Lets try and stay focused on the important stuff, like this 2018 article showing a link between CCL5 over expression in mutated pancreas cancer cells and the likelihood the increase is responsible for proliferation and over expression of the CCR5 receptors.
CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells
Santosh Kumar Singh, Manoj K. Mishra, Isam-Eldin A. Eltoum, Sejong Bae, James W. Lillard Jr. & Rajesh Singh
Scientific Reports volume 8, Article number: 1323 (2018) Cite this article
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Abstract
Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.
Introduction
Pancreatic adenocarcinoma is one of the most deadly cancers for solid malignancies and remains a major challenge in oncology because of its poor response to chemotherapy and radiation as well as its invasive and metastatic nature1. As evidenced by the fact that the 5-year survival rates of pancreatic cancer (PC) patients are below 5%, the mortality rate equals its incidence2,3. This is because, the majority of pancreatic cancers (PCs) are diagnosed at an advanced stage, beyond any possibility of cure4. Current predictions suggest that PC death rates are on the rise5. Despite a progressive advancement in potential chemotherapeutics to cure cancer, agents effective in other cancer types were found to be unsuccessful in PC cells3. The most intimidating factor of PC is the lack of symptoms and its highly aggressive malignancy with invasive and metastasizing properties2. These features indicate that PC possesses unique mechanisms that are not yet well understood. A better understanding of the early neoplastic changes within the pancreas will help in diagnosis and prevent the progression of PC4. In addition to this, the second criterion that determines the fate of patients with PC is its distant metastasis that is detected in two-thirds of the patients. The most common site of distant metastasis in PC is the liver and then the brain2,6.
Many aspects of a series of molecules were found to implicate the progression and metastasis of cancer cells. However, the precise mechanism involved in the directional migration of cancer cells to distant organs is not clearly known7. Chemokines are proinflammatory chemoattractant cytokines that function primarily in leukocyte trafficking and other biological activities, such as development, angiogenesis, and hematopoiesis8. Chemokines bind to their cognate receptors, most of which belong to the G-protein coupled receptor family, and are expressed on endothelial cells and lymphocytes. In addition to their role in several pathological conditions, it has become progressively evident that chemokines and their receptors find a significant position in determining the metastatic destination of tumor’s cells9.
Among the known chemokines, CCL5 (CC chemokine ligand 5) also known as RANTES (regulated on activation, normal T cell expressed and secreted), strongly promotes carcinogenesis and stroma genesis, which was initially recognized for its important role in inflammatory diseases10. CCL5 has three different chemokine C-C motif receptors (CCRs): CCR1, CCR3, and CCR511. CCL5 was also revealed to bind G protein-coupled receptor 75 (GPR75)12. CCL5 reported to be produced by cancer cells or nonmalignant stromal cells at the primary or metastatic sites13. Thus, the elevated level of CCL5 in tissues or plasma is indicative of unfavorable outcome in patients with either melanoma, breast, cervical, prostate, gastric or even pancreatic cancer10,14. Among the receptors of CCL5, its interaction with CCR5 was very well established and elucidated in tumor progression and recruitment of tumor infiltration leukocytes in several cancer types. Evaluating the mechanism of pancreatic adenocarcinoma cell evasion from the immune system highlighted the importance of CCL5/CCR5 interaction. CCR5 is expressed on various immune cell populations such as macrophages, dendritic cells and memory T cells in the immune system; endothelium, epithelium, vascular smooth muscle and fibroblasts; microglia, neurons, and astrocytes in the central nervous system15. In addition, its expression on cancer cells, along with CCL5 has found to play an important role in cancer progression and metastasis. It is reported that in human breast cancer, specimens increased expression of CCR5 along with its ligand CCL5 in the basal and HER-2 genetic subtypes16. Besides, CCL5 has gained an utmost importance as an inflammatory chemokine, CCL5 and CCR5 were regarded as a poor prognosis signature marker in various cancer types such as renal17, prostate18, breast19, cervical20, lung21 and ovarian22 cancers. However, CCR5/CCL5 participation in activating invasion and metastasis of PC has not been reported yet.
In this study, we present our investigative reports on CCR5/CCL5 expression in PC cases and show their association with disease progression using immunohistochemistry staining. We further investigated the effect of CCL5 on CCR5 expressing cells by a series of in vitro experiments by CCL5 stimulation and CCR5 blockade and also reported that the CCR5/CCL5 axis played a major role in PC cell invasion and metastasis.
CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells
Santosh Kumar Singh, Manoj K. Mishra, Isam-Eldin A. Eltoum, Sejong Bae, James W. Lillard Jr. & Rajesh Singh
Scientific Reports volume 8, Article number: 1323 (2018) Cite this article
4808 Accesses
26 Citations
13 Altmetric
Metricsdetails
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.
Introduction
Pancreatic adenocarcinoma is one of the most deadly cancers for solid malignancies and remains a major challenge in oncology because of its poor response to chemotherapy and radiation as well as its invasive and metastatic nature1. As evidenced by the fact that the 5-year survival rates of pancreatic cancer (PC) patients are below 5%, the mortality rate equals its incidence2,3. This is because, the majority of pancreatic cancers (PCs) are diagnosed at an advanced stage, beyond any possibility of cure4. Current predictions suggest that PC death rates are on the rise5. Despite a progressive advancement in potential chemotherapeutics to cure cancer, agents effective in other cancer types were found to be unsuccessful in PC cells3. The most intimidating factor of PC is the lack of symptoms and its highly aggressive malignancy with invasive and metastasizing properties2. These features indicate that PC possesses unique mechanisms that are not yet well understood. A better understanding of the early neoplastic changes within the pancreas will help in diagnosis and prevent the progression of PC4. In addition to this, the second criterion that determines the fate of patients with PC is its distant metastasis that is detected in two-thirds of the patients. The most common site of distant metastasis in PC is the liver and then the brain2,6.
Many aspects of a series of molecules were found to implicate the progression and metastasis of cancer cells. However, the precise mechanism involved in the directional migration of cancer cells to distant organs is not clearly known7. Chemokines are proinflammatory chemoattractant cytokines that function primarily in leukocyte trafficking and other biological activities, such as development, angiogenesis, and hematopoiesis8. Chemokines bind to their cognate receptors, most of which belong to the G-protein coupled receptor family, and are expressed on endothelial cells and lymphocytes. In addition to their role in several pathological conditions, it has become progressively evident that chemokines and their receptors find a significant position in determining the metastatic destination of tumor’s cells9.
Among the known chemokines, CCL5 (CC chemokine ligand 5) also known as RANTES (regulated on activation, normal T cell expressed and secreted), strongly promotes carcinogenesis and stroma genesis, which was initially recognized for its important role in inflammatory diseases10. CCL5 has three different chemokine C-C motif receptors (CCRs): CCR1, CCR3, and CCR511. CCL5 was also revealed to bind G protein-coupled receptor 75 (GPR75)12. CCL5 reported to be produced by cancer cells or nonmalignant stromal cells at the primary or metastatic sites13. Thus, the elevated level of CCL5 in tissues or plasma is indicative of unfavorable outcome in patients with either melanoma, breast, cervical, prostate, gastric or even pancreatic cancer10,14. Among the receptors of CCL5, its interaction with CCR5 was very well established and elucidated in tumor progression and recruitment of tumor infiltration leukocytes in several cancer types. Evaluating the mechanism of pancreatic adenocarcinoma cell evasion from the immune system highlighted the importance of CCL5/CCR5 interaction. CCR5 is expressed on various immune cell populations such as macrophages, dendritic cells and memory T cells in the immune system; endothelium, epithelium, vascular smooth muscle and fibroblasts; microglia, neurons, and astrocytes in the central nervous system15. In addition, its expression on cancer cells, along with CCL5 has found to play an important role in cancer progression and metastasis. It is reported that in human breast cancer, specimens increased expression of CCR5 along with its ligand CCL5 in the basal and HER-2 genetic subtypes16. Besides, CCL5 has gained an utmost importance as an inflammatory chemokine, CCL5 and CCR5 were regarded as a poor prognosis signature marker in various cancer types such as renal17, prostate18, breast19, cervical20, lung21 and ovarian22 cancers. However, CCR5/CCL5 participation in activating invasion and metastasis of PC has not been reported yet.
In this study, we present our investigative reports on CCR5/CCL5 expression in PC cases and show their association with disease progression using immunohistochemistry staining. We further investigated the effect of CCL5 on CCR5 expressing cells by a series of in vitro experiments by CCL5 stimulation and CCR5 blockade and also reported that the CCR5/CCL5 axis played a major role in PC cell invasion and metastasis.
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