Yves St-Pierre - Academia.edu (original) (raw)

Papers by Yves St-Pierre

Blood, 1998

The ability of a tumor cell to survive is critical for successful dissemination to sites distant ... more The ability of a tumor cell to survive is critical for successful dissemination to sites distant from the primary tumor. Tumor cells must enter blood circulation, resist hemodynamic shear stress of the blood circulation, successfully extravasate, and then migrate through dense tissue stroma to a site favorable for tumor growth. Some tumor cells must therefore be endowed with peculiar abilities to successfully metastasize, whereas others, although capable of forming tumor in specific organs, cannot metastasize. This property has often been associated with the homing ability of a given tumor cell, likely through the expression of organ-specific homing receptors that are critical for the extravasation process. The present work was aimed at establishing the point at which metastatic and nonmetastatic lymphoma cells diverge. Although 164T2 and 267T2 lymphoma cell lines can successfully form thymic lymphoma when injected intrathymically, only the 164T2 clone can efficiently form tumor in ...

Oncoscience, 2015

This is an open-access article distributed under the terms of the Creative Commons Attribution Li... more This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Matrix metalloproteinase (MMP) 10 (stromelysin-2) is known to degrade various components of the e... more Matrix metalloproteinase (MMP) 10 (stromelysin-2) is known to degrade various components of the extracellular matrix; however, the signals that regulate its expression and its role in lymphoma growth remain unknown. In the present work, we report the up-regulated expression of MMP10 in T lymphoma cells following contact with endothelial cells. The induction of MMP10 was found to be dependent on the specific interaction between LFA-1 and ICAM-1, which play a central role in regulating the expression of genes involved in the rate-limiting steps of lymphoma development. MMP10, but not MMP3 (stromelysin-1), was also up-regulated in human B lymphoma cells following exposure to IL-4, IL-6, and IL-13, but not to IL-1. To gain further insight into the role of MMP10 in lymphoma development, we generated lymphoma cell lines constitutively expressing high levels of MMP10 and studied these cells for their ability to form thymic lymphoma in vivo. Mice injected with lymphoma cells constitutively expressing MMP10 developed thymic lymphoma more rapidly than those injected with control lymphoma cells. These results provide the first in vivo evidence that overexpression of MMP10 promotes tumor development, and indicate that MMP10 induction is an important pathway activated not only upon ICAM-1/LFA-1-mediated intercellular contact, but also following activation of tumor cells with inflammatory cytokines.

Developmental Immunology, 2000

Reprints available directly from the publisher Photocopying permitted by license only (C) 2000 OP... more Reprints available directly from the publisher Photocopying permitted by license only (C) 2000 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint, part of the Gordon and Breach Publishing Group.

Cancer Research, 2015

Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of agg... more Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 was recently shown to be specifically expressed in basal-like and HER-2 positive but not in luminal subtypes of human breast cancer. Galectin-7 also increases the metastatic behavior of breast cancer cells since overexpression of this protein in poorly metastatic breast cancer cells increases their ability to metastasize to the bone and to the lung. This pro-tumoral activity of galectin-7 in breast cancer is surprising since galectin-7 had been previously associated with activation of p53 and breast cancer cells often harbor a transcriptionally inactive form of p53. We have recently reconcile this apparent contradiction by showing that elevated levels of galectin-7 in breast cancer cells occurs via a gain-of-function mechanism of mutant p53. In p53-null breast cancer cells, we have shown that C/EBPβ-2 (also known as LAP2), the most transcriptionally active of the C/EBPβ isoforms, is responsible for the upregulation of galectin-7. How galectin-7 contributes to the progression of breast cancer remains unclear. Up to now, regulation of apoptosis by intracellular galectins has been largely attributed to their ability to translocate to mitochondria, possibly following their interaction with bcl-2. Here, we report that a mutant of galectin-7 that is unable to translocate to mitochondria induces resistance of human breast cancer cells to apoptosis induced by etoposide or by hypoxia-mimicking conditions. Surprisingly, this mutant and the wild-type form of galectin-7 bind equally well to bcl-2 in vitro and in vivo. Interestingly, both forms decreases the translocation of p53 to the nucleus and reduce the expression of p21 following treatment with doxorubicin. We also found that galectin-7 was released by breast cancer cells and that recombinant galectin-7 increased apoptosis of monocytes, T CD4+ and T CD8+ cells. This suggests that galectin-7 contributes to the establishment of an immunosuppressive tumor microenvironment by killing helper and effector T cells. Taken together, these results challenges the current paradigm that mitochondrial galectins are important for resistance to apoptosis and call for a greater focus on the role of galectin-7 in breast cancer. They also indicate that targeting both cytosolic and extracellular galectin-7 could improve the efficacy of anti-cancer drugs for the treatment of aggressive forms of breast cancer. Citation Format: Yves St-Pierre, Andree-Anne Grosset, Marilyne Labrie, Donald Gagne, Maria-Claudia Vladoiu, Louis Gaboury, Nicolas Doucet. Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-16.

