nuray gül - Academia.edu (original) (raw)
Papers by nuray gül
Fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic ... more Fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic lymphocytic leukemia (CLL) cells by red labeled human macrophages in the presence of the anti-CD20 mAb rituximab. Time is indicated in minutes. Scale bar = 20 μm.
Overlay of bright field and fluorescent images from live cell imaging experiment demonstrated upt... more Overlay of bright field and fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic lymphocytic leukemia (CLL) cells by red labeled human macrophages in the presence of the anti-CD20 mAb rituximab. Time is indicated in minutes. Scale bar = 20 μm.
During resection of primary colorectal tumors malignant cells disseminate from the tumor mass and... more During resection of primary colorectal tumors malignant cells disseminate from the tumor mass and are shed into the portal circulation. Surgical trauma leads to decreased vessel wall integrity and subsequent exposure of underlying extracellular matrix proteins enhances adhesion of disseminated tumor cells. Although surgical resection of colorectal tumors is the only curative option to ascertain survival, trauma inflicted by this procedure may lead to enhanced outgrowth of distant metastases and decreases both overall and disease free survival in a cohort of patients. Perioperative treatment with specific monoclonal antibodies (mAb) directed against circulating tumor cells alleviated surgically induced liver metastases of colorectal tumors in several animal models. Successful elimination of circulating tumour cells was mediated by liver macrophages (Kuppfer cells). We now demonstrate that by using the fully human mAb Zalutumumab directed against the epithelial growth factor receptor ...
Surgical resection of primary colorectal tumors is currently the preferred and only treatment tha... more Surgical resection of primary colorectal tumors is currently the preferred and only treatment that can create long-term disease free survival. However, abdominal surgery caused increased tumor cell adhesion to the peritoneal wall or in the liver that grew out into metastases. Interestingly, depletion of PMNs diminished tumor recurrence, suggesting that PMNs might play a role in surgery-induced tumor development. Therefore, in the current study we investigated the role of PMNs in liver metastases formation. Increased levels of PMNs and tumor cells were observed in the livers of rats that underwent laparotomy, which were even higher in the livers of rats in which colonic resection was performed. As colectomy results in bacterial contamination, we next investigated the role of bacterial products in enhanced PMNs and tumor cell adhesion. Significantly more PMNs and tumor cells were observed in livers of rats that had been treated with the bacterial product lipopolysaccharide (LPS). More...
Surgical resection of the primary tumor provides the best chance of cure for patients with colore... more Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal cancer (CRC). However, we previously demonstrated that laparotomy led to enhanced adhesion of tumor cells in the liver vasculature. Moreover, it was demonstrated that patients with anastomotic leakage after resection of the tumor had poorer survival, supporting that resection of primary CRC paradoxically may have a negative impact on metastases development and long-term patient outcome. Therefore, the aim of this study was to investigate the influence of bacterial contamination during surgery on liver metastases development. Rats underwent a sham operation (laparotomy, opening and closure of peritoneal cavity), colectomy (resection of part of the colon and anastomosis), or received anesthesia alone, after which tumor cells were injected into the portal circulation. When swaps of the colon wall were taken at the beginning of surgery, no bacterial outgrowth was observed. However, an i...
OncoImmunology, 2018
Surgical resection of the primary tumor provides the best chance of cure for patients with colore... more Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham-or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per-and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. In vitro stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.
Cancer research, 2015
Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as... more Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer. Cancer Res; 75(23); 5008...
Oncoimmunology, 2014
Monoclonal antibodies (mAbs) are increasingly being used to treat cancer. In response to mAb ther... more Monoclonal antibodies (mAbs) are increasingly being used to treat cancer. In response to mAb therapy, we have identified macrophages in the liver as major effector cells removing circulating tumor cells via antibody-dependent phagocytosis, an immune cell-mediated process that prevented liver metastasis. This discovery extends our understanding of the mechanisms of mAb therapy, and may help to optimize mAb-based anticancer therapeutics.
Journal of Clinical Investigation, 2014
The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the la... more The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (FcγRI) and the low-affinity IgG-binding Fc receptor (FcγRIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity. Authorship note: Nuray Gül and Liane Babes, as well as Paul Kubes and Marjolein van Egmond, contributed equally to this work.
