Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00173849
Status:
UNKNOWN
Last Update Posted:
2005-09-15
First Post:
2005-09-13
Brief Title:
The Role of SDF-1CXCR4 in Metastasis of Oral Squamous Cell Carcinoma
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
None
Status:
UNKNOWN
Status Verified Date:
2005-06
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Investigate the role of SDF-1CXCR4 in the metastasis of oral squamous cell carcinoma
Detailed Description:
Oral cancer is the most common head and neck malignancy constituting near 9 of all cancers 1 Squamous cell carcinoma SCC is the most common histopathologic type of the oral malignancies accounting for more than 90 of cancers occurring in this region 2 The presence or absence of regional lymph node metastases is the single most important factor affecting prognosis in patients with oral cancer Cure rates for oral cancer are decreased by approximately 50 percent in patients having cervical lymph node metastasis 3
Tumor metastasis is the hallmark of malignancy and is probably a result of the interaction between tumor cells and a supportive microenvironment Malignant cells that have the capability to metastasize to a particular organ may have various properties supporting their tissue invasion or growth such as enhanced adherence to the microvascular cells of the organ higher responsiveness to chemotactic signals released from the target organs and increased response to local soluble or tissue associated growth signals in the target organ 45 Though there are several molecules expressed or produced in cancer cells are considered the metastatic factors it remains unknown which factors produced by the lymph node or tissue affect the metastasis of cancer cells
Chemokines are a large family of pro-inflammatory polypeptide cytokines consisting of small 7-15 kDa structurally related heparin-binding proteins They are grouped into CXC chemokines and CC chemokines on the basis of the characteristic presence of four conserved cysteine residues 6-8 Chemokines are produced locally in the tissues and act on target cells through G-protein-coupled receptors which are characterized structurally by seven transmembrane spanning domains Chemokines are involved in the attraction and activation of mononuclear and polymorphonuclear leukocytes to sites of inflammatory responses bacterial or viral infections allergy cardiovascular diseases and wound healing 4 8-13 Chemokines are known to also function as regulatory molecules in the leukocyte maturation trafficking and homing of T and B lymphocytes in the development of lymphoid tissues and in dendritic cell maturation 1415 Other functions of chemokines have been described more recently particularly for the CXC chemokines The role of chemokines in malignant tumors is not clear yet Some chemokines may enhance innate or specific host immunity against tumor dissemination On the other hand some may advocate tumor growth and metastasis by promoting tumor cell proliferation migration or angiogenesis in tumor tissue 4 Reports have suggested that several types of cancer such as breast 16 ovary 17 prostate 18 kidney 19 brain 20 lung 21 and thyroid 22 expressed the chemokine receptor and used the chemokines to metastasize to the target organ as in the homing of hematopoietic cells
SDF-1 belongs to the CXC chemokine family and is a ligand for CXCR4 23 24 SDF-1 was initially cloned by Tashiro et al 25 and later identified as a growth factor for B cell progenitors a chemotactic factor for T cells and monocytes and in B-cell lymphopoiesis and bone marrow myelopoiesis 23 26-27 Most of the chemokine receptors interact with pleural ligands and vice versa but the SDF-1CXCR4 receptor ligand system has been shown to involve a one-on-one interaction 28 29 Recently several studies have been conducted to detect the mRNA expression of CXCR4 and SDF-1 in solid tumors The results are not uniform and the relevance to cancer progression is not determined 30 31 Sehgal et al 30 32 concluded that CXCR4 plays an important role of proliferation and tumorigenic properties of human glioblastoma tumors Muller et al 33 have reported that SDF-1 signaling through CXCR4 interaction appears to determine the directional migration of breast cancer cells through the basement membrane Furthermore in vivo the interaction between SDF-1 and CXCR4 significantly represses the metastatic potential of breast cancer cells to lymph node and lung Barnard and his colleagues 34 35 showed the contrary results that CXCR4 mRNA expression was reduced in hepatocellular carcinoma tissue when compared with noncancerous tissue but was not changed in colon esophageal and gastric cancer They also found reduced mRNA expression of SDF-1 in these malignant tissues 31 Thus there is a diversity of views on the role of the SDF-1CXCR4 receptor ligand system in malignant tissues And such studies are limited in oral cancer
Since metastasis of oral cancer occur frequently through the lymphatic system and metastasis is a key prognostic factor for the disease Evaluation of the relationship between SDF-1CXCR4 system and metastasis in oral cancer could help us understand whether this system is important in the metastasis of this disease
We hypothesized that SDF-1CXCR4 ligandreceptor system plays an important role in oral cancer metastasis To test this hypothesis we will investigate 1 the distribution of CXCR4 protein expression in cancer and lymph node tissues by means of immunohistochemical analysis of tissue samples obtained from surgical operation 2 the relationship between CXCR4 expression and clinicopathological findings with special reference to cancer metastasis 3 the expression of SDF-1 and CXCR4 in the cancer cell lines cells and tissues 4 the chemotactic activity and the growth-promoting effect of SDF-1 on cancer cell lines cells 5 the role of Src MAPK and Akt signal transduction pathway in this response 6 the effect of the blocking agent on this response