Leukemia Research, 1987

The development of RadLV-induced T-cell leukemia is a multistep process which evolves along the b... more The development of RadLV-induced T-cell leukemia is a multistep process which evolves along the bone marrow-thymus axis. This process has been shown to be under the control of resistance and susceptibility genes. The relative importance of bone marrow and thymic phenotypes in this genetic control have not been established. We have constructed radiation chimeras with bone marrow from susceptible C57BL/Ka and thymus from resistant B10.A(5R) mice (and vice versa). The rate of leukemia development in the various groups indicates that the phenotype of the bone marrow and not that of the thymus determines the expression of resistance or susceptibility.

Journal of immunology (Baltimore, Md. : 1950), 1990

The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag b... more The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag by endocytosis followed by processing, probably proteolysis, in an intracellular acidic compartment. However, there remains considerable controversy as to the precise route taken by the antigen and the MHC class II protein during this process. The unusual stability of Ag-MHC class II protein complexes has led to speculation that antigen can only associate with newly synthesized MHC class II molecules. An alternate possibility is that the MHC class II binding site can be regenerated within the cell during internalization and recycling of MHC class II proteins. To address these possibilities, three different murine B lymphoma lines were tested for their ability to process and present native protein Ag in the presence of the protein synthesis inhibitor cycloheximide or the protein synthesis inhibitor cycloheximide or the protein export inhibitor, Brefeldin A. Both agents blocked the presenta...

The Journal of rheumatology, 2007

To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with in... more To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with inflamed joints, and if so, what isoform(s); and to examine whether there was a correlation between the levels of these proteins and those of MMP-1 and MMP-3 in the same samples. In general, 2 sets of synovial and serum samples were analyzed. The first set of 17 SF -samples from patients with inflamed joints were analyzed for 14-3-3 eta isoform by Western blot. The second set of 12 matching serum and SF samples were analyzed for 14-3-3 eta, gamma, MMP-1, and MMP-3 by the same procedure. The MMP-1 stimulatory effect of various concentrations of 14-3-3 eta in cultured fibroblasts was then evaluated. We found that of the seven 14-3-3 isoforms tested (beta, gamma, epsilon, eta, sigma, Theta, and zeta), the levels of only 2 isoforms, eta and gamma, were easily detectable in SF samples from patients with inflammatory joint diseases. The levels of these proteins were significantly higher in infla...

Arthritis research & therapy, 2006

Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibit... more Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis pa...

Journal of immunology (Baltimore, Md. : 1950), 1998

Human leukocyte elastase (HLE) participates in tissue destruction in a number of inflammatory dis... more Human leukocyte elastase (HLE) participates in tissue destruction in a number of inflammatory disorders, including rheumatoid arthritis and cystic fibrosis. Since HLE has been shown to bind to Mac-1, and ICAM-1 plays a key role during the recruitment and the activation of leukocytes at inflamed sites, we investigated the capacity of HLE to cleave ICAM-1. Flow-cytometric analyses showed a dose-dependent cleavage of ICAM-1 by HLE on different human cell lines. The cleavage was completely inhibited by alpha1-antitrypsin, a natural HLE protease inhibitor. The ability of HLE to degrade ICAM-1 was further confirmed by electrophoretic analysis using a soluble form of ICAM-1 (D1-D5). Enzymatic removal of N-linked glycosylation did not significantly modulate ICAM-1 cleavage by HLE, while removal of sialic acid residues partially reduced the sensitivity of ICAM-1 to HLE. We further showed that sputum of cystic fibrosis patients contains high levels of HLE activity capable of cleavage of cell ...

Journal of immunology (Baltimore, Md. : 1950), 1998

It has been hypothesized that the intercellular adhesion receptors used by normal cells could als... more It has been hypothesized that the intercellular adhesion receptors used by normal cells could also be operative in the spreading of circulating malignant cells to target organs. In the present work, we show that genetic ablation of the ICAM-1 gene confers resistance to T cell lymphoma metastasis. Following i.v. inoculation of LFA-1-expressing malignant T lymphoma cells, we found that ICAM-1-deficient mice were almost completely resistant to the development of lymphoid malignancy compared with wild-type control mice that developed lymphoid tumors in the kidneys, spleen, and liver. Histologic examinations confirmed that ICAM-1-deficient mice, in contrast to wild-type mice, had no evidence of lymphoid infiltration in these organs. The effect of ICAM-1 on T cell lymphoma metastasis was observed in two distinct strains of ICAM-1-deficient animals. Nonetheless, lymphoma cells migrated with the same efficiency to target organs in both normal and ICAM-1-deficient mice, indicating not only t...

