Ignite Creation Date:
2024-05-05 @ 11:54 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00173381
Status:
UNKNOWN
Last Update Posted:
2006-03-30
First Post:
2005-09-12
Brief Title:
The Role of Lymphangiogenesis in Head and Neck Cancer Metastasis
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:
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:
The purpose of this study is to investigate the role of lymphangiogenesis in the metastasis of head and neck cancer
Detailed Description:
Head and neck cancer is a major worldwide cause of morbidity and mortality As long as the neoplasm is confined to its organ of origin the patient can be cured through surgical removal of the tumor mass Unfortunately many cancers metastasize to other sites in the body and metastasis is the leading cause of death in cancer patients In principle cancer cells can spread within the body by different mechanisms such as direct invasion of surrounding tissues per continuitatem spread via the blood vascular system hematogenous metastasis and spread via the lymphatic system lymphatic metastasis Tumor cells can invade either the blood or lymphatic vessels to access the general circulation and then establish themselves in other tissues Clinicopathological data suggest that the lymphatics are an initial route for the spread of solid tumors Infiltration of lymphatic vessels by tumor cells has been found at the periphery of many experimental and human tumors and the lymphatic system has been recognized as a conduit for tumor cell dissemination Though the significance of angiogenesis for tumor progression has been well documented the molecular mechanisms regulating the growth and function of lymphatic vessels are largely unknown
Vascular endothelial growth factors first identified in 1989 are well-known angiogenic agents and targets for anti-cancer therapies Now it appears that VEGF-C one recently-cloned member of the vascular endothelial growth factor VEGF family is also involved in developmental and tumor-induced lymphangiogenesis VEGF signals through two tyrosine kinase receptors VEGFR-1 and VEGFR-2 which are expressed predominantly but not exclusively on vascular endothelial cells As neither VEGFR-1 nor VEGFR-2 appears to be highly expressed in lymphatic endothelium it was not surprising that a third VEGF receptor VEGFR-3 was found to be predominantly expressed on lymphatic vessels during development What was surprising however was that VEGF was not found to bind to VEGFR-3 Instead VEGF-C was discovered to be ligand for VEGFR-3 Research groups provide direct evidence that VEGF-C is not only an important regulator of lymph vessel growth lymphangiogenesis in vivo but it also enhances lymphatic metastasis Using experimental approaches Mäkinen et al Skobe et al as well as Mandriota et al demonstrate an important role of VEGFR-3 and its ligand VEGF-C in developmental and tumor-induced lymphangiogenesis In normal adult human tissues the VEGF-C receptor VEGFR-3 FLT-4 is predominantly expressed by lymphatic endothelia Expression of VEGF-C occurs in a variety of human tumors such as breast colon lung thyroid gastric squamous cell cancers mesotheliomas neuroblastomas sarcomas and melanomas Moreover expression of VEGF-C mRNA has recently been shown to correlate with the rate of metastasis to lymph nodes in breast colorectal gastric thyroid lung and prostate cancers To date however lymphangiogenesis has not been causally linked to tumor metastasis
Cyclooxygenase-2 COX-2 enzyme catalyzes the synthesis of prostaglandins COX-2 is an immediate-early response gene induced by inflammation growth factors tumor promoters oncogenes and carcinogens Increased levels of COX-2 may contribute to carcinogenesis by modulating xenobiotic metabolism apoptosis immune surveillance and angiogenesis Any significant increase in tumor mass must be preceded by an increase in vascular supply to deliver nutrients and oxygen to the tumor Recently levels of COX-2 were found to correlate with both VEGF expression and tumor vascularization in HNSCC This finding in human tissues is consistent with prior evidence that overexpression of COX-2 in epithelial cells led to enhanced production of VEGF and the formation of capillary-like networks Although COX-2 contributes to the regulation of angiogenesis its role in lymphangiogenesis is not clear
IL-6 is a secreted multifunctional glycoprotein Through binding to α-chain IL-6-R gp80 and subsequently recruiting the β-chain gp130 of the receptor IL-6 performs various biological functions The diversity of IL-6 signaling mediated via gp130 explains its functional pleiotropy IL-6 regulates inflammatory reactions immune responses hepatic acute-phase protein synthesis and several other important physiological processes Interestingly the influence of IL-6 in human cancers is varied depending on the cell types For example IL-6 has been demonstrated to promote growth of multiple myeloma Kaposis sarcoma and prostatic cancer cells while inhibiting the proliferation of lung and breast cancer cells Previous investigations have confirmed that IL-6 is important in both physiological and pathological angiogenesis Additionally recent study supports the hypothesis that IL-6 facilitates tumorigenesis of cervical cancer via VEGF-mediated angiogenesis Nevertheless whether IL-6 could regulate the expression of VEGF-C and what is its role in lymphangiogenesis still need to be clarified
Inhibition of angiogenesis is currently considered one of the most promising therapeutic strategies to inhibit cancer growth because it presumably can act on any tumor type does not induce resistance of tumor cells and can therefore be used in repeated therapeutic cycles and has little effect on normal tissues It now needs to be determined whether the same holds true for tumor lymphangiogenesis
