Suzanne Spong - Academia.edu (original) (raw)

Papers by Suzanne Spong

Research paper thumbnail of CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis

Fibrogenesis & Tissue Repair, 2012

CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate... more CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl 4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiationinduced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis.

Research paper thumbnail of The integrin α v β 6 is critical for keratinocyte migration on both its known ligand , fibronectin , and on vitronectin

The integrin αvβ6 is expressed on a variety of epithelial cells during dynamic processes includin... more The integrin αvβ6 is expressed on a variety of epithelial cells during dynamic processes including organogenesis, tissue injury and malignant transformation. However, because of the lack of tools to specifically inhibit the function of this integrin, little is known about its effects on cell behavior. To directly examine the role of this integrin in cell migration, we used keratinocytes derived from wildtype mice or mice expressing a null mutation in the β6 subunit (β6−/−) to perform migration assays in vitro. Migration on the known αvβ6 ligand, fibronectin was reduced in keratinocytes from β6−/− mice. Interestingly, keratinocytes from β6−/− mice also demonstrated markedly reduced migration on vitronectin, a protein not previously known to be a ligand for αvβ6. An anti-αvβ6 monoclonal antibody 10D5, generated by immunization of β6−/− mice with murine keratinocytes, inhibited adhesion and migration of wild-type keratinocyte on both vitronectin and fibronectin to levels similar to tho...

Research paper thumbnail of Treatments for cancer

Research paper thumbnail of Role of Connective Tissue Growth Factor (CTGF) in Survival and Chemosensitivity of Acute Lymphoblastic Leukemia

Blood

2593 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involv... more 2593 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in 75% of acute lymphoblastic leukemia (Br J Haematol, 2007; 138(6):740–8), and that increased expression of CTGF is associated with inferior outcome in B-ALL (Blood, 2007; 109(7):3080–3). In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knock-down CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA (479.3±37.2 and 57.3±5.9 copies per 100 copies of ABL1, respectively). Silencing of CTGF (CTGF-knockdown, CTGF-kd) resulted in significant suppression of leukemia cell growth (57% in RS4;11 and by 70% in REH) compared to control vector. CTGF knockdown moderately reduced adhesion of RS4;11 to fibronectin (27%±0.1%). In the...

Research paper thumbnail of Targeting Connective Tissue Growth Factor (CTGF) In Acute Lymphoblastic Leukemia Pre-Clinical Models: Anti-CTGF Monoclonal Antibody Attenuates Tumor Growth In Mouse Models of ALL

Blood

3257 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involv... more 3257 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. In pancreatic cancer, CTGF derived from tumor cells is a critical regulator of tumor growth, and CTGF-specific antibody attenuates tumor growth and metastases in vivo (Cancer Res., 2006; 66(11):5816-27). Elevated CTGF levels have been detected in a number of malignancies, including in lymphoblasts from patients with acute lymphoblastic leukaemia (ALL), while no expression of CTGF was detected in normal peripheral blood mononuclear cells. Most importantly, recent studies with microarrays of B-ALL cells showed evidence of increased expression of CTGF, which was significantly associated with inferior outcome (Blood, 2007; 109(7):3080-3). In this study, we characterized mRNA expression and function of CTGF in ALL cell lines (Jurkat, REH, RS4;11, Nalm6) and in samples from primary ALL samples...

Research paper thumbnail of Treatments for pancreatic cancer metastases

Research paper thumbnail of Treatments for Pancreatic Cancer

Research paper thumbnail of Treatments for cancer

Research paper thumbnail of Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

Oncotarget, Jan 11, 2015

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined... more Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by F...

Research paper thumbnail of CD44 Metalloproteinase-14 and Cleavage of on Laminin5 with Activation of Mature Human Thymocytes Migrate

We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature... more We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ␥ 2 chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.