Cytometry, 1997

Specific detection and accurate enumeration of microorganisms in the environment have been hamper... more Specific detection and accurate enumeration of microorganisms in the environment have been hampered by the lack of suitable techniques. A three-parameter flow cytometric method (FCM) was developed to detect quantitatively Sphingomonas sp. strain 107 inoculated into soil samples. By combining light scattering profiles (i.e., morphological properties), ethidium bromide (EtBr) influx (i.e., wall permeability), and fluorescence in situ hybridization against the 16S rRNA (i.e., detection specificity), we could accurately discriminate the bacterium of interest from the indigenous microflora and soil debris. EtBr was used, first, to determine the optimal cell wall permeabilization treatment to allow oligonucleotide probes to enter the bacterial cells and, second, to achieve clear discrimination of fixed cells from debris in soil samples. This method allowed effective qualitative and quantitative analysis by fluorescence in situ hybridization. The results showed that the detection threshold by FCM was 3 x 10(4) cells/g of dry soil. Cell counts deduced from FCM analysis were similar to those obtained by the colony forming unit assay when soils contained fewer than 3 x 106 cells/g dry soil. This method should be useful for either quantitative monitoring of microorganisms inoculated in contaminated soil samples during bioremediation or detecting known bacterial strains in environmental samples.

Critical Reviews™ in Immunology, 2005

Clinical Immunology Newsletter, 1997

Taylor-Robinresponse to Treponema pallidum antigens: impli-syphilis by immunoglobulin M (lgM) and... more Taylor-Robinresponse to Treponema pallidum antigens: impli-syphilis by immunoglobulin M (lgM) and lgA ira-son D, Goldmeier D: Use of the polymerase cations for improved serodiagnosis of congenital munoblotting. Clin Diagn Lab Immunol 1:32-37. chain reaction to detect DNA sequences specific syphilis.

Expert Opinion on Drug Discovery, 2009

Galectins are a family of proteins defined by having at least one characteristic carbohydrate rec... more Galectins are a family of proteins defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. Over the recent years, with a better understanding of their role in normal and pathological conditions, they have emerged as promising diagnostic and therapeutic targets in cancer. Whereas most of these studies have focused on galectin-1 and galectin-3, very little attention has been paid to galectin-7, a member of the family that has recently been associated with various forms of cancer. We review the role of galectin-7 in cancer and examine the possible directions that could be exploited to inhibit its role in cancer on the basis of recently identified galectin ligands. Although efforts have been made to develop drugs aimed at inhibiting the cancer-promoting propensity of galectins, most of these inhibitors were specific for the CRD region of the molecule and have focused on extracellular functions of galectins. However, galectins may also be involved in protein-protein interactions, most notably in the nucleus. As galectin-7 is expressed in the cytoplasm and the nucleus in cancer cells, it will be important to investigate its nucleocytoplasmic trafficking and how putative drugs will affect its functions in cancer.

FEBS Journal, 2007

Acidic extracellular pH is a common feature of tumor tissues. We have reported that culturing cel... more Acidic extracellular pH is a common feature of tumor tissues. We have reported that culturing cells at acidic pH (5.4-6.5) induced matrix metalloproteinase-9 expression through phospholipase D, extracellular signal regulated kinase 1/2 and p38 mitogen-activated protein kinases and nuclear factor-kappaB. Here, we show that acidic extracellular pH signaling involves both pathways of phospholipase D triggered by Ca2+ influx and acidic sphingomyelinase in mouse B16 melanoma cells. We found that BAPTA-AM [1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl) ester], a chelator of intracellular free calcium, and the voltage dependent Ca2+ channel blockers, mibefradil (for T-type) and nimodipine (for L-type), dose-dependently inhibited acidic extracellular pH-induced matrix metalloproteinase-9 expression. Intracellular free calcium concentration ([Ca2+]i) was transiently elevated by acidic extracellular pH, and this [Ca2+]i elevation was repressed by EGTA and the voltage dependent Ca2+ channel blockers but not by phospholipase C inhibitor, suggesting that acidic extracellular pH increased [Ca2+]i through voltage dependent Ca2+ channel. In contrast, SR33557, an L-type voltage dependent Ca2+ channel blocker and acidic sphingomyelinase inhibitor, attenuated matrix metalloproteinase-9 induction but did not affect calcium influx. We found that acidic sphingomyelinase activity was induced by acidic extracellular pH and that the specific acidic sphingomyelinase inhibitors (perhexiline and desipramine) and siRNA targeting aSMase/smpd1 could inhibit acidic extracellular pH-induced matrix metalloproteinase-9 expression. BAPTA-AM reduced acidic extracellular pH-induced phospholipase D but not acidic sphingomyelinase acitivity. The acidic sphingomyelinase inhibitors did not affect the phosphorylation of extracellular signal regulated kinase 1/2 and p38, but they suppressed nuclear factor-kappaB activity. These data suggest that the calcium influx-triggered phospholipase D and acidic sphingomyelinase pathways of acidic extracellular pH induced matrix metalloproteinase-9 expression, at least in part, through nuclear factor-kappaB activation.

