The Experts below are selected from a list of 8043 Experts worldwide ranked by ideXlab platform
Francesca Caccuri - One of the best experts on this subject based on the ideXlab platform.
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role of autophagy in hiv 1 matrix protein p17 driven Lymphangiogenesis
Journal of Virology, 2017Co-Authors: Pietro Mazzuca, Arnaldo Caruso, Cinzia Giagulli, Stefania Marsico, Marina C Pils, Kai Schulze, Stefania Mitola, Carlos A. Guzmán, Francesca CaccuriAbstract:ABSTRACT AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1-infected (HIV + ) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV + patients under successful cART. The viral protein displays potent lymphangiogenic activity in vitro and in vivo . This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node-derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes Lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered Lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy-incompetent mice. Our findings reveal a previously unrecognized role of autophagy in Lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumor-driven Lymphangiogenesis in HIV + patients. IMPORTANCE AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV + ) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced Lymphangiogenesis occurs in the lymph nodes of HIV + patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting Lymphangiogenesis. Here, we show that p17 promotes Lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs.
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angiogenic lymphangiogenic and adipogenic effects of hiv 1 matrix protein p17
Pathogens and Disease, 2015Co-Authors: Arnaldo Caruso, Francesca Caccuri, Olga Latinovic, Mark K Lafferty, Daniele Basta, Robert C Gallo, Joseph Bryant, Wuyuan Lu, Alfredo GarzinodemoAbstract:Abstract Lymphangiogenesis and concurrent angiogenesis are essential in supporting proliferation and survival of AIDS-related lymphomas, which are often metastatic. In vitro studies suggest a candidate angiogienic and lymphangiogenic factor encoded by HIV: the matrix protein p17. p17 accumulates in lymph nodes of patients even when they are undergoing highly active antiretroviral therapy. p17 has been found to affect immune cells, and recent data showed that a variant p17, called S75X, induces cell growth by triggering MAPK/ERK and PI3K/AKT pathways. We tested the in vivo angiogenic activity of p17 by injecting it in Matrigel plugs in nude mice. Plugs were retrieved 7 days after injection, and assessed macroscopically, and by light and confocal microscopy. Our data revealed that both reference and S75X variant p17 promote angiogenesis and Lymphangiogenesis in vivo. Our results suggest that the induction of angiogenesis and Lymphangiogenesis by HIV-1 p17 may generate a favorable microenvironment that could trigger tumor growth and maintenance. Moreover, the presence of adipocytes infiltration observed at the histological level suggests a possible interplay between angiogenesis, Lymphangiogenesis and adipogenesis. These findings offer new opportunities for the development of treatment strategies to combat HIV-related cancers.
Kari Alitalo - One of the best experts on this subject based on the ideXlab platform.
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roles of prostaglandin e2 ep3 ep4 receptor signaling in the enhancement of Lymphangiogenesis during fibroblast growth factor 2 induced granulation formation
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Kanako Hosono, Shuh Narumiya, Kari Alitalo, Tatsunori Suzuki, Hideaki Tamaki, Hiroyuki Sakagami, Izumi Hayashi, Masataka MajimaAbstract:Objective— One of the hallmarks of inflammation is lymphangiogesis that drains the interstitial fluids. During chronic inflammation, angiogenesis is induced by a variety of inflammatory mediators, such as prostaglandins (PGs). However, it remains unknown whether they enhance Lymphangiogenesis. We examined the roles of cyclooxygenase-2 (COX-2) and PGE2 receptor signaling in enhancement of Lymphangiogenesis during proliferative inflammation. Methods and Results— Lymphangiogenesis estimated by podoplanin/vascular endothelial growth factor (VEGF) receptor-3/LYVE-1 expression was upregulated during proliferative inflammation seen around and into subcutaneous Matrigel plugs containing fibroblast growth factor-2 (125 ng/site). A COX-2 inhibitor (celecoxib) significantly reduced Lymphangiogenesis in a dose-dependent manner, whereas topical PGE2 enhanced Lymphangiogenesis. Topical injection of fluorescein isothiocyanate–dextran into the Matrigel revealed that lymphatic flow from the Matrigels was COX-2 dependent. Lymphangiogenesis was suppressed in the granulation tissues of mice lacking either EP3 or EP4, suggesting that these molecules are receptors in response to endogenous PGE2. An EP3-selective agonist (ONO-AE-248) increased the expression of VEGF-C and VEGF-D in cultured macrophages, whereas an EP4-selective agonist (ONO-AE1-329) increased VEGF-C expression in cultured macrophages and increased VEGF-D expression in cultured fibroblasts. Conclusion— Our findings suggest that COX-2 and EP3/EP4 signaling contributes to Lymphangiogenesis in proliferative inflammation, possibly via induction of VEGF-C and VEGF-D, and may become a therapeutic target for controlling Lymphangiogenesis.
