Imaging transforming growth factor-Β signaling dynamics and therapeutic response in breast cancer bone metastasis

Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Nature medicine (Impact Factor: 28.05). 09/2009; 15(8):960-6. DOI: 10.1038/nm.1943
Source: PubMed

ABSTRACT Although the transforming growth factor-beta (TGF-beta) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.

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    • "Following osteoclast maturation, the " vicious cycle " of lytic bone metastasis takes place whereby degradation of the bone matrix by osteoclasts releases various growth factors such as IGFs, TGFβ, EGFs and FGFs, spurring tumor cell growth and further promoting osteoclast activation (Hauschka et al., 1986; Mundy, 2002). Dynamic in vivo imaging coupled with genetic and pharmacological inhibition of the TGFβ pathway showed that TGFβ signaling is most important in the early establishment of breast cancer metastatic lesions (Korpal et al., 2009), and a milestone study by Yin and colleagues demonstrated that blockade of TGFβ signaling in tumor cells inhibits PTHrP secretion and reduces osteolysis (Yin et al., 1999). In addition to inducing RANKL production from osteoblasts to increase osteoclastogenesis , the pro-metastatic function of PTHrP has been attributed to other important functions. "
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    ABSTRACT: Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor-stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating bone metastasis.
    Pharmacology [?] Therapeutics 10/2013; DOI:10.1016/j.pharmthera.2013.10.006 · 7.75 Impact Factor
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    • "Much recent research has been focused on targeted agents that disrupt specific closely involved signaling pathways in cancer. Effects of these treatments can be highly complex , which present challenges for the characterization of treatment response owing to the numerous mechanisms involved [4]. For example , recent studies in skeletal metastases have revealed important interactions between the tumor and its microenvironment [5] [6] [7] [8] [9]. "
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    ABSTRACT: Cancer drug development generally performs in vivo evaluation of treatment effects that have traditionally relied on detection of morphologic changes. The emergence of new targeted therapies, which may not result in gross morphologic changes, has spurred investigation into more specific imaging methods to quantify response, such as targeted fluorescent probes and bioluminescent cells. The present study investigated tissue response to docetaxel or zoledronic acid (ZA) in a mouse model of bony metastasis. Intratibial implantations of breast cancer cells (MDA-MB-231) were monitored throughout this study using several modalities: molecular resonance imaging (MRI) tumor volume and apparent diffusion coefficient (ADC), micro-computed tomography (µCT) bone volume, bioluminescence imaging (BLI) reporting cancer cell apoptosis, and fluorescence using Osteosense 800 and CatK 680-FAST. Docetaxel treatment resulted in tumor cell kill reflected by ADC and BLI increases and tumor volume reduction, with delayed bone recovery seen in µCT prefaced by increased osteoblastic activity (Osteosense 800). In contrast, the ZA treatment group produced similar values in MRI, BLI, and Osteosense 800 fluorescence imaging readouts when compared to controls. However, µCT bone volume increased significantly by the first week post-treatment and the CatK 680-FAST signal was slightly diminished by 4 weeks following ZA treatment. Multimodality imaging provides a more comprehensive tool for new drug evaluation and efficacy screening through identification of morphology as well as function and apoptotic signaling.
    Translational oncology 12/2012; 5(6):415-21. DOI:10.1593/tlo.12298 · 3.40 Impact Factor
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    • "The systemic delivery of Ad.sTbRFc will result in the uptake of the virus and its replication in tumor cells at the bone site. Ad.sTbRFc-mediated production of sTGFbRIIFc will target TGF-b, inhibiting TGF-b signaling in the various cellular components involved in the ''vicious cycle'' at the tumor–bone environment (Yin et al., 1999; Iyer et al., 2005; Kingsley et al., 2007; Akhtari et al., 2008; Korpal et al., 2009; Serganova et al., 2009). Although Ad(E1 "
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    ABSTRACT: We have investigated whether systemic delivery of an oncolytic adenovirus, Ad.sTβRFc, expressing the soluble form of transforming growth factor-β receptor II fused with human immunoglobulin Fc fragment (sTGFβRIIFc), could inhibit breast cancer bone metastasis in a mouse model. MDA-MB-231 (human breast cancer) cells were inoculated into the left heart ventricles of nude mice. Once the skeletal tumors were visible by X-rays, mice were intravenously injected with either buffer, Ad.sTβRFc, Ad(E1⁻).sTβRFc (a replication-deficient adenovirus expressing sTGFβRIIFc), or Ad.luc2 (a replicating adenovirus expressing firefly luciferase gene). On days 2 and 7 after viral injections, viral replication and sTGFβRIIFc expression were detected in the skeletal tumors in Ad.sTβRFc-treated group; only viral replication in Ad.luc2 group, and sTGFβRIIFc expression in the Ad(E1⁻).sTβRFc group, were detected. To examine the therapeutic effects, buffer or various viral vectors were administered on days 4 and 7 after intracardiac injection of MDA-MB-231 cells. On day 28, X-ray radiography showed a highly significant reduction in lesion size by Ad.sTβRFc, a significant reduction by Ad.luc2, and some reduction by Ad(E1⁻).sTβRFc. Goldner's trichrome and hematoxylin-eosin staining of the bone sections revealed a significant reduction of tumor burden in the Ad.sTβRFc group, but not in the Ad(E1⁻).sTβRFc or Ad.luc2 group. There were significant reductions in free calcium levels by Ad.sTβRFc, Ad(E1⁻).sTβRFc, and Ad.luc2; however, only in the Ad.sTβRFc group were calcium levels reduced to the normal values. These results suggest that concomitant viral replication and sTGFβRIIFc production are important to inhibit bone metastasis and osteolysis, and that Ad.sTβRFc could be developed for targeting breast cancer bone metastases.
    Human gene therapy 11/2010; 21(11):1623-9. DOI:10.1089/hum.2010.018 · 3.62 Impact Factor
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