PLoS ONE, 2014

Galectin-7 is considered a gene under the control of p53. However, elevated expression of galecti... more Galectin-7 is considered a gene under the control of p53. However, elevated expression of galectin-7 has been reported in several forms of cancer harboring an inactive p53 pathway. This is especially true for breast cancer where galectin-7 expression is readily expressed in a high proportion in basal-like breast cancer tissues, conferring cancer cells with increased resistance to cell death and metastatic properties. These observations suggest that other transcription factors are capable of inducing galectin-7 expression. In the present work, we have examined the role of CCAAT/enhancer-binding protein beta (C/ EBPb) in inducing expression of galectin-7. C/EBP proteins have been shown to contribute to breast cancer by upregulating pro-metastatic genes. We paid particular attention to C/EBPb-2 (also known as LAP2), the most transcriptionally active of the C/EBPb isoforms. Our results showed that ectopic expression of C/EBPb-2 in human breast cancer cells was sufficient to induce expression of galectin-7 at both the mRNA and protein levels. In silico analysis further revealed the presence of an established CEBP element in the galectin-7 promoter. Mutation of this binding site abolished the transcriptional activity of the galectin-7 promoter. Chromatin immunoprecipitation analysis confirmed that C/EBPb-2 binds to the endogenous galectin-7 promoter. Analysis of galectin-7 protein expression in normal epithelia and in breast carcinoma by immunohistochemistry further showed the expression pattern of C/EBPb closely micmicked that of galectin-7, most notably in mammary myoepithelial cells and basal-like breast cancer where galectin-7 is preferentially expressed. Taken together, our findings suggest that C/EBPb is an important mediator of galectin-7 gene activation in breast cancer cells and highlight the different transcriptional mechanisms controlling galectin-7 in cancer cells.

International Journal of Cancer, 1999

Dysregulation of metalloproteinase production at tumor sites contributes to the modification of l... more Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxically, MMP-9 expression by tumor cells, most notably by lymphoma cells, is concomitant with the expression of its physiological inhibitor, TIMP-1. Not only are both genes often co-expressed in the most aggressive forms of lymphomas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressive lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclear whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the development of lymphoma. To gain further insight into the respective roles of MMP-9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce the net physiological balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thymic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progression of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma.

Frontiers in Bioscience, 2012

Introduction 3. Galectin-7: Comparison with other members of the galectin family 3.1. Galectins 3... more Introduction 3. Galectin-7: Comparison with other members of the galectin family 3.1. Galectins 3.2. Distinctive expression pattern of galectin-7 3.3. Cellular localization of galectin-7 4. Galectin-7 in cancer 4.1. The pro-apoptotic function of galectin-7: a logical role in suppressing tumor growth 4.2. Unexpected roles of galectin-7 4.3. Galectin-7: a marker for mammary myoepithelial cells and aggressive breast cancer? 5. Other functions for galectin-7 6. Concluding remarks 7. Acknowledgement 8. References

Frontiers in Bioscience, 2005

The role of cell adhesion molecules in cancer progression 2.1. Recruitment of effector cells 2.2.... more The role of cell adhesion molecules in cancer progression 2.1. Recruitment of effector cells 2.2. The role of ICAM-1 in the dissemination of tumor cells 2.3. The role of selectins in cancer progression 3. Soluble forms of adhesion molecules during cancer 3.1. The presence of circulating forms of adhesion molecules 3.2. Sensitivity of LFA-1-ICAM-1 interactions to proteolytic cleavage 3.3. Alternative splicing regulates the cleavage of adhesion molecules 3.4. The cleavage of adhesion molecules by proteases of different sources 4. Implications of the proteolytic cleavage of adhesion molecules during anti-tumoral immune response 4.1. Modulating the recruitment of effector cells 4.2. Escaping immune surveillance through the absence of co-stimulatory signals 5. Conclusions 6. Acknowledgement 7.

