The Role of Lymphangiogenesis in Head and Neck Cancer Metastasis

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Brief Title

The Role of Lymphangiogenesis in Head and Neck Cancer Metastasis

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, 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



Oral Cancer


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Estimated Enrollment


Start Date

August 2004

Eligibility Criteria

        Inclusion Criteria:

          -  Head and neck squamous cell carcinoma

        Exclusion Criteria:

          -  Other pathological type




30 Years - 75 Years

Accepts Healthy Volunteers



Ching-Ting Tan, MD, PhD, 886-2-23123456, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Study Sponsor

National Taiwan University Hospital

Study Sponsor

Ching-Ting Tan, MD, PhD, Principal Investigator, National Taiwan University Hospital

Verification Date

June 2005