Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang YImaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med 15: 960-966

Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Nature medicine (Impact Factor: 27.36). 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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    • "Accordingly, many studies have shown that disruption of the TGF-β signalling early in metastasis can substantially reduce metastasis burden and that the effect becomes less effective when lesions become well-established [59-61]. It has been argued that well-established bone lesions may become less dependent on bone destruction and TGF-β signalling and, as a consequence, become less sensitive to TGF-β inhibitors [59]. "
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    ABSTRACT: The transforming growth factor beta (TGF-beta) signalling pathway is known to control human breast cancer invasion and metastasis. We demonstrate that the zebrafish xenograft assay is a robust and dependable animal model for examining the role of pharmacological modulators and genetic perturbation of TGF-beta signalling in human breast tumour cells. We injected cancer cells into the embryonic circulation (duct of cuvier) and examined their invasion and metastasis into the avascular collagenous tail. Various aspects of the TGF-beta signalling pathway were blocked by chemical inhibition, small interfering RNA (siRNA), or small hairpin RNA (shRNA). Analysis was conducted using fluorescent microscopy. Breast cancer cells with different levels of malignancy, according to in vitro and in vivo mouse studies, demonstrated invasive and metastatic properties within the embryonic zebrafish model that nicely correlated with their differential tumourigenicity in mouse models. Interestingly, MCF10A M2 and M4 cells invaded into the caudal hematopoietic tissue and were visible as a cluster of cells, whereas MDA MB 231 cells invaded into the tail fin and were visible as individual cells. Pharmacological inhibition with TGF-beta receptor kinase inhibitors or tumour specific Smad4 knockdown disturbed invasion and metastasis in the zebrafish xenograft model and closely mimicked the results we obtained with these cells in a mouse metastasis model. Inhibition of matrix metallo proteinases, which are induced by TGF-beta in breast cancer cells, blocked invasion and metastasis of breast cancer cells. The zebrafish-embryonic breast cancer xenograft model is applicable for the mechanistic understating, screening and development of anti-TGF-beta drugs for the treatment of metastatic breast cancer in a timely and cost-effective manner.
    Breast cancer research: BCR 11/2013; 15(6):R106. DOI:10.1186/bcr3573 · 5.49 Impact Factor
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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; 141(2). DOI:10.1016/j.pharmthera.2013.10.006 · 9.72 Impact Factor
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    • "The TGF-β superfamily also includes other factors involved in bone homeostasis including: activins, inhibins, and bone morphogeneticproteins (BMPs). TGF-β that is released from bone is activated by either proteolytic cleavage, interaction with integrins, or pH changes in the local microenvironment [9]. In addition, TGF-β stimulates tumor production of pre-osteolytic and osteolytic factors that stimulate further bone resorption [10,11]. "
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    ABSTRACT: Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.
    Advances in Bioscience and Biotechnology 10/2013; 4(10C):15-30. DOI:10.4236/abb.2013.410A4003
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