Blood, 1998

The ability of a tumor cell to survive is critical for successful dissemination to sites distant ... more The ability of a tumor cell to survive is critical for successful dissemination to sites distant from the primary tumor. Tumor cells must enter blood circulation, resist hemodynamic shear stress of the blood circulation, successfully extravasate, and then migrate through dense tissue stroma to a site favorable for tumor growth. Some tumor cells must therefore be endowed with peculiar abilities to successfully metastasize, whereas others, although capable of forming tumor in specific organs, cannot metastasize. This property has often been associated with the homing ability of a given tumor cell, likely through the expression of organ-specific homing receptors that are critical for the extravasation process. The present work was aimed at establishing the point at which metastatic and nonmetastatic lymphoma cells diverge. Although 164T2 and 267T2 lymphoma cell lines can successfully form thymic lymphoma when injected intrathymically, only the 164T2 clone can efficiently form tumor in ...

Oncoscience, 2015

This is an open-access article distributed under the terms of the Creative Commons Attribution Li... more This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Matrix metalloproteinase (MMP) 10 (stromelysin-2) is known to degrade various components of the e... more Matrix metalloproteinase (MMP) 10 (stromelysin-2) is known to degrade various components of the extracellular matrix; however, the signals that regulate its expression and its role in lymphoma growth remain unknown. In the present work, we report the up-regulated expression of MMP10 in T lymphoma cells following contact with endothelial cells. The induction of MMP10 was found to be dependent on the specific interaction between LFA-1 and ICAM-1, which play a central role in regulating the expression of genes involved in the rate-limiting steps of lymphoma development. MMP10, but not MMP3 (stromelysin-1), was also up-regulated in human B lymphoma cells following exposure to IL-4, IL-6, and IL-13, but not to IL-1. To gain further insight into the role of MMP10 in lymphoma development, we generated lymphoma cell lines constitutively expressing high levels of MMP10 and studied these cells for their ability to form thymic lymphoma in vivo. Mice injected with lymphoma cells constitutively expressing MMP10 developed thymic lymphoma more rapidly than those injected with control lymphoma cells. These results provide the first in vivo evidence that overexpression of MMP10 promotes tumor development, and indicate that MMP10 induction is an important pathway activated not only upon ICAM-1/LFA-1-mediated intercellular contact, but also following activation of tumor cells with inflammatory cytokines.

Developmental Immunology, 2000

Reprints available directly from the publisher Photocopying permitted by license only (C) 2000 OP... more Reprints available directly from the publisher Photocopying permitted by license only (C) 2000 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint, part of the Gordon and Breach Publishing Group.

Cancer Research, 2015

Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of agg... more Resistance to apoptosis induced by anti-cancer drugs is a major obstacle for the treatment of aggressive forms of breast cancer. Galectin-7 was recently shown to be specifically expressed in basal-like and HER-2 positive but not in luminal subtypes of human breast cancer. Galectin-7 also increases the metastatic behavior of breast cancer cells since overexpression of this protein in poorly metastatic breast cancer cells increases their ability to metastasize to the bone and to the lung. This pro-tumoral activity of galectin-7 in breast cancer is surprising since galectin-7 had been previously associated with activation of p53 and breast cancer cells often harbor a transcriptionally inactive form of p53. We have recently reconcile this apparent contradiction by showing that elevated levels of galectin-7 in breast cancer cells occurs via a gain-of-function mechanism of mutant p53. In p53-null breast cancer cells, we have shown that C/EBPβ-2 (also known as LAP2), the most transcriptionally active of the C/EBPβ isoforms, is responsible for the upregulation of galectin-7. How galectin-7 contributes to the progression of breast cancer remains unclear. Up to now, regulation of apoptosis by intracellular galectins has been largely attributed to their ability to translocate to mitochondria, possibly following their interaction with bcl-2. Here, we report that a mutant of galectin-7 that is unable to translocate to mitochondria induces resistance of human breast cancer cells to apoptosis induced by etoposide or by hypoxia-mimicking conditions. Surprisingly, this mutant and the wild-type form of galectin-7 bind equally well to bcl-2 in vitro and in vivo. Interestingly, both forms decreases the translocation of p53 to the nucleus and reduce the expression of p21 following treatment with doxorubicin. We also found that galectin-7 was released by breast cancer cells and that recombinant galectin-7 increased apoptosis of monocytes, T CD4+ and T CD8+ cells. This suggests that galectin-7 contributes to the establishment of an immunosuppressive tumor microenvironment by killing helper and effector T cells. Taken together, these results challenges the current paradigm that mitochondrial galectins are important for resistance to apoptosis and call for a greater focus on the role of galectin-7 in breast cancer. They also indicate that targeting both cytosolic and extracellular galectin-7 could improve the efficacy of anti-cancer drugs for the treatment of aggressive forms of breast cancer. Citation Format: Yves St-Pierre, Andree-Anne Grosset, Marilyne Labrie, Donald Gagne, Maria-Claudia Vladoiu, Louis Gaboury, Nicolas Doucet. Galectin-7 increases resistance of breast cancer cells to drug-induced apoptosis and promotes tumor escape by killing T cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-16.