Metastases of head and neck cancers occur frequently through the lymphatic system and the extent of lymph node involvement is a key prognostic factor for the diseases In this study we will conduct a systematic analysis of VEGF-C COX-2 and IL-6 expressions and will try to find the correlation between their expressions lymphatic metastases and patient survival Next we will investigate the relationship between VEGF-C COX-2 and IL-6 and further clarify their effects on tumor growth Undoubtedly the findings of this study will help us understand whether lymphangiogenesis could be a focal point of anti-cancer research If HNSCC tumors that express high levels of VEGF-C show a consistently higher incidence of lymphatic metastasis then inhibition of VEGFR-3 function may be a novel approach to inhibit lymphatic metastasis in patients
Vascular endothelial growth factors first identified in 1989 are well-known angiogenic agents and targets for anti-cancer therapies Now it appears that VEGF-C one recently-cloned member of the vascular endothelial growth factor VEGF family is also involved in developmental and tumor-induced lymphangiogenesis VEGF signals through two tyrosine kinase receptors VEGFR-1 and VEGFR-2 which are expressed predominantly but not exclusively on vascular endothelial cells As neither VEGFR-1 nor VEGFR-2 appears to be highly expressed in lymphatic endothelium it was not surprising that a third VEGF receptor VEGFR-3 was found to be predominantly expressed on lymphatic vessels during development What was surprising however was that VEGF was not found to bind to VEGFR-3 Instead VEGF-C was discovered to be ligand for VEGFR-3 Research groups provide direct evidence that VEGF-C is not only an important regulator of lymph vessel growth lymphangiogenesis in vivo but it also enhances lymphatic metastasis Using experimental approaches Mäkinen et al Skobe et al as well as Mandriota et al demonstrate an important role of VEGFR-3 and its ligand VEGF-C in developmental and tumor-induced lymphangiogenesis In normal adult human tissues the VEGF-C receptor VEGFR-3 FLT-4 is predominantly expressed by lymphatic endothelia Expression of VEGF-C occurs in a variety of human tumors such as breast colon lung thyroid gastric squamous cell cancers mesotheliomas neuroblastomas sarcomas and melanomas Moreover expression of VEGF-C mRNA has recently been shown to correlate with the rate of metastasis to lymph nodes in breast colorectal gastric thyroid lung and prostate cancers To date however lymphangiogenesis has not been causally linked to tumor metastasis
Cyclooxygenase-2 COX-2 enzyme catalyzes the synthesis of prostaglandins COX-2 is an immediate-early response gene induced by inflammation growth factors tumor promoters oncogenes and carcinogens Increased levels of COX-2 may contribute to carcinogenesis by modulating xenobiotic metabolism apoptosis immune surveillance and angiogenesis Any significant increase in tumor mass must be preceded by an increase in vascular supply to deliver nutrients and oxygen to the tumor Recently levels of COX-2 were found to correlate with both VEGF expression and tumor vascularization in HNSCC This finding in human tissues is consistent with prior evidence that overexpression of COX-2 in epithelial cells led to enhanced production of VEGF and the formation of capillary-like networks Although COX-2 contributes to the regulation of angiogenesis its role in lymphangiogenesis is not clear
IL-6 is a secreted multifunctional glycoprotein Through binding to α-chain IL-6-R gp80 and subsequently recruiting the β-chain gp130 of the receptor IL-6 performs various biological functions The diversity of IL-6 signaling mediated via gp130 explains its functional pleiotropy IL-6 regulates inflammatory reactions immune responses hepatic acute-phase protein synthesis and several other important physiological processes Interestingly the influence of IL-6 in human cancers is varied depending on the cell types For example IL-6 has been demonstrated to promote growth of multiple myeloma Kaposis sarcoma and prostatic cancer cells while inhibiting the proliferation of lung and breast cancer cells Previous investigations have confirmed that IL-6 is important in both physiological and pathological angiogenesis Additionally recent study supports the hypothesis that IL-6 facilitates tumorigenesis of cervical cancer via VEGF-mediated angiogenesis Nevertheless whether IL-6 could regulate the expression of VEGF-C and what is its role in lymphangiogenesis still need to be clarified
Inhibition of angiogenesis is currently considered one of the most promising therapeutic strategies to inhibit cancer growth because it presumably can act on any tumor type does not induce resistance of tumor cells and can therefore be used in repeated therapeutic cycles and has little effect on normal tissues It now needs to be determined whether the same holds true for tumor lymphangiogenesis
Metastases of head and neck cancers occur frequently through the lymphatic system and the extent of lymph node involvement is a key prognostic factor for the diseases In this study we will conduct a systematic analysis of VEGF-C COX-2 and IL-6 expressions and will try to find the correlation between their expressions lymphatic metastases and patient survival Next we will investigate the relationship between VEGF-C COX-2 and IL-6 and further clarify their effects on tumor growth Undoubtedly the findings of this study will help us understand whether lymphangiogenesis could be a focal point of anti-cancer research If HNSCC tumors that express high levels of VEGF-C show a consistently higher incidence of lymphatic metastasis then inhibition of VEGFR-3 function may be a novel approach to inhibit lymphatic metastasis in patients
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