Vimentin-ERK Signaling Uncouples Slug Gene Regulatory Function.
; ; 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 ▲]Detailed reference viewed: 23 (0 ULg)
EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP.
Paye, Alexandra ; Truong, Alice ; Yip, Cassandre 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 ▲]Detailed reference viewed: 74 (27 ULg)
Myoferlin is a key regulator of EGFR activity in breast cancer.
Turtoi, Andrei ; Blomme, Arnaud ; Bellahcene, Akeila 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 ▲]Detailed reference viewed: 93 (14 ULg)
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel ; ; Blacher, Silvia 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 ▲]Detailed reference viewed: 42 (13 ULg)
Identification and characterization of novel galectin-9 splice variants in endothelial cells
Heusschen, Roy ; ; et al
in Cancer Research (2011)Detailed reference viewed: 9 (0 ULg)
Dual function of ERR alpha in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin.
; ; 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 ▲]Detailed reference viewed: 43 (5 ULg)
PET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide.
; ; WITHOFS, Nadia 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 ▲]Detailed reference viewed: 34 (3 ULg)
De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation.
; ; 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 ▲]Detailed reference viewed: 34 (0 ULg)
Benefit 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
; ; et al
in Cancer Research (2009, December 15), 69Detailed reference viewed: 11 (0 ULg)
Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines.
Pignon, Jean-Christophe ; Koopmansch, Benjamin ; Nolens, Grégory 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 ▲]Detailed reference viewed: 62 (24 ULg)
Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
; ; Tabruyn, Sébastien et al
in Cancer Research (2009), 69(10), 4527-36
Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear ... [more ▼]
Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels. [less ▲]Detailed reference viewed: 15 (2 ULg)
Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer.
; ; et al
in Cancer Research (2009), 69(3), 747-52
Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumoral cells grown on an extracellular matrix (ECM). The core machinery controlling ... [more ▼]
Invadopodia are proteolytically active membrane protrusions that extend from the ventral surface of invasive tumoral cells grown on an extracellular matrix (ECM). The core machinery controlling invadopodia biogenesis is regulated by the Rho GTPase Cdc42. To understand the upstream events regulating invadopodia biogenesis, we investigated the role of Fgd1, a Cdc42-specific guanine nucleotide exchange factor. Loss of Fgd1 causes the rare inherited human developmental disease faciogenital dysplasia. Here, we show that Fgd1 is required for invadopodia biogenesis and ECM degradation in an invasive cell model and functions by modulation of Cdc42 activation. We also find that Fgd1 is expressed in human prostate and breast cancer as opposed to normal tissue and that expression levels matched tumor aggressiveness. Our findings suggest a central role for Fgd1 in the focal degradation of the ECM in vitro and, for the first time, show a connection between Fgd1 and cancer progression, proposing that it might function during tumorigenesis. [less ▲]Detailed reference viewed: 66 (1 ULg)
Selective Inhibition of Matrix Metalloproteinase-14 Blocks Tumor Growth, Invasion, and Angiogenesis
; ; et al
in Cancer Research (2009), 69(4), 1517-1526
Inhibition of specific matrix metalloproteinases (MNIP) is an attractive noncytotoxic approach to cancer therapy. MMP-14, a membrane-bound zinc endopeptidase, has been proposed to play a central role in ... [more ▼]
Inhibition of specific matrix metalloproteinases (MNIP) is an attractive noncytotoxic approach to cancer therapy. MMP-14, a membrane-bound zinc endopeptidase, has been proposed to play a central role in tumor growth, invasion, and neovascularization. Besides cleaving matrix proteins, MMP-14 activates proMMP-2 leading to an amplification of pericellular proteolytic activity. To examine the contribution of MMP-14 to tumor growth and angiogenesis, we used DX-2400, a highly selective fully human MMP-14 inhibitory antibody discovered using phage display technology. DX-2400 blocked proMMP-2 processing on tumor and endothelial cells, inhibited angiogenesis, and slowed tumor progression and formation of metastatic lesions. The combination of potency, selectivity, and robust in vivo activity shows the potential of a selective MMP-14 inhibitor for the treatment of solid tumors. [Cancer Res 2009;69(4):1517-26] [less ▲]Detailed reference viewed: 20 (3 ULg)
ADAMTS-1 metalloproteinase induces a stromal reaction and propotes tumor development in mice.
Rocks, Natacha ; Paulissen, Geneviève ; Quesada Calvo, Florence et al
in Cancer Research (2008), 68(22), 9541-50
ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor ... [more ▼]
ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorageindependent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1–overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor B (TGF-B), and interleukin-1B (IL-1B). Neutralizing antibodies against TGF-B and IL-1B blocked the chemotactic effect of medium conditioned by ADAMTS-1–expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1–induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling. [less ▲]Detailed reference viewed: 172 (25 ULg)
A six-gene signature predicting breast cancer lung metastasis.