Undoubtedly the findings of this study will help us understand whether SDF-1CXCR4 system could be a focal point of anti-cancer research If oral SCC that express high levels of CXCR4 show a consistently higher incidence of lymphatic and distant metastasis then blocking SDF-1CXCR4 signaling may be a novel approach to inhibit metastasis in these patients The development of SDF-1CXCR4 system antagonists will provide opportunity to improve the survival rate
Tumor metastasis is the hallmark of malignancy and is probably a result of the interaction between tumor cells and a supportive microenvironment Malignant cells that have the capability to metastasize to a particular organ may have various properties supporting their tissue invasion or growth such as enhanced adherence to the microvascular cells of the organ higher responsiveness to chemotactic signals released from the target organs and increased response to local soluble or tissue associated growth signals in the target organ 45 Though there are several molecules expressed or produced in cancer cells are considered the metastatic factors it remains unknown which factors produced by the lymph node or tissue affect the metastasis of cancer cells
Chemokines are a large family of pro-inflammatory polypeptide cytokines consisting of small 7-15 kDa structurally related heparin-binding proteins They are grouped into CXC chemokines and CC chemokines on the basis of the characteristic presence of four conserved cysteine residues 6-8 Chemokines are produced locally in the tissues and act on target cells through G-protein-coupled receptors which are characterized structurally by seven transmembrane spanning domains Chemokines are involved in the attraction and activation of mononuclear and polymorphonuclear leukocytes to sites of inflammatory responses bacterial or viral infections allergy cardiovascular diseases and wound healing 4 8-13 Chemokines are known to also function as regulatory molecules in the leukocyte maturation trafficking and homing of T and B lymphocytes in the development of lymphoid tissues and in dendritic cell maturation 1415 Other functions of chemokines have been described more recently particularly for the CXC chemokines The role of chemokines in malignant tumors is not clear yet Some chemokines may enhance innate or specific host immunity against tumor dissemination On the other hand some may advocate tumor growth and metastasis by promoting tumor cell proliferation migration or angiogenesis in tumor tissue 4 Reports have suggested that several types of cancer such as breast 16 ovary 17 prostate 18 kidney 19 brain 20 lung 21 and thyroid 22 expressed the chemokine receptor and used the chemokines to metastasize to the target organ as in the homing of hematopoietic cells
SDF-1 belongs to the CXC chemokine family and is a ligand for CXCR4 23 24 SDF-1 was initially cloned by Tashiro et al 25 and later identified as a growth factor for B cell progenitors a chemotactic factor for T cells and monocytes and in B-cell lymphopoiesis and bone marrow myelopoiesis 23 26-27 Most of the chemokine receptors interact with pleural ligands and vice versa but the SDF-1CXCR4 receptor ligand system has been shown to involve a one-on-one interaction 28 29 Recently several studies have been conducted to detect the mRNA expression of CXCR4 and SDF-1 in solid tumors The results are not uniform and the relevance to cancer progression is not determined 30 31 Sehgal et al 30 32 concluded that CXCR4 plays an important role of proliferation and tumorigenic properties of human glioblastoma tumors Muller et al 33 have reported that SDF-1 signaling through CXCR4 interaction appears to determine the directional migration of breast cancer cells through the basement membrane Furthermore in vivo the interaction between SDF-1 and CXCR4 significantly represses the metastatic potential of breast cancer cells to lymph node and lung Barnard and his colleagues 34 35 showed the contrary results that CXCR4 mRNA expression was reduced in hepatocellular carcinoma tissue when compared with noncancerous tissue but was not changed in colon esophageal and gastric cancer They also found reduced mRNA expression of SDF-1 in these malignant tissues 31 Thus there is a diversity of views on the role of the SDF-1CXCR4 receptor ligand system in malignant tissues And such studies are limited in oral cancer
Since metastasis of oral cancer occur frequently through the lymphatic system and metastasis is a key prognostic factor for the disease Evaluation of the relationship between SDF-1CXCR4 system and metastasis in oral cancer could help us understand whether this system is important in the metastasis of this disease
We hypothesized that SDF-1CXCR4 ligandreceptor system plays an important role in oral cancer metastasis To test this hypothesis we will investigate 1 the distribution of CXCR4 protein expression in cancer and lymph node tissues by means of immunohistochemical analysis of tissue samples obtained from surgical operation 2 the relationship between CXCR4 expression and clinicopathological findings with special reference to cancer metastasis 3 the expression of SDF-1 and CXCR4 in the cancer cell lines cells and tissues 4 the chemotactic activity and the growth-promoting effect of SDF-1 on cancer cell lines cells 5 the role of Src MAPK and Akt signal transduction pathway in this response 6 the effect of the blocking agent on this response
Undoubtedly the findings of this study will help us understand whether SDF-1CXCR4 system could be a focal point of anti-cancer research If oral SCC that express high levels of CXCR4 show a consistently higher incidence of lymphatic and distant metastasis then blocking SDF-1CXCR4 signaling may be a novel approach to inhibit metastasis in these patients The development of SDF-1CXCR4 system antagonists will provide opportunity to improve the survival rate
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None