Gut, 2011
Objective Resection of primary colorectal cancer is associated with enhanced risk of development ... more Objective Resection of primary colorectal cancer is associated with enhanced risk of development of liver metastases. It was previously demonstrated that surgery initiated an early inflammatory response resulting in elevated tumour cell adhesion in the liver. Because reactive oxygen species (ROS) are shown to be produced and released during surgery, the effects of ROS on the liver vascular lining and tumour cell adhesion were investigated. Methods Human endothelial cell monolayers (human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells of the lung (HMEC-1s)) were exposed to ROS production, after which electrical impedance, cellular integrity and tumour cell adhesion were investigated. Furthermore, surgery-induced tumour cell adhesion as well as the role of ROS and liver macrophages (Kupffer cells) in this process were studied in vivo. Results Production of ROS decreased cellular impedance of endothelial monolayers dramatically. Moreover, formation of intercellular gaps in endothelial monolayers was observed, exposing subendothelial extracellular matrix (ECM) on which colon carcinoma cells adhered via integrin molecules. Endothelial damage was, however, prevented in the presence of ROSscavenging enzymes. Additionally, surgery induced downregulation of both rat and human liver tight junction molecules. Treatment of rats with the ROS scavenger edaravone prevented surgery-induced tumour cell adhesion and downregulation of tight junction proteins in the liver. Interestingly, depletion of Kupffer cells prior to surgery significantly reduced the numbers of adhered tumour cells and prevented disruption of expression of tight junction proteins. Conclusions In this study it is shown that surgeryinduced ROS production by macrophages damages the vascular lining by downregulating tight junction proteins. This leads to exposure of ECM, to which circulating tumour cells bind. In light of this, perioperative therapeutic intervention, preventing surgery-induced inflammatory reactions, may reduce the risk of developing liver metastases, thereby improving the clinical outcome of patients with colorectal cancer.
European Journal of Cancer, 2012
Link to publication in VU Research Portal citation for published version (APA) Gül, N. (2012). Su... more Link to publication in VU Research Portal citation for published version (APA) Gül, N. (2012). Surgery-induced liver metastasis: how it begins and how to end it. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic ... more Fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic lymphocytic leukemia (CLL) cells by red labeled human macrophages in the presence of the anti-CD20 mAb rituximab. Time is indicated in minutes. Scale bar = 20 μm.
Overlay of bright field and fluorescent images from live cell imaging experiment demonstrated upt... more Overlay of bright field and fluorescent images from live cell imaging experiment demonstrated uptake of blue labeled chronic lymphocytic leukemia (CLL) cells by red labeled human macrophages in the presence of the anti-CD20 mAb rituximab. Time is indicated in minutes. Scale bar = 20 μm.
During resection of primary colorectal tumors malignant cells disseminate from the tumor mass and... more During resection of primary colorectal tumors malignant cells disseminate from the tumor mass and are shed into the portal circulation. Surgical trauma leads to decreased vessel wall integrity and subsequent exposure of underlying extracellular matrix proteins enhances adhesion of disseminated tumor cells. Although surgical resection of colorectal tumors is the only curative option to ascertain survival, trauma inflicted by this procedure may lead to enhanced outgrowth of distant metastases and decreases both overall and disease free survival in a cohort of patients. Perioperative treatment with specific monoclonal antibodies (mAb) directed against circulating tumor cells alleviated surgically induced liver metastases of colorectal tumors in several animal models. Successful elimination of circulating tumour cells was mediated by liver macrophages (Kuppfer cells). We now demonstrate that by using the fully human mAb Zalutumumab directed against the epithelial growth factor receptor ...
Surgical resection of primary colorectal tumors is currently the preferred and only treatment tha... more Surgical resection of primary colorectal tumors is currently the preferred and only treatment that can create long-term disease free survival. However, abdominal surgery caused increased tumor cell adhesion to the peritoneal wall or in the liver that grew out into metastases. Interestingly, depletion of PMNs diminished tumor recurrence, suggesting that PMNs might play a role in surgery-induced tumor development. Therefore, in the current study we investigated the role of PMNs in liver metastases formation. Increased levels of PMNs and tumor cells were observed in the livers of rats that underwent laparotomy, which were even higher in the livers of rats in which colonic resection was performed. As colectomy results in bacterial contamination, we next investigated the role of bacterial products in enhanced PMNs and tumor cell adhesion. Significantly more PMNs and tumor cells were observed in livers of rats that had been treated with the bacterial product lipopolysaccharide (LPS). More...
Surgical resection of the primary tumor provides the best chance of cure for patients with colore... more Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal cancer (CRC). However, we previously demonstrated that laparotomy led to enhanced adhesion of tumor cells in the liver vasculature. Moreover, it was demonstrated that patients with anastomotic leakage after resection of the tumor had poorer survival, supporting that resection of primary CRC paradoxically may have a negative impact on metastases development and long-term patient outcome. Therefore, the aim of this study was to investigate the influence of bacterial contamination during surgery on liver metastases development. Rats underwent a sham operation (laparotomy, opening and closure of peritoneal cavity), colectomy (resection of part of the colon and anastomosis), or received anesthesia alone, after which tumor cells were injected into the portal circulation. When swaps of the colon wall were taken at the beginning of surgery, no bacterial outgrowth was observed. However, an i...
