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VCAM-1 Promotes Osteolytic Expansion of Indolent Bone Micrometastasis of Breast Cancer by Engaging α4β1-Positive Osteoclast Progenitors

Department of Molecular Biology, Princeton University, NJ 08544, USA.
Cancer cell (Impact Factor: 23.89). 11/2011; 20(6):701-14. DOI: 10.1016/j.ccr.2011.11.002
Source: PubMed

ABSTRACT Breast cancer patients often develop locoregional or distant recurrence years after mastectomy. Understanding the mechanism of metastatic recurrence after dormancy is crucial for improving the cure rate for breast cancer. Here, we characterize a bone metastasis dormancy model to show that aberrant expression of vascular cell adhesion molecule 1 (VCAM-1), in part dependent on the activity of the NF-κB pathway, promotes the transition from indolent micrometastasis to overt metastasis. By interacting with the cognate receptor integrin α4β1, VCAM-1 recruits monocytic osteoclast progenitors and elevates local osteoclast activity. Antibodies against VCAM-1 and integrin α4 effectively inhibit bone metastasis progression and preserve bone structure. These findings establish VCAM-1 as a promising target for the prevention and inhibition of metastatic recurrence in bone.

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    • "Furthermore, we evaluated expression of endothelial cell markers in patients receiving the TSU-68 plus S-1 combination therapy. VCAM-1 is aberrantly expressed in breast cancer cells and mediates pro-metastatic tumor-stroma interactions [25, 26]. In HCC, serum VCAM-1 level appears to reflect the severity of the underlying chronic liver disease rather than the tumor status [27, 28], and low preoperative serum VCAM-1 levels are predictive of better disease-free survival after surgery [28]. "
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    ABSTRACT: Purpose We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. Patients and methods Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. Results Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. Conclusion The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.
    Investigational New Drugs 05/2014; 32(5). DOI:10.1007/s10637-014-0109-2 · 2.93 Impact Factor
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    • "At the preclinical level, priority should be given to research that aims to identify and validate novel therapeutic targets that block cancer metastasis in vivo. With modern intravital imaging techniques, each step of the metastatic cascade can be quantitatively visualized in vivo [25] [32] [34] [80]. Modern gene silencing techniques continue to allow researchers to conduct genome wide screens to identify the genes that control metastatic dissemination of cancer from the primary tumor [81-84]. "
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    ABSTRACT: Metastasis is the main cause of prostate cancer-associated deaths. While significant progress has been made in the treatment of primary tumors, efficient therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precludes these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.
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    • "Vascular-endothelial molecule-1 (VCAM-1) is expressed in breast cancer cells by ectopically expressed NF-κB, which mediates this interaction. VCAM-1 binds α4β7 and α4β1 (VLA-4) integrins on OCL progenitors with high affinity, causing OCL differentiation and osteoclastogenesis [23, 24]. α4 or VCAM-1 blocking antibodies effectively inhibit bone metastasis [24]. "
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    ABSTRACT: Metastasis is a multistep process, which refers to the ability to leave a primary tumor through circulation toward the distant tissue and form a secondary tumor. Bone is a common site of metastasis, in which osteolytic and osteoblastic metastasis are observed. Signaling pathways, chemokines, growth factors, adhesion molecules, and cellular interactions as well as miRNAs have been known to play an important role in the development of bone metastasis. These factors provide an appropriate environment (soil) for growth and survival of metastatic tumor cells (seed) in bone marrow microenvironment. Recognition of these factors and determination of their individual roles in the development of metastasis and disruption of cellular interactions can provide important therapeutic targets for treatment of these patients, which can also be used as prognostic and diagnostic biomarkers. Thus, in this paper, we have attempted to highlight the molecular regulation of bone marrow metastasis in prostate and breast cancers.
    03/2014; 2014(4). DOI:10.1155/2014/405920
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