Leukemia Research, 1987

The development of RadLV-induced T-cell leukemia is a multistep process which evolves along the b... more The development of RadLV-induced T-cell leukemia is a multistep process which evolves along the bone marrow-thymus axis. This process has been shown to be under the control of resistance and susceptibility genes. The relative importance of bone marrow and thymic phenotypes in this genetic control have not been established. We have constructed radiation chimeras with bone marrow from susceptible C57BL/Ka and thymus from resistant B10.A(5R) mice (and vice versa). The rate of leukemia development in the various groups indicates that the phenotype of the bone marrow and not that of the thymus determines the expression of resistance or susceptibility.

Journal of immunology (Baltimore, Md. : 1950), 1990

The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag b... more The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag by endocytosis followed by processing, probably proteolysis, in an intracellular acidic compartment. However, there remains considerable controversy as to the precise route taken by the antigen and the MHC class II protein during this process. The unusual stability of Ag-MHC class II protein complexes has led to speculation that antigen can only associate with newly synthesized MHC class II molecules. An alternate possibility is that the MHC class II binding site can be regenerated within the cell during internalization and recycling of MHC class II proteins. To address these possibilities, three different murine B lymphoma lines were tested for their ability to process and present native protein Ag in the presence of the protein synthesis inhibitor cycloheximide or the protein synthesis inhibitor cycloheximide or the protein export inhibitor, Brefeldin A. Both agents blocked the presenta...

The Journal of rheumatology, 2007

To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with in... more To investigate whether 14-3-3 proteins were detectable in synovial fluid (SF) of patients with inflamed joints, and if so, what isoform(s); and to examine whether there was a correlation between the levels of these proteins and those of MMP-1 and MMP-3 in the same samples. In general, 2 sets of synovial and serum samples were analyzed. The first set of 17 SF -samples from patients with inflamed joints were analyzed for 14-3-3 eta isoform by Western blot. The second set of 12 matching serum and SF samples were analyzed for 14-3-3 eta, gamma, MMP-1, and MMP-3 by the same procedure. The MMP-1 stimulatory effect of various concentrations of 14-3-3 eta in cultured fibroblasts was then evaluated. We found that of the seven 14-3-3 isoforms tested (beta, gamma, epsilon, eta, sigma, Theta, and zeta), the levels of only 2 isoforms, eta and gamma, were easily detectable in SF samples from patients with inflammatory joint diseases. The levels of these proteins were significantly higher in infla...

Arthritis research & therapy, 2006

Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibit... more Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis pa...

Journal of immunology (Baltimore, Md. : 1950), 1998

Human leukocyte elastase (HLE) participates in tissue destruction in a number of inflammatory dis... more Human leukocyte elastase (HLE) participates in tissue destruction in a number of inflammatory disorders, including rheumatoid arthritis and cystic fibrosis. Since HLE has been shown to bind to Mac-1, and ICAM-1 plays a key role during the recruitment and the activation of leukocytes at inflamed sites, we investigated the capacity of HLE to cleave ICAM-1. Flow-cytometric analyses showed a dose-dependent cleavage of ICAM-1 by HLE on different human cell lines. The cleavage was completely inhibited by alpha1-antitrypsin, a natural HLE protease inhibitor. The ability of HLE to degrade ICAM-1 was further confirmed by electrophoretic analysis using a soluble form of ICAM-1 (D1-D5). Enzymatic removal of N-linked glycosylation did not significantly modulate ICAM-1 cleavage by HLE, while removal of sialic acid residues partially reduced the sensitivity of ICAM-1 to HLE. We further showed that sputum of cystic fibrosis patients contains high levels of HLE activity capable of cleavage of cell ...

Journal of immunology (Baltimore, Md. : 1950), 1998

It has been hypothesized that the intercellular adhesion receptors used by normal cells could als... more It has been hypothesized that the intercellular adhesion receptors used by normal cells could also be operative in the spreading of circulating malignant cells to target organs. In the present work, we show that genetic ablation of the ICAM-1 gene confers resistance to T cell lymphoma metastasis. Following i.v. inoculation of LFA-1-expressing malignant T lymphoma cells, we found that ICAM-1-deficient mice were almost completely resistant to the development of lymphoid malignancy compared with wild-type control mice that developed lymphoid tumors in the kidneys, spleen, and liver. Histologic examinations confirmed that ICAM-1-deficient mice, in contrast to wild-type mice, had no evidence of lymphoid infiltration in these organs. The effect of ICAM-1 on T cell lymphoma metastasis was observed in two distinct strains of ICAM-1-deficient animals. Nonetheless, lymphoma cells migrated with the same efficiency to target organs in both normal and ICAM-1-deficient mice, indicating not only t...