OncoImmunology, 2018
Surgical resection of the primary tumor provides the best chance of cure for patients with colore... more Surgical resection of the primary tumor provides the best chance of cure for patients with colorectal carcinoma (CRC). However, bacterial translocation during intestinal surgery has been correlated with poor long-term oncological outcome. Therefore, we investigated the influence of bacterial contamination during colon surgery on CRC liver metastases development. Blood and liver samples of patients undergoing resection of primary CRC or liver metastases were collected. Cell numbers, activation markers and inflammatory mediators were determined. Tumor cell adhesion and outgrowth after sham-or colectomy operations were determined in a rat model, in which tumor cells had been injected into the portal vein. White blood cells and granulocytes were increased in per-and post-operative patient blood samples. IL-6 was also increased post-operatively compared to the preoperative level. Expression of NOX-2, NOX-4 and polymorphonuclear cells (PMNs) numbers were elevated in post-operative human liver samples. In vitro stimulation of macrophages with plasma of rats after colectomy resulted in production of reactive oxygen species (ROS). Colectomy in rats increased D-lactate levels in plasma, supporting bacterial translocation. Decreased expression of tight junction molecules and increased tumor cell adhesion and outgrowth was observed. Treatment with a selective decontamination of the digestive tract (SDD) cocktail decreased tumor cell adherence after colectomy. In conclusion, postoperative bacterial translocation may activate liver macrophages and PMNs, resulting in ROS production. As we previously showed that ROS release led to liver vasculature damage, circulating tumor cells may adhere to exposed extracellular matrix and grow out into liver metastases. This knowledge is pivotal for development of therapeutic strategies to prevent surgery-induced liver metastases development.
Cancer research, 2015
Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as... more Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer. Cancer Res; 75(23); 5008...
Oncoimmunology, 2014
Monoclonal antibodies (mAbs) are increasingly being used to treat cancer. In response to mAb ther... more Monoclonal antibodies (mAbs) are increasingly being used to treat cancer. In response to mAb therapy, we have identified macrophages in the liver as major effector cells removing circulating tumor cells via antibody-dependent phagocytosis, an immune cell-mediated process that prevented liver metastasis. This discovery extends our understanding of the mechanisms of mAb therapy, and may help to optimize mAb-based anticancer therapeutics.
Journal of Clinical Investigation, 2014
The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the la... more The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (FcγRI) and the low-affinity IgG-binding Fc receptor (FcγRIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity. Authorship note: Nuray Gül and Liane Babes, as well as Paul Kubes and Marjolein van Egmond, contributed equally to this work.
Gut, 2011
Objective Resection of primary colorectal cancer is associated with enhanced risk of development ... more Objective Resection of primary colorectal cancer is associated with enhanced risk of development of liver metastases. It was previously demonstrated that surgery initiated an early inflammatory response resulting in elevated tumour cell adhesion in the liver. Because reactive oxygen species (ROS) are shown to be produced and released during surgery, the effects of ROS on the liver vascular lining and tumour cell adhesion were investigated. Methods Human endothelial cell monolayers (human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells of the lung (HMEC-1s)) were exposed to ROS production, after which electrical impedance, cellular integrity and tumour cell adhesion were investigated. Furthermore, surgery-induced tumour cell adhesion as well as the role of ROS and liver macrophages (Kupffer cells) in this process were studied in vivo. Results Production of ROS decreased cellular impedance of endothelial monolayers dramatically. Moreover, formation of intercellular gaps in endothelial monolayers was observed, exposing subendothelial extracellular matrix (ECM) on which colon carcinoma cells adhered via integrin molecules. Endothelial damage was, however, prevented in the presence of ROSscavenging enzymes. Additionally, surgery induced downregulation of both rat and human liver tight junction molecules. Treatment of rats with the ROS scavenger edaravone prevented surgery-induced tumour cell adhesion and downregulation of tight junction proteins in the liver. Interestingly, depletion of Kupffer cells prior to surgery significantly reduced the numbers of adhered tumour cells and prevented disruption of expression of tight junction proteins. Conclusions In this study it is shown that surgeryinduced ROS production by macrophages damages the vascular lining by downregulating tight junction proteins. This leads to exposure of ECM, to which circulating tumour cells bind. In light of this, perioperative therapeutic intervention, preventing surgery-induced inflammatory reactions, may reduce the risk of developing liver metastases, thereby improving the clinical outcome of patients with colorectal cancer.
European Journal of Cancer, 2012
Link to publication in VU Research Portal citation for published version (APA) Gül, N. (2012). Su... more Link to publication in VU Research Portal citation for published version (APA) Gül, N. (2012). Surgery-induced liver metastasis: how it begins and how to end it. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.