Metastasis Research Laboratory


Metastasis Research Laboratory

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Poltronieri J.,Federal University of São Carlos | Becceneri A.B.,Federal University of São Carlos | Fuzer A.M.,Federal University of São Carlos | Filho J.C.C.,Federal University of São Carlos | And 5 more authors.
Mini-Reviews in Medicinal Chemistry | Year: 2014

For many years, ginger or ginger root, the rhizome of the plant Zingiber officinale, has been consumed as a delicacy, medicine, or spice. Several studies have been conducted on the medicinal properties of ginger against various disorders, including cancer. Cancer is the second leading cause of death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer initiation or progression. Evidence that ginger-derived compounds have inhibitory effects on various cancer cell types is increasingly being reported in the scientific literature. In this review we focused on the cancer chemopreventive effects of [6]-gingerol, the major pungent component of ginger, and its impact on different steps of the metastatic process. © 2014 Bentham Science Publishers.

Pirotte S.,Metastasis Research Laboratory | Lamour V.,Metastasis Research Laboratory | Lambert V.,Laboratory of Biology of Tumor and Development | Lambert V.,University of Liège | And 6 more authors.
Blood | Year: 2011

Dentin matrix protein 1 (DMP1) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although proangiogenic activities have been demonstrated for 2 SIBLINGs, the role of DMP1 in angiogenesis has not yet been addressed. We demonstrate that this extracellular matrix protein induced the expression of vascular endothelial cadherin (VE-cadherin), a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate vascular endothelial growth factor receptor 2 (VEGFR-2) activity, the major high-affinity receptor for VEGF. DMP1 induced VE-cadherin and p27Kip1 expression followed by cell-cycle arrest in human umbilical vein endothelial cells (HUVECs) in a CD44-dependent manner. VEGF-induced proliferation, migration, and tubulogenesis responses were specifically blocked on DMP1 pretreatment of HUVECs. Indeed, after VEcadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with basic fibroblast growth factor-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis. © 2011 by The American Society of Hematology.

Ooms L.M.,Monash University | Binge L.C.,Monash University | Davies E.M.,Monash University | Rahman P.,Monash University | And 16 more authors.
Cancer Cell | Year: 2015

Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer. Ooms et al. identify the inositol polyphosphate 5-phosphatase PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer. PIPP depletion increases transformation and accelerates oncogene-driven tumor growth in vivo, while paradoxically reducing cell migration, invasion, and metastasis. © 2015 Elsevier Inc.

Kasler H.G.,Gladstone | Lim H.W.,Gladstone | Mottet D.,Gladstone | Mottet D.,Metastasis Research Laboratory | And 3 more authors.
EMBO Journal | Year: 2012

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-ΔP) in thymocytes. We find that HDAC7-ΔP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. © 2012 European Molecular Biology Organization | All Rights Reserved.

Ciocca D.R.,CONICET | Cuello-Carrion F.D.,CONICET | Natoli A.L.,Metastasis Research Laboratory | Restall C.,Metastasis Research Laboratory | And 2 more authors.
Histochemistry and Cell Biology | Year: 2012

In a previous study, we measured caveolin-1 protein levels, both in the normal breast and in breast cancer. The study revealed no association between caveolin-1 expression in the epithelial compartment and clinical disease outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu expression was accelerated in mice lacking caveolin-1. We have analysed the heat shock protein (Hsp) response in the tumors of mice lacking caveolin-1. In all cases, the mammary tumors were estrogen and progesterone receptor negative, and the levels of Her-2/neu (evaluated by immunohistochemistry) were not different between the caveolin-1 +/+ (n = 8) and the caveolin-1 -/- (n = 7) tumors. However, a significant reduction in the extent of apoptosis was observed in mammary tumors from animals lacking caveolin-1. While Bcl-2, Bax, and survivin levels in the tumors were not different, the amount of HSPA (Hsp70) was almost double in the caveolin-1 -/- tumors. In contrast, HSPB1 (Hsp27/Hsp25) levels were significantly lower in the caveolin-1 -/- tumors. The mammary tumors from caveolin-1 null mice expressed more HSPC4 (gp96 or grp94), but HSPC1 (Hsp90), HSPA5 (grp78), HSPD1 (Hsp60), and CHOP were not altered. No significant changes in these proteins were found in the stroma surrounding these tumors. These results demonstrate that the disruption of the Cav-1 gene can cause alterations of specific Hsps as well as tumor development. © 2011 Springer-Verlag.

Miao Y.R.,Metastasis Research Laboratory | Miao Y.R.,University of Melbourne | Eckhardt B.L.,University of Houston | Cao Y.,Metastasis Research Laboratory | And 8 more authors.
Clinical Cancer Research | Year: 2013

Purpose: The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Because tumor cell dissemination is often an early event in breast cancer progression and can occur before diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose-regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which are localized at the plasma membrane. Experimental Design and Results: Here, we show that matched primary tumors and metastases from patients whodied from advanced breast cancer also express high levels of GRP78. We used a peptidomimetic targeting strategy that uses a known GRP78-binding peptide fused to a proapoptotic moiety [designated bone metastasis targeting peptide 78 (BMTP78)] and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Furthermore, in preclinical metastasis models, we show that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases. Conclusions: The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide-mediated targeting of cell surface-localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated. ©2013 AACR.