Cytometry, 1997

Specific detection and accurate enumeration of microorganisms in the environment have been hamper... more Specific detection and accurate enumeration of microorganisms in the environment have been hampered by the lack of suitable techniques. A three-parameter flow cytometric method (FCM) was developed to detect quantitatively Sphingomonas sp. strain 107 inoculated into soil samples. By combining light scattering profiles (i.e., morphological properties), ethidium bromide (EtBr) influx (i.e., wall permeability), and fluorescence in situ hybridization against the 16S rRNA (i.e., detection specificity), we could accurately discriminate the bacterium of interest from the indigenous microflora and soil debris. EtBr was used, first, to determine the optimal cell wall permeabilization treatment to allow oligonucleotide probes to enter the bacterial cells and, second, to achieve clear discrimination of fixed cells from debris in soil samples. This method allowed effective qualitative and quantitative analysis by fluorescence in situ hybridization. The results showed that the detection threshold by FCM was 3 x 10(4) cells/g of dry soil. Cell counts deduced from FCM analysis were similar to those obtained by the colony forming unit assay when soils contained fewer than 3 x 106 cells/g dry soil. This method should be useful for either quantitative monitoring of microorganisms inoculated in contaminated soil samples during bioremediation or detecting known bacterial strains in environmental samples.

Critical Reviews™ in Immunology, 2005

Clinical Immunology Newsletter, 1997

Taylor-Robinresponse to Treponema pallidum antigens: impli-syphilis by immunoglobulin M (lgM) and... more Taylor-Robinresponse to Treponema pallidum antigens: impli-syphilis by immunoglobulin M (lgM) and lgA ira-son D, Goldmeier D: Use of the polymerase cations for improved serodiagnosis of congenital munoblotting. Clin Diagn Lab Immunol 1:32-37. chain reaction to detect DNA sequences specific syphilis.

Expert Opinion on Drug Discovery, 2009

Galectins are a family of proteins defined by having at least one characteristic carbohydrate rec... more Galectins are a family of proteins defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. Over the recent years, with a better understanding of their role in normal and pathological conditions, they have emerged as promising diagnostic and therapeutic targets in cancer. Whereas most of these studies have focused on galectin-1 and galectin-3, very little attention has been paid to galectin-7, a member of the family that has recently been associated with various forms of cancer. We review the role of galectin-7 in cancer and examine the possible directions that could be exploited to inhibit its role in cancer on the basis of recently identified galectin ligands. Although efforts have been made to develop drugs aimed at inhibiting the cancer-promoting propensity of galectins, most of these inhibitors were specific for the CRD region of the molecule and have focused on extracellular functions of galectins. However, galectins may also be involved in protein-protein interactions, most notably in the nucleus. As galectin-7 is expressed in the cytoplasm and the nucleus in cancer cells, it will be important to investigate its nucleocytoplasmic trafficking and how putative drugs will affect its functions in cancer.

FEBS Journal, 2007

Acidic extracellular pH is a common feature of tumor tissues. We have reported that culturing cel... more Acidic extracellular pH is a common feature of tumor tissues. We have reported that culturing cells at acidic pH (5.4-6.5) induced matrix metalloproteinase-9 expression through phospholipase D, extracellular signal regulated kinase 1/2 and p38 mitogen-activated protein kinases and nuclear factor-kappaB. Here, we show that acidic extracellular pH signaling involves both pathways of phospholipase D triggered by Ca2+ influx and acidic sphingomyelinase in mouse B16 melanoma cells. We found that BAPTA-AM [1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl) ester], a chelator of intracellular free calcium, and the voltage dependent Ca2+ channel blockers, mibefradil (for T-type) and nimodipine (for L-type), dose-dependently inhibited acidic extracellular pH-induced matrix metalloproteinase-9 expression. Intracellular free calcium concentration ([Ca2+]i) was transiently elevated by acidic extracellular pH, and this [Ca2+]i elevation was repressed by EGTA and the voltage dependent Ca2+ channel blockers but not by phospholipase C inhibitor, suggesting that acidic extracellular pH increased [Ca2+]i through voltage dependent Ca2+ channel. In contrast, SR33557, an L-type voltage dependent Ca2+ channel blocker and acidic sphingomyelinase inhibitor, attenuated matrix metalloproteinase-9 induction but did not affect calcium influx. We found that acidic sphingomyelinase activity was induced by acidic extracellular pH and that the specific acidic sphingomyelinase inhibitors (perhexiline and desipramine) and siRNA targeting aSMase/smpd1 could inhibit acidic extracellular pH-induced matrix metalloproteinase-9 expression. BAPTA-AM reduced acidic extracellular pH-induced phospholipase D but not acidic sphingomyelinase acitivity. The acidic sphingomyelinase inhibitors did not affect the phosphorylation of extracellular signal regulated kinase 1/2 and p38, but they suppressed nuclear factor-kappaB activity. These data suggest that the calcium influx-triggered phospholipase D and acidic sphingomyelinase pathways of acidic extracellular pH induced matrix metalloproteinase-9 expression, at least in part, through nuclear factor-kappaB activation.