; ; Bellahcene, Akeila et al
in Cancer Research (2008), 68(15), 6092-9
The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene ... [more ▼]
The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of using tissue surgically resected from lung metastatic lesions and comparing their gene expression profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph node-negative breast cancer patients, we developed a 6-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the 6-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we show that the signature improves risk stratification independently of known standard clinical variables and a previously established lung metastasis signature based on an experimental breast cancer metastasis model. [less ▲]Detailed reference viewed: 61 (2 ULg)
A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden
; Bellahcene, Akeila ; et al
in Cancer Research (2007), 67(20), 9894-9902
Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immohistochemistry revealed that cathepsin K ... [more ▼]
Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immohistochemistry revealed that cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with cathepsin K-expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of cathepsin K inhibitor (CKI; 50 mg/kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/kg, twice daily) or a single clinical dose of 100 mu g/kg zoledronic acid (osteoclast inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced skeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting skeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not block the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that cathepsin K could be a therapeutic target for the treatment of bone metastases. [less ▲]Detailed reference viewed: 27 (0 ULg)
Preconditioning of the Tumor Vasculature and Tumor Cells by Intermittent Hypoxia: Implications for Anticancer Therapies
Martinive, Philippe ; ; et al
in Cancer Research (2006), 66(24), 11736-44
Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by ... [more ▼]
Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O2 diffusion–limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO2 within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1α (HIF-1α)–targeting small interfering RNA led us to document that the accumulation of HIF-1α during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1α to resensitize the tumor vasculature to anticancer treatments. (Cancer Res 2006; 66(24): 11736-44) [less ▲]Detailed reference viewed: 26 (2 ULg)
Mechanism of reoxygenation after antiangiogenic therapy using SU5416 and its importance for guiding combined antitumor therapy
; ; et al
in Cancer Research (2006), 66(19), 9698704
Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated ... [more ▼]
Emerging preclinical studies support the concept of a transient "normalization" of tumor vasculature during the early stage of antiangiogenic treatment, with possible beneficial effects on associated radiotherapy or chemotherapy. One key issue in this area of research is to determine whether this feature is common to all antiangiogenic drugs and whether the phenomenon occurs in all types of tumors. In the present study, we characterized the evolution of the tumor oxygenation (in transplantable liver tumor and FSAII tumor models) after administration of SU5416, an antagonist of the vascular endothelial growth factor receptor. SU5416 induced an early increase in tumor oxygenation [measured by electronic paramagnetic resonance (EPR)], which did not correlate with remodeling of the tumor vasculature (assessed by CD31 labeling using immunohistochemistry) or with tumor perfusion (measured by dynamic contrast enhanced-magnetic resonance imaging). Inhibition of mitochondrial respiration (measured by EPR) was responsible for this early reoxygenation. Consistent with these unique findings in the tumor microenvironment, we found that SU5416 potentiated tumor response to radiotherapy but not to chemotherapy. In addition to the fact that the characterization of the tumor oxygenation is essential to enable correct application of combined therapies, our results show that the long-term inhibition of oxygen consumption is a potential novel target in this class of compounds. [less ▲]Detailed reference viewed: 40 (9 ULg)
Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases
; Sounni, Nor Eddine ; et al
in Cancer Research (2006), 66(10), 5165-5172
Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been ... [more ▼]
Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been well documented, the significance of other MT-MMPs is rather unknown. We have investigated the involvement of MT4-MMP, a glycosylphosphatidylinositol-anchored protease, in breast cancer progression. Interestingly, immunohistochemical analysis shows that MT4-MMP production at protein level is strongly increased in epithelial cancer cells of human breast carcinomas compared with normal epithelial cells. Positive staining for MT4-MMP is also detected in lymph node metastases. In contrast, quantitative reverse transcription-PCR analysis reveals similar MT4-MMP mRNA levels in human breast adenocarcinomas and normal breast tissues. Stable transfection of MT4-MMP cDNA in human breast adenocarcinoma MDA-MB-231 cells does not affect in vitro cell proliferation or invasion but strongly promotes primary tumor growth and associated metastases in RAG-1 immunodeficient mice. We provide for the first time evidence that MT4-MMP overproduction accelerates in vivo tumor growth, induces enlargement of i.t. blood vessels, and is associated with increased lung metastases. These results identify MT4-MMP as a new putative target to design anticancer strategies. [less ▲]Detailed reference viewed: 77 (23 ULg)
Earlier onset of tumoral anglogenesis in matrix metalloproteinase-19-deficient mice
; ; et al
in Cancer Research (2006), 66(10), 5234-5241
Among matrix metalloproteinases (MMP), MMP-19 displays unique structural features and tissue distribution. In contrast to most MMPs, MMP-19 is expressed in normal human epidermis and down-regulated during ... [more ▼]
Among matrix metalloproteinases (MMP), MMP-19 displays unique structural features and tissue distribution. In contrast to most MMPs, MMP-19 is expressed in normal human epidermis and down-regulated during malignant transformation and dedifferentiation. The contribution of MMP-19 during tumor angiogenesis is presently unknown. In an attempt to give new insights into MMP-19 in vivo functions, angiogenic response of mutant mice lacking MMP-19 was analyzed after transplantation of murine malignant PDVA keratinocytes and after injection of Matrigel supplemented with basic fibroblast growth factor. In situ hybridization and immunohistochemical analysis revealed that MMP-19 is produced by host mesenchymal cells but not by endothelial capillary cells or CD11b-positive inflammatory cells. Based on a new computer-assisted method of quantification, we provide evidence that host MMP-19 deficiency was associated with an increased early angiogenic response. In addition, increased tumor invasion was observed in MMP-19-/- mice. We conclude that, in contrast to most MMPs that promote tumor progression, MMP-19 is a negative regulator of early steps of tumor angiogenesis and invasion. These data highlight the requirement to understand the individual functions of each MMP to improve anticancer strategies. [less ▲]Detailed reference viewed: 47 (10 ULg)