Kusuma N.,Metastasis Research Laboratory | Anderson R.L.,Metastasis Research Laboratory | Anderson R.L.,University of Melbourne | Pouliot N.,Metastasis Research Laboratory | Pouliot N.,University of Melbourne
Clinical and Experimental Metastasis | Year: 2011

The basement membrane protein laminin-511 has been implicated in breast cancer progression and metastasis. To identify peptides from LM-511 that modulate the metastatic properties of breast tumours, we screened laminin alpha 5 chain-derived peptides for their ability to promote adhesion of metastatic mammary carcinoma cells. Two selected adhesive peptides, α5A13b (FHVAYVLIKF) from the LN domain and A5G27 (RLVSYNGIIFFLK) from the LG-globular domain, were further characterised for their inhibitory properties against LM-511 activities in vitro and metastasis in vivo. In vitro, these peptides strongly inhibited LM-511-dependent adhesion and migration of highly metastatic 4T1.2 mammary carcinoma cells. In addition, A5G27 but not α5A13b significantly reduced breast tumour cell proliferation and inhibited laminin-511-induced matrix metalloproteinase-9 expression. Surprisingly, despite its potent inhibitory activity in vitro, A5G27 promoted rather than inhibited 4T1.2 experimental pulmonary metastasis in vivo, regardless of its route of administration. Adhesion of 4T1.2 cells to A5G27 was not inhibited by antibodies directed against α6, β1 or β3 integrins or CD44 but was significantly reduced in the presence of heparin suggesting a role for cell surface glycans. Treatment of the cells with α-l-fucosidase but not neuraminidase or heparinase II also partially inhibited cell adhesion to A5G27 and to LM-511 indicating that these interactions are mediated in part via terminal fucosyl residues. Overall, these results show that LMα5 peptides exhibit distinct functional properties in vitro and in vivo and suggest that interactions between the RLVSYNGIIFFLK sequence present in LM-511 and cell surface glycans may regulate LM-511 metastatic properties in vivo. © 2011 Springer Science+Business Media B.V.

Pouliot N.,Metastasis Research Laboratory | Pouliot N.,University of Melbourne | Kusuma N.,Metastasis Research Laboratory | Kusuma N.,University of Melbourne
Cell Adhesion and Migration | Year: 2013

Laminins are major constituents of basement membranes. At least 16 isoforms have now been described, each with distinct spatio-temporal expression patterns and functions. The laminin-511 heterotrimer (α5β1γ1) is one of the more recent isoforms to be identified and a potent adhesive and promigratory substrate for a variety of normal and tumor cell lines in vitro. As our understanding of its precise function in normal tissues and in pathologies is rapidly unraveling, current evidence suggests an important regulatory role in cancer. This review describes published data on laminin-511 expression in several malignancies and experimental evidence from both in vitro and in vivo studies supporting its functional role during tumor progression. A particular emphasis is put on more recent studies from our laboratory and that of others indicating that laminin-511 contributes to tumor dissemination and metastasis in advanced breast carcinomas and other tumor types. Collectively, the experimental evidence suggests that high expression of laminin-511 has prognostic significance and that targeting tumor-laminin-511 interactions may have therapeutic potential in advanced cancer patients. © 2013 Landes Bioscience.

Pouliot N.,Metastasis Research Laboratory | Pouliot N.,University of Melbourne | Denoyer D.,Deakin University
Cancer Forum | Year: 2014

Cancer progression is characterised by extensive metabolic reprogramming. Renewed enthusiasm in this field has been sparked in part by the realisation that metabolic pathways, oncogenes and tumour suppressors are intimately linked and regulate tumour growth and metastasis through complex reciprocal interactions. The identification of key pathways and enzymes regulating metabolism in cancer cells provides new opportunities for cancer therapy. This has motivated the development of several specific inhibitors targeting metabolic pathways and their therapeutic evaluation in pre-clinical models or in cancer patients. The unravelling of metabolic pathways associated with cancer progression has also highlighted the extensive metabolic heterogeneity that exists between, and within, each cancer type as well as between metastatic sites. The translation of these findings into personalised therapy remains a considerable challenge. To this end, the use of positron emission tomography to non-invasively visualise tumour metabolism is likely to facilitate the implementation of and assessment of new targeted therapies. Here, we briefly review the key metabolic changes associated with cancer progression and discuss recent advances in the field of positron emission tomography for metabolic imaging of cancer and their potential to improve the clinical management of cancer patients.

Tulley S.,Metastasis Research Laboratory | Chen W.-T.,Metastasis Research Laboratory
Journal of Biological Chemistry | Year: 2014

Background: Seprase is an integral membrane serine protease implicated in the cellular invasiveness of tumor, endothelial, and fibroblast cells of various human tumors. Results: Seprase is transcriptionally targeted in invasive melanoma cells via TGF-β signaling. Conclusion: Seprase-expressing melanoma cells produce high levels of autocrine TGF-β and display invasive phenotypes in vitro. Significance: This study provides the first insight into TGF-β-driven seprase transcription in cancer. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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