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preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor Lymphangiogenesis and lymphatic metastasis
Cancer Research, 2004Co-Authors: Iiro Rajantie, Taija Makinen, Maritta Ilmonen, Marika J Karkkainen, Paula Haiko, Petri Salven, Kari AlitaloAbstract:Endothelial progenitor cells have been shown to contribute to angiogenesis in various tumor models. Here, we have studied the relative contributions of bone marrow (BM)-derived endothelial progenitors and pre-existing lymphatic vessels to tumor Lymphangiogenesis. We did not find significant incorporation of genetically marked BM-derived cells in lymphatic vessels during tumor- or vascular endothelial growth factor C-induced Lymphangiogenesis. The degree of tumor Lymphangiogenesis correlated with lymphatic vessel density in the peritumoral area, and despite tumor Lymphangiogenesis, lymphatic metastasis failed to occur in gene-targeted vascular endothelial growth factor C(+/-) mice that have hypoplasia of the lymphatic network. Our data demonstrate that during tumor Lymphangiogenesis and cancer cell dissemination via the lymphatics, the newly formed lymphatic vessels sprout from the pre-existing local lymphatic network with little if any incorporation of BM-derived endothelial progenitor cells.
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blockade of vascular endothelial growth factor receptor 3 signaling inhibits fibroblast growth factor 2 induced Lymphangiogenesis in mouse cornea
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Hajime Kubo, Ebba Brakenhielm, Renhai Cao, Taija Makinen, Yihai Cao, Kari AlitaloAbstract:Vascular endothelial growth factor receptor-3 (VEGFR-3) is a major mediator of Lymphangiogenesis. Recently, VEGFR-3 ligands, VEGF-C, and VEGF-D were reported to promote tumor Lymphangiogenesis and lymphatic metastasis, and these processes were inhibited by blocking of the VEGFR-3-signaling pathway. Here, we have adapted the mouse corneal angiogenesis assay to study potential lymphangiogenic factors and inhibitors. Immunohistochemical analysis with lymphatic endothelial markers showed that VEGF-C induces lymphatic as well as blood vessel growth in the cornea. By contrast, VEGF induced angiogenesis but not Lymphangiogenesis. Fibroblast growth factor-2 (FGF-2) stimulated both Lymphangiogenesis and angiogenesis. FGF-2 up-regulated VEGF-C expression in vascular endothelial and perivascular cells. Furthermore, administration of blocking anti-VEGFR-3 antibodies inhibited the FGF-2-induced Lymphangiogenesis. These findings show that VEGFR-3 can mediate Lymphangiogenesis induced by other growth factors. Because increased expression of FGF-2 and VEGF-C has been associated with lymphatic metastasis, our results provide a potential strategy for the inhibition of lymphatic metastasis in cancer therapy.
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induction of tumor Lymphangiogenesis by vegf c promotes breast cancer metastasis
Nature Medicine, 2001Co-Authors: Mihaela Skobe, Paula Velasco, Kari Alitalo, David G Jackson, Thomas Hawighorst, Remko Prevo, Lauren Janes, Lucia Riccardi, Kevin P Claffey, Michael DetmarAbstract:Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (Lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral Lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral Lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor Lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral Lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor Lymphangiogenesis and metastasis.
Daniele Basta - One of the best experts on this subject based on the ideXlab platform.
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angiogenic lymphangiogenic and adipogenic effects of hiv 1 matrix protein p17
Pathogens and Disease, 2015Co-Authors: Arnaldo Caruso, Francesca Caccuri, Olga Latinovic, Mark K Lafferty, Daniele Basta, Robert C Gallo, Joseph Bryant, Wuyuan Lu, Alfredo GarzinodemoAbstract:Abstract Lymphangiogenesis and concurrent angiogenesis are essential in supporting proliferation and survival of AIDS-related lymphomas, which are often metastatic. In vitro studies suggest a candidate angiogienic and lymphangiogenic factor encoded by HIV: the matrix protein p17. p17 accumulates in lymph nodes of patients even when they are undergoing highly active antiretroviral therapy. p17 has been found to affect immune cells, and recent data showed that a variant p17, called S75X, induces cell growth by triggering MAPK/ERK and PI3K/AKT pathways. We tested the in vivo angiogenic activity of p17 by injecting it in Matrigel plugs in nude mice. Plugs were retrieved 7 days after injection, and assessed macroscopically, and by light and confocal microscopy. Our data revealed that both reference and S75X variant p17 promote angiogenesis and Lymphangiogenesis in vivo. Our results suggest that the induction of angiogenesis and Lymphangiogenesis by HIV-1 p17 may generate a favorable microenvironment that could trigger tumor growth and maintenance. Moreover, the presence of adipocytes infiltration observed at the histological level suggests a possible interplay between angiogenesis, Lymphangiogenesis and adipogenesis. These findings offer new opportunities for the development of treatment strategies to combat HIV-related cancers.
