Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

Drake, Justin M.; Danke, Joshua R; Henry, Michael D.

doi:10.4161/cbt.9.8.11112

Cited by 28 publications

(17 citation statements)

References 45 publications

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“…We found all cell types to be negative for IL-1β (Figure 4a) and unable to metastasize in our animal model, despite successfully arriving to the skeleton via the arterial circulation and homing as DTCs. This is consistent with our previous work with DU-145 cells 85 , with the lack of published studies with LNCaP and VCaP cells in pre-clinical models of bone metastasis, and only two existing reports for 22Rv1 cells 2324 , the results of which could not be reproduced in our hands. We then generated PC3-ML cells stably expressing both the fluorescent protein mCherry and RedLuc, to be paired with the various non-metastatic cell lines, which were engineered to express GFP and Luc2.…”

Section: Resultssupporting

confidence: 91%

Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche

et al. 2016

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The growth of disseminated tumor cells (DTCs) into metastatic lesions depends on the establishment of a favorable microenvironment in the stroma of the target organs. Here we show that mice treated with anakinra, an antagonist of the IL-1β receptor (IL-1R), or harboring a targeted deletion of IL-1R are significantly less prone to develop bone tumors when inoculated in the arterial circulation with human prostate cancer (PCa) cells expressing IL-1β. Interestingly, human mesenchymal stem cells (hMSCs) exposed in vitro to medium conditioned by IL-1β-expressing cancer cells responded by up regulating S100A4, a marker of cancer-associated fibroblasts (CAFs), and this effect was blocked by anakinra. Analogously, the stroma adjacent to skeletal metastases generated in mice by IL-1β-expressing cancer cells showed a dramatic increase in S100A4, COX-2 and the alteration of thirty tumor-related genes as measured by Nanostring analysis. These effects were not observed in the stroma associated to the rare and much smaller metastases generated by the same cells in IL-1R knockout animals, confirming that tumor-secreted IL-1β generates skeletal CAFs and conditions the surrounding bone microenvironment. In skeletal lesions from patients with metastatic PCa, histological and molecular analyses revealed that IL-1β is highly expressed in cancer cells in which the androgen receptor (AR) is not detected (AR−) whereas this cytokine is uniformly absent in the AR-positive (AR+) metastatic cells. The stroma conditioned by IL-1β-expressing cancer cells served as a supportive niche also for coexisting IL-1β-lacking cancer cells, which are otherwise unable to generate tumors after independently seeding the skeleton of mice. This niche is established very early following tumor seeding and hints to a role of IL-1β in promoting early colonization of PCa at the skeletal level.

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Section: Resultssupporting

confidence: 91%

Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche

et al. 2016

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“…Intracardiac injection of 10 5 luciferase-expressing 22Rv1 cells into male SCID mice was done as described previously. [47, 51] Weekly bioluminescence imaging with X-ray overlay monitored tumor development. Between weeks three and four after cell injection, mice were randomized into two groups using an algorithm to minimize between group variance in total photon count, at which point daily subcutaneous injections of PBS or 1.5 mg/kg GGOHBP began.…”

Section: Methodsmentioning

confidence: 99%

Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis

Reilly

Neighbors

Tong

et al. 2015

Clin Exp Metastasis

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The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase (GGDPS), reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100%), adrenal glands (72%), mesentery (22%), liver (17%), and the thoracic cavity (6%). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed areduction in adrenal gland tumors corresponding to a 54% (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis.

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“…88 In nearly all patients with advanced prostate cancer, the disease metastasizes to bone and causes osteoblastic growth. 106 Primary tumors may govern the bone marrow through signaling cascades that direct cells in the bone niche and facilitate its colonization. Osteoblasts, bone marrow stromal cells and hematopoietic stem cells form part of the tumoral microenvironment and engage with tumoral cells through cell to cell interactions mediated by integrins such as a4b1, vascular cell adhesion molecule 1, chemokines such as CXCL12/CXCR4, glycoproteins such as CD34, adhesion molecules as PECAM, cadherin superfamily, bone morphogenic proteins, Notch, nestin and OPN, among other factors.…”

Section: The Strut Of Chemokines and Their Receptors In The Metastatimentioning

confidence: 99%

Advanced prostate cancer: reinforcing the strings between inflammation and the metastatic behavior

Gueron

Siervi

Vázquez

2011

Prostate Cancer Prostatic Dis

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It is currently estimated that inflammatory responses are linked to 15-20% of all deaths from cancer worldwide. Although many studies point to an important role of inflammation in prostate growth, the contribution of inflammation to castration-resistant prostate cancer is not completely understood. The presence of inflammatory mediators in tumor microenvironment raises the question whether genetic events that participate in cancer development and progression are responsible for the inflammatory milieu inside and surrounding tumors. Activated oncogenes, cytokines, chemokines and their receptors, sustained oxidative stress and antioxidant imbalance share the capacity to orchestrate these pro-inflammatory programs; however, the diversity of the inflammatory cell components will determine the final response in the prostate tissue. These observations give rise to the concept that early genetic events generate an inflammatory microenvironment promoting prostate cancer progression and creating a continuous loop that stimulates a more aggressive stage. It is imperative to dissect the molecular pathologic mechanism of inflammation involved in the generation of the castration-resistant phenotype in prostate cancer. Here, we present a hypothesis where molecular signaling triggered by inflammatory mediators may evolve in prostate cancer progression. Thus, treatment of chronic inflammation may represent an important therapeutic target in advanced prostate cancer.

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Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

Cited by 28 publications

References 45 publications

Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche

Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche

Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis

Advanced prostate cancer: reinforcing the strings between inflammation and the metastatic behavior

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