Research paper thumbnail of Abstract B33: Inhibition of stromal-derived CTGF sensitizes murine pancreatic adenocarcinoma to gemcitabine treatment

Research paper thumbnail of Abstract B58: Connective tissue growth factor (CTGF) as a novel therapeutic target in high grade serous ovarian cancer

Clinical Cancer Research, 2013

Research paper thumbnail of Expression of connective tissue growth factor in pancreatic cancer cell lines

International Journal of Oncology, 2007

PURPOSE. Connective tissue growth factor (CTGF) appears to play a significant role in mediating f... more PURPOSE. Connective tissue growth factor (CTGF) appears to play a significant role in mediating fibrosis in several tissues. To gain further understanding of the role of CTGF in the scar formation that occurs after glaucoma filtering surgery (GFS), experiments were performed in a rabbit model. METHODS. Three experiments were performed: (1) CTGF and transforming growth factor (TGF)-␤ expression were measured quantitatively after GFS, using ELISA. (2) After GFS conjunctival bleb tissues were immunostained for the presence of CTGF and TGF-␤. (3) Exogenous CTGF was injected into mitomycin-C (MMC)-treated filtering blebs and the scaring response compared to TGF-␤ and physiological saline-injected blebs. RESULTS. CTGF and TGF-␤ were expressed maximally by day 5 after surgery and were both shown to be present in the bleb tissues after GFS. The addition of exogenous CTGF and TGF-␤ increased the rate of failure of GFS blebs. CONCLUSIONS. These data support the hypothesis that CTGF plays an important role in scarring and wound contracture after GFS. Inhibition of CTGF synthesis or its action may help prevent bleb failure and improve long-term GFS outcomes.

Research paper thumbnail of CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Proceedings of the National Academy of Sciences, 2013

Research paper thumbnail of Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Molecular Cancer Therapeutics, 2006

Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell mig... more Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-B1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.

Research paper thumbnail of Mature Human Thymocytes Migrate on Laminin-5 with Activation of Metalloproteinase-14 and Cleavage of CD44

The Journal of Immunology, 2004

We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature... more We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ␥ 2 chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.

Research paper thumbnail of Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Molecular Cancer Therapeutics, May 1, 2006

Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell mig... more Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-B1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.

Research paper thumbnail of CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis

Fibrogenesis & Tissue Repair, 2012

CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate... more CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl 4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiationinduced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis.

Research paper thumbnail of The integrin α v β 6 is critical for keratinocyte migration on both its known ligand , fibronectin , and on vitronectin

The integrin αvβ6 is expressed on a variety of epithelial cells during dynamic processes includin... more The integrin αvβ6 is expressed on a variety of epithelial cells during dynamic processes including organogenesis, tissue injury and malignant transformation. However, because of the lack of tools to specifically inhibit the function of this integrin, little is known about its effects on cell behavior. To directly examine the role of this integrin in cell migration, we used keratinocytes derived from wildtype mice or mice expressing a null mutation in the β6 subunit (β6−/−) to perform migration assays in vitro. Migration on the known αvβ6 ligand, fibronectin was reduced in keratinocytes from β6−/− mice. Interestingly, keratinocytes from β6−/− mice also demonstrated markedly reduced migration on vitronectin, a protein not previously known to be a ligand for αvβ6. An anti-αvβ6 monoclonal antibody 10D5, generated by immunization of β6−/− mice with murine keratinocytes, inhibited adhesion and migration of wild-type keratinocyte on both vitronectin and fibronectin to levels similar to tho...

Research paper thumbnail of Treatments for cancer

Research paper thumbnail of Role of Connective Tissue Growth Factor (CTGF) in Survival and Chemosensitivity of Acute Lymphoblastic Leukemia

Blood

2593 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involv... more 2593 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in 75% of acute lymphoblastic leukemia (Br J Haematol, 2007; 138(6):740–8), and that increased expression of CTGF is associated with inferior outcome in B-ALL (Blood, 2007; 109(7):3080–3). In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knock-down CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA (479.3±37.2 and 57.3±5.9 copies per 100 copies of ABL1, respectively). Silencing of CTGF (CTGF-knockdown, CTGF-kd) resulted in significant suppression of leukemia cell growth (57% in RS4;11 and by 70% in REH) compared to control vector. CTGF knockdown moderately reduced adhesion of RS4;11 to fibronectin (27%±0.1%). In the...

Research paper thumbnail of Targeting Connective Tissue Growth Factor (CTGF) In Acute Lymphoblastic Leukemia Pre-Clinical Models: Anti-CTGF Monoclonal Antibody Attenuates Tumor Growth In Mouse Models of ALL

Blood

3257 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involv... more 3257 Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of proteins involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. In pancreatic cancer, CTGF derived from tumor cells is a critical regulator of tumor growth, and CTGF-specific antibody attenuates tumor growth and metastases in vivo (Cancer Res., 2006; 66(11):5816-27). Elevated CTGF levels have been detected in a number of malignancies, including in lymphoblasts from patients with acute lymphoblastic leukaemia (ALL), while no expression of CTGF was detected in normal peripheral blood mononuclear cells. Most importantly, recent studies with microarrays of B-ALL cells showed evidence of increased expression of CTGF, which was significantly associated with inferior outcome (Blood, 2007; 109(7):3080-3). In this study, we characterized mRNA expression and function of CTGF in ALL cell lines (Jurkat, REH, RS4;11, Nalm6) and in samples from primary ALL samples...

