The Role of Lymphangiogenesis in Head and Neck Cancer Metastasis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00173381
Recruitment Status : Unknown
Verified June 2005 by National Taiwan University Hospital.
Recruitment status was:  Recruiting
First Posted : September 15, 2005
Last Update Posted : March 30, 2006
Information provided by:
National Taiwan University Hospital

Brief Summary:
The purpose of this study is to investigate the role of lymphangiogenesis in the metastasis of head and neck cancer.

Condition or disease
Oral Cancer Laryngeal Cancer Hypopharyngeal Cancer

  Hide Detailed Description

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, Kaposi's 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 Type : Observational
Enrollment : 100 participants
Allocation: Random Sample
Observational Model: Natural History
Time Perspective: Longitudinal
Time Perspective: Retrospective/Prospective
Study Start Date : August 2004

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   30 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Head and neck squamous cell carcinoma

Exclusion Criteria:

  • Other pathological type

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00173381

Contact: Ching-Ting Tan, MD, PhD 886-2-23123456 ext 5222

National Taiwan University Hospital Recruiting
Taipei, Taiwan, 100
Contact: Ching-Ting Tan, MD, PhD    886-2-23123456 ext 5222   
Sponsors and Collaborators
National Taiwan University Hospital
Principal Investigator: Ching-Ting Tan, MD, PhD National Taiwan University Hospital Identifier: NCT00173381     History of Changes
Other Study ID Numbers: 9461700657
First Posted: September 15, 2005    Key Record Dates
Last Update Posted: March 30, 2006
Last Verified: June 2005

Keywords provided by National Taiwan University Hospital:
head and neck squamous cell carcinoma (HNSCC)
vascular endothelial growth factor-C (VEGF-C)
cyclooxygenase-2 (COX-2)
interleukin-6 (IL-6)

Additional relevant MeSH terms:
Mouth Neoplasms
Laryngeal Neoplasms
Hypopharyngeal Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Mouth Diseases
Stomatognathic Diseases
Otorhinolaryngologic Neoplasms
Laryngeal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Otorhinolaryngologic Diseases
Pharyngeal Neoplasms
Pharyngeal Diseases