optical and single-photon emission computed tomography (SPECT) imaging modalities. U33 IgG labeled with 111In had a remarkable tumor uptake of 43.2% injected dose per gram (%ID/g) 72hr post tail vein injection of the radiolabeled probe in subcutaneous xenografts. Additionally, U33 was able to image active uPA in small soft-tissue and osseous metastatic lesions using a cardiac dissemination prostate cancer model that recapitulated metastatic human cancer. The favorable imaging properties were the direct result of U33 IgG internalization through an uPA receptor mediated mechanism where U33 mimicked the function of the endogenous inhibitor of uPA to gain entry into the cancer cell. Overall, our imaging probe targets a prostate cancer-associated protease, through a unique mechanism, allowing for the non-invasive preclinical imaging of prostate cancer lesions.

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“…The intratibial bone injection was performed in 4-to 5-week-old BALB/c, male nude mice (nu/nu) anesthetized with pentobarbital (50 mg/kg) via a percutaneous approach (25). The procedures were approved by the Animal Care and Use Committee of the East China Normal University (ECNU; Shanghai, P.R.…”

Section: Intratibial Injection Of Primary Gctb Cellsmentioning

confidence: 99%

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

Luo

Jin

et al. 2016

Molecular Cancer Therapeutics

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Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-kB signaling-related cytokines, including TNFa, MCP-1, IL1a, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-kB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cellinduced bone destruction in vivo. As a result, bortezomib suppressed NF-kB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-kB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB.

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Preclinical Mouse Models of Human Prostate Cancer and Their Utility in Drug Discovery

Cited by 72 publications

References 49 publications

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

Imaging Active Urokinase Plasminogen Activator in Prostate Cancer

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption

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