Research paper thumbnail of Treatments for pancreatic cancer metastases

Research paper thumbnail of Treatments for Pancreatic Cancer

Research paper thumbnail of Treatments for cancer

Research paper thumbnail of Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

Oncotarget, Jan 11, 2015

Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined... more Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by F...

Research paper thumbnail of CD44 Metalloproteinase-14 and Cleavage of on Laminin5 with Activation of Mature Human Thymocytes Migrate

We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature... more We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ␥ 2 chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.

Research paper thumbnail of Abstract B33: Inhibition of stromal-derived CTGF sensitizes murine pancreatic adenocarcinoma to gemcitabine treatment

Research paper thumbnail of Abstract B58: Connective tissue growth factor (CTGF) as a novel therapeutic target in high grade serous ovarian cancer

Clinical Cancer Research, 2013

Research paper thumbnail of Expression of connective tissue growth factor in pancreatic cancer cell lines

International Journal of Oncology, 2007

PURPOSE. Connective tissue growth factor (CTGF) appears to play a significant role in mediating f... more PURPOSE. Connective tissue growth factor (CTGF) appears to play a significant role in mediating fibrosis in several tissues. To gain further understanding of the role of CTGF in the scar formation that occurs after glaucoma filtering surgery (GFS), experiments were performed in a rabbit model. METHODS. Three experiments were performed: (1) CTGF and transforming growth factor (TGF)-␤ expression were measured quantitatively after GFS, using ELISA. (2) After GFS conjunctival bleb tissues were immunostained for the presence of CTGF and TGF-␤. (3) Exogenous CTGF was injected into mitomycin-C (MMC)-treated filtering blebs and the scaring response compared to TGF-␤ and physiological saline-injected blebs. RESULTS. CTGF and TGF-␤ were expressed maximally by day 5 after surgery and were both shown to be present in the bleb tissues after GFS. The addition of exogenous CTGF and TGF-␤ increased the rate of failure of GFS blebs. CONCLUSIONS. These data support the hypothesis that CTGF plays an important role in scarring and wound contracture after GFS. Inhibition of CTGF synthesis or its action may help prevent bleb failure and improve long-term GFS outcomes.

Research paper thumbnail of CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

Proceedings of the National Academy of Sciences, 2013

Research paper thumbnail of Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Molecular Cancer Therapeutics, 2006

Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell mig... more Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-B1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.

Research paper thumbnail of Mature Human Thymocytes Migrate on Laminin-5 with Activation of Metalloproteinase-14 and Cleavage of CD44

The Journal of Immunology, 2004

We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature... more We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ␥ 2 chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.

Research paper thumbnail of Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer

Molecular Cancer Therapeutics, May 1, 2006

Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell mig... more Connective tissue growth factor (CTGF) plays an important role in fibrosis by modulating cell migration and cell growth but may also modify tumor growth and metastasis. Because CTGF is overexpressed in pancreatic ductal adenocarcinoma, we investigated the in vitro effects of CTGF on the proliferation and invasiveness of PANC-1 pancreatic cancer cells and examined the consequences of its in vivo inhibition on the growth and metastasis of these cells using a fully human CTGF-specific monoclonal antibody (FG-3019) in an orthotopic nude mouse model. Although PANC-1 cells expressed relatively high levels of endogenous CTGF mRNA, the addition of CTGF to conditioned medium increased the proliferation and invasiveness of PANC-1 cells. Moreover, transforming growth factor-B1 caused a further increase in CTGF expression in these cells. In vivo, the twice weekly i.p. administration of FG-3019 decreased tumor growth and metastasis and attenuated tumor angiogenesis and cancer cell proliferation. FG-3019 did not enhance apoptosis and did not attenuate the inhibitory effects of gemcitabine on tumor growth and metastasis. These findings suggest that CTGF may contribute to aberrant autocrine and paracrine pathways that promote pancreatic cancer cell growth, invasion, metastasis, and angiogenesis. Therefore, blocking CTGF actions with FG-3019 may represent a novel therapeutic approach in pancreatic ductal adenocarcinoma.