PLoS ONE, 2014

Galectin-7 is considered a gene under the control of p53. However, elevated expression of galecti... more Galectin-7 is considered a gene under the control of p53. However, elevated expression of galectin-7 has been reported in several forms of cancer harboring an inactive p53 pathway. This is especially true for breast cancer where galectin-7 expression is readily expressed in a high proportion in basal-like breast cancer tissues, conferring cancer cells with increased resistance to cell death and metastatic properties. These observations suggest that other transcription factors are capable of inducing galectin-7 expression. In the present work, we have examined the role of CCAAT/enhancer-binding protein beta (C/ EBPb) in inducing expression of galectin-7. C/EBP proteins have been shown to contribute to breast cancer by upregulating pro-metastatic genes. We paid particular attention to C/EBPb-2 (also known as LAP2), the most transcriptionally active of the C/EBPb isoforms. Our results showed that ectopic expression of C/EBPb-2 in human breast cancer cells was sufficient to induce expression of galectin-7 at both the mRNA and protein levels. In silico analysis further revealed the presence of an established CEBP element in the galectin-7 promoter. Mutation of this binding site abolished the transcriptional activity of the galectin-7 promoter. Chromatin immunoprecipitation analysis confirmed that C/EBPb-2 binds to the endogenous galectin-7 promoter. Analysis of galectin-7 protein expression in normal epithelia and in breast carcinoma by immunohistochemistry further showed the expression pattern of C/EBPb closely micmicked that of galectin-7, most notably in mammary myoepithelial cells and basal-like breast cancer where galectin-7 is preferentially expressed. Taken together, our findings suggest that C/EBPb is an important mediator of galectin-7 gene activation in breast cancer cells and highlight the different transcriptional mechanisms controlling galectin-7 in cancer cells.

International Journal of Cancer, 1999

Dysregulation of metalloproteinase production at tumor sites contributes to the modification of l... more Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxically, MMP-9 expression by tumor cells, most notably by lymphoma cells, is concomitant with the expression of its physiological inhibitor, TIMP-1. Not only are both genes often co-expressed in the most aggressive forms of lymphomas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressive lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclear whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the development of lymphoma. To gain further insight into the respective roles of MMP-9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce the net physiological balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thymic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progression of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma.

Frontiers in Bioscience, 2012

Introduction 3. Galectin-7: Comparison with other members of the galectin family 3.1. Galectins 3... more Introduction 3. Galectin-7: Comparison with other members of the galectin family 3.1. Galectins 3.2. Distinctive expression pattern of galectin-7 3.3. Cellular localization of galectin-7 4. Galectin-7 in cancer 4.1. The pro-apoptotic function of galectin-7: a logical role in suppressing tumor growth 4.2. Unexpected roles of galectin-7 4.3. Galectin-7: a marker for mammary myoepithelial cells and aggressive breast cancer? 5. Other functions for galectin-7 6. Concluding remarks 7. Acknowledgement 8. References

Frontiers in Bioscience, 2005

The role of cell adhesion molecules in cancer progression 2.1. Recruitment of effector cells 2.2.... more The role of cell adhesion molecules in cancer progression 2.1. Recruitment of effector cells 2.2. The role of ICAM-1 in the dissemination of tumor cells 2.3. The role of selectins in cancer progression 3. Soluble forms of adhesion molecules during cancer 3.1. The presence of circulating forms of adhesion molecules 3.2. Sensitivity of LFA-1-ICAM-1 interactions to proteolytic cleavage 3.3. Alternative splicing regulates the cleavage of adhesion molecules 3.4. The cleavage of adhesion molecules by proteases of different sources 4. Implications of the proteolytic cleavage of adhesion molecules during anti-tumoral immune response 4.1. Modulating the recruitment of effector cells 4.2. Escaping immune surveillance through the absence of co-stimulatory signals 5. Conclusions 6. Acknowledgement 7.