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See detailTissue factor induced by epithelial-mesenchymal transition triggers a pro-coagulant state that drives metastasis of circulating tumor cells.
Bourcy, Morgane ULg; Suarez-Carmona, Meggy ULg; Lambert, Justine ULg et al

in Cancer Research (2016)

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific ... [more ▼]

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTC with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related pro-coagulant properties in the blood. TF blockade by antibody or shRNA diminished the pro-coagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis which triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTC. [less ▲]

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See detailA phase 1b study of Trebananib plus Paclitaxel and Trastuzumab or Capecitabine and Lapatinib in patients with HER2+ locally recurrent or metastatic breast cancer
Kaufman, P.A.; Freyer, G.; Kemeny, M. et al

in Cancer Research (2015, May), 75(9), 5-19-14

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See detailVimentin-ERK Signaling Uncouples Slug Gene Regulatory Function.
Virtakoivu, Reetta; Mai, Anja; Mattila, Elina et al

in Cancer research (2015), 75(11), 2349-62

Epithelial-mesenchymal transition (EMT) in cells is a developmental process adopted during tumorigenesis that promotes metastatic capacity. In this study, we advance understanding of EMT control in cancer ... [more ▼]

Epithelial-mesenchymal transition (EMT) in cells is a developmental process adopted during tumorigenesis that promotes metastatic capacity. In this study, we advance understanding of EMT control in cancer cells with the description of a novel vimentin-ERK axis that regulates the transcriptional activity of Slug (SNAI2). Vimentin, ERK, and Slug exhibited overlapping subcellular localization in clinical specimens of triple-negative breast carcinoma. RNAi-mediated ablation of these gene products inhibited cancer cell migration and cell invasion through a laminin-rich matrix. Biochemical analyses demonstrated direct interaction of vimentin and ERK, which promoted ERK activation and enhanced vimentin transcription. Consistent with its role as an intermediate filament, vimentin acted as a scaffold to recruit Slug to ERK and promote Slug phosphorylation at serine-87. Site-directed mutagenesis established a requirement for ERK-mediated Slug phosphorylation in EMT initiation. Together, these findings identified a pivotal step in controlling the ability of Slug to organize hallmarks of EMT. [less ▲]

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See detailEGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.
Paye, Alexandra ULg; Truong, Alice ULg; Yip, Cassandre ULg et al

in Cancer Research (2014), 74(23), 6758-70

MT4-MMP (MMP-17) is a GPI-anchored matrix metalloprotease expressed on the surface of cancer cells which promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of ... [more ▼]

MT4-MMP (MMP-17) is a GPI-anchored matrix metalloprotease expressed on the surface of cancer cells which promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein (Rb) inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGF- and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expression were correlated in human triple negative breast cancer specimens. Altogether our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. [less ▲]

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See detailThe SNAP trial : schedules of nab-Paclitaxel in metastatic breast cancer. International breast cancer study group (ICGSG 42-12) and breast international group (BIG 2-12)
Gennari, Alessandra; JERUSALEM, Guy ULg; Maibach, Rudolf

in Cancer Research (2013, December), 73(24), 3-1-02

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See detailSafety analysis of BOLERO-3 : a phase III trial of daily Everolimus vs placebo, both with weekly Trastuzumab and Vinorelbine in Trastuzumab-resistant, advanced breast cancer
JERUSALEM, Guy ULg; Masuda, Norikazu; Andre, Fabrice et al

in Cancer Research (2013, December), 73(24), 3-15-03

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See detailBOLERO-3 : Quality-of-life maintained in patients with HER-2 positive metastatic breast cancer treated with Everolimus plus Trastuzumab plus Vinorelbine
Isaacs, Claudine; Ozguroglu, Mustafa; JERUSALEM, Guy ULg et al

in Cancer Research (2013, December), 73(24), 4-12-18

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See detailBOLERO-3 : Everolimus plus Trastuzumab and Vinorelbine in asian patients with HER2-positive metastatic breast cancer
Toi, Masakazu; Masuda, Norikazu; ANDRE, Fabrice et al