Arnaldo Caruso - One of the best experts on this subject based on the ideXlab platform.
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role of autophagy in hiv 1 matrix protein p17 driven Lymphangiogenesis
Journal of Virology, 2017Co-Authors: Pietro Mazzuca, Arnaldo Caruso, Cinzia Giagulli, Stefania Marsico, Marina C Pils, Kai Schulze, Stefania Mitola, Carlos A. Guzmán, Francesca CaccuriAbstract:ABSTRACT AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1-infected (HIV + ) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV + patients under successful cART. The viral protein displays potent lymphangiogenic activity in vitro and in vivo . This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node-derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes Lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered Lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy-incompetent mice. Our findings reveal a previously unrecognized role of autophagy in Lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumor-driven Lymphangiogenesis in HIV + patients. IMPORTANCE AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV + ) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced Lymphangiogenesis occurs in the lymph nodes of HIV + patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting Lymphangiogenesis. Here, we show that p17 promotes Lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs.
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angiogenic lymphangiogenic and adipogenic effects of hiv 1 matrix protein p17
Pathogens and Disease, 2015Co-Authors: Arnaldo Caruso, Francesca Caccuri, Olga Latinovic, Mark K Lafferty, Daniele Basta, Robert C Gallo, Joseph Bryant, Wuyuan Lu, Alfredo GarzinodemoAbstract:Abstract Lymphangiogenesis and concurrent angiogenesis are essential in supporting proliferation and survival of AIDS-related lymphomas, which are often metastatic. In vitro studies suggest a candidate angiogienic and lymphangiogenic factor encoded by HIV: the matrix protein p17. p17 accumulates in lymph nodes of patients even when they are undergoing highly active antiretroviral therapy. p17 has been found to affect immune cells, and recent data showed that a variant p17, called S75X, induces cell growth by triggering MAPK/ERK and PI3K/AKT pathways. We tested the in vivo angiogenic activity of p17 by injecting it in Matrigel plugs in nude mice. Plugs were retrieved 7 days after injection, and assessed macroscopically, and by light and confocal microscopy. Our data revealed that both reference and S75X variant p17 promote angiogenesis and Lymphangiogenesis in vivo. Our results suggest that the induction of angiogenesis and Lymphangiogenesis by HIV-1 p17 may generate a favorable microenvironment that could trigger tumor growth and maintenance. Moreover, the presence of adipocytes infiltration observed at the histological level suggests a possible interplay between angiogenesis, Lymphangiogenesis and adipogenesis. These findings offer new opportunities for the development of treatment strategies to combat HIV-related cancers.
Alfredo Garzinodemo - One of the best experts on this subject based on the ideXlab platform.
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angiogenic lymphangiogenic and adipogenic effects of hiv 1 matrix protein p17
Pathogens and Disease, 2015Co-Authors: Arnaldo Caruso, Francesca Caccuri, Olga Latinovic, Mark K Lafferty, Daniele Basta, Robert C Gallo, Joseph Bryant, Wuyuan Lu, Alfredo GarzinodemoAbstract:Abstract Lymphangiogenesis and concurrent angiogenesis are essential in supporting proliferation and survival of AIDS-related lymphomas, which are often metastatic. In vitro studies suggest a candidate angiogienic and lymphangiogenic factor encoded by HIV: the matrix protein p17. p17 accumulates in lymph nodes of patients even when they are undergoing highly active antiretroviral therapy. p17 has been found to affect immune cells, and recent data showed that a variant p17, called S75X, induces cell growth by triggering MAPK/ERK and PI3K/AKT pathways. We tested the in vivo angiogenic activity of p17 by injecting it in Matrigel plugs in nude mice. Plugs were retrieved 7 days after injection, and assessed macroscopically, and by light and confocal microscopy. Our data revealed that both reference and S75X variant p17 promote angiogenesis and Lymphangiogenesis in vivo. Our results suggest that the induction of angiogenesis and Lymphangiogenesis by HIV-1 p17 may generate a favorable microenvironment that could trigger tumor growth and maintenance. Moreover, the presence of adipocytes infiltration observed at the histological level suggests a possible interplay between angiogenesis, Lymphangiogenesis and adipogenesis. These findings offer new opportunities for the development of treatment strategies to combat HIV-related cancers.