in Cancer Research (2013, December), 73(24), 4-12-19

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See detail The role of TGF­alpha in the resistance to mesothelioma chemotherapy
Neelature Sriramareddy, Sathyanarayana ULg; Vandermeers, Fabian; Costa, Chrisostome et al

in Cancer Research (2013, April 15), 73(8), 1538-7445

 Malignant mesothelioma (MM) is a cancer of the pleura caused mainly by the inhalation of asbestos fibers. The impact of chemotherapy on the outcome of patients with MM  is  still  unclear.  We  ... [more ▼]

 Malignant mesothelioma (MM) is a cancer of the pleura caused mainly by the inhalation of asbestos fibers. The impact of chemotherapy on the outcome of patients with MM  is  still  unclear.  We  hypothesized  that  unresponsiveness  to  chemotherapy  is  due  to inadequate  gene  expression  in  tumor  cells.  We  have  previously  shown  that  inhibitors  of histones  deacetylases  (such  as  valproate,  VPA)  significantly  increases  the  efficacy  of compounds used in chemotherapy (Vandermeers et al, 2010, Clinical Cancer Research 15: 2818). A recent clinical trial on relapsing MM patients has shown that VPA in combination with  doxorubicin  improves  response  rates  and  quality  of  life  (Scherpereel  et  al,  2011, European Respiratory Journal 37:129). [less ▲]

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See detailMyoferlin is a key regulator of EGFR activity in breast cancer.
Turtoi, Andrei ULg; Blomme, Arnaud ULg; Bellahcene, Akeila ULg et al

in Cancer Research (2013), 73

Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair and endocytosis. While some reports have implicated myoferlin in cancer, the extent of its ... [more ▼]

Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair and endocytosis. While some reports have implicated myoferlin in cancer, the extent of its expression in and contributions to cancer are not well established. In this study, we show that myoferlin is overexpressed in human breast cancers and that it is has a critical role in controlling degradation of the EGFR after its activation and internalization in breast cancer cells. Myoferlin depletion blocked EGF-induced cell migration and epithelial-to-mesenchymal transition. Both effects were induced as a result of impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homooligomerization. In parallel, myoferlin depletion reduced tumor development in a chicken chorioallantoic membrane xenograft model of human breast cancer. Considering the therapeutic significance of EGFR targeting, our findings identify myoferlin as an novel candidate function to target for future drug development. [less ▲]

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See detailStromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel ULg; Raymond-Letron, I; Blacher, Silvia ULg et al

in Cancer Research (2012), 72(12), 3010-3019

Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor 􏰀 (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro ... [more ▼]

Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor 􏰀 (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ERalpha-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERalpha-deficient mice, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2- positive cells, but still expressed by bone marrow derived cells. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore suggest that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERα (not hematopoiteic but Tie2-dependent expression of ERalpha), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumor demand preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. [less ▲]

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See detailThe 2006 Adjuvant Trastuzumab Convention in Belgium: 5 years later
VANDERHAEGEN, J; PARIDAENS, R; PICCART, M et al

in Cancer Research (2012)

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See detailIdentification and characterization of novel galectin-9 splice variants in endothelial cells
Heusschen, Roy ULg; De Bree, Martijn; Griffioen, Arjan et al

in Cancer Research (2011)

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See detailDual function of ERR alpha in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin.
Fradet, Anais; Sorel, Helene; Bouazza, Lamia et al

in Cancer Research (2011), 71(17), 5728-38

Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRalpha) has been implicated in breast cancer and bone ... [more ▼]

Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRalpha) has been implicated in breast cancer and bone development, prompting us to examine whether ERRalpha may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer, overexpression of wild-type ERRalpha reduced metastasis, whereas overexpression of a dominant negative mutant promoted metastasis. Osteoclasts were directly affected and ERRalpha upregulated the osteoclastogenesis inhibitor, osteoprotegerin (OPG), providing a direct mechanistic basis for understanding how ERRalpha reduced breast cancer cell growth in bone. In contrast, ERRalpha overexpression increased breast cancer cell growth in the mammary gland. ERRalpha-overexpressing primary tumors were highly vascularized, consistent with an observed upregulation of angiogenic growth factor, the VEGF. In support of these findings, we documented that elevated expression of ERRalpha mRNA in breast carcinomas was associated with high expression of OPG and VEGF and with disease progression. In conclusion, our results show that ERRalpha plays a dual role in breast cancer progression in promoting the local growth of tumor cells, but decreasing metastatic growth of osteolytic lesions in bone. [less ▲]

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See detailSignificant efficacy in a phase 2 study of NKTR-102, a novel polymer conjugate of Irinotecan, in patients with pre-treated metastatic breast cancer (MBC)
Awada, Ahmad; Chan, Stephan; JERUSALEM, Guy ULg et al

in Cancer Research (2010, December), 70(24), 6-11-01

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See detailPET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide.
Nielsen, Carsten H; Kimura, Richard H; WITHOFS, Nadia ULg et al

in Cancer Research (2010), 70(22), 9022-30

Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on ... [more ▼]

Due to the high mortality of lung cancer, there is a critical need to develop diagnostic procedures enabling early detection of the disease while at a curable stage. Targeted molecular imaging builds on the positive attributes of positron emission tomography/computed tomography (PET/CT) to allow for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01+/-0.61 versus 4.36+/-0.68; P<0.05). Ex vivo biodistribution showed 64Cu-DOTA-knottin 2.5F to have a fast renal clearance combined with low nonspecific accumulation in the thorax. Collectively, these results show 64Cu-DOTA-knottin 2.5F to be a promising candidate for clinical translation for earlier detection and improved characterization of lung cancer. [less ▲]

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See detailDe novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.
Rysman, Evelien; Brusselmans, Koen; Scheys, Katryn et al

in Cancer Research (2010), 70(20), 8117-26

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the ... [more ▼]

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. [less ▲]

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See detailBenefit of the sequential administration of Docetaxel after standard FEC regimen for node-positive breast cancer : long-term follow-up results of the FNCLCC-PACS 01 trial
Coudert, Bruno; Campone, Mario; Spielmann, Marc et al

in Cancer Research (2009, December 15), 69

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See detailAndrogen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines.
Pignon, Jean-Christophe ULg; Koopmansch, Benjamin ULg; Nolens, Grégory ULg et al

in Cancer Research (2009), 69(7), 2941-2949

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR ... [more ▼]

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR and ERBB2 expression in PCa cells. In steroid-depleted medium (SDM), EGFR protein was less abundant in androgen-sensitive LNCaP than in androgen ablation-resistant 22Rv1 cells, whereas transcript levels were similar. Dihydrotestosterone (DHT) treatment increased both EGFR mRNA and protein levels and stimulated RNA polymerase II recruitment to the EGFR gene promoter, whereas it decreased ERBB2 transcript and protein levels in LNCaP cells. DHT altered neither EGFR or ERBB2 levels nor the abundance of prostate-specific antigen (PSA), TMEPA1, or TMPRSS2 mRNAs in 22Rv1 cells, which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain (ARDeltaCTD). The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms. Silencing of both isoforms strongly reduced PSA, TMEPA1, and TMPRSS2 transcript levels. Inhibition of both AR isoforms did not affect EGFR and ERBB2 transcript levels but decreased EGFR and increased ERBB2 protein levels. Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and ARDeltaCTD. A further decrease was obtained with PKI166, an EGFR/ERBB2 kinase inhibitor. Overall, we showed that ARDeltaCTD is responsible for constitutive EGFR expression and ERBB2 repression in 22Rv1 cells and that ARDeltaCTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth. [less ▲]

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