The Role of SDF-1/CXCR4 in Metastasis of Oral Squamous Cell Carcinoma

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Brief Title

The Role of SDF-1/CXCR4 in Metastasis of Oral Squamous Cell Carcinoma

Brief Summary

      Investigate the role of SDF-1/CXCR4 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 (4,5).
      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 (14,15). 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

      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-1/CXCR4 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-1/CXCR4 receptor ligand system in malignant tissues. And such studies are limited in oral

      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-1/CXCR4 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-1/CXCR4 (ligand/receptor) 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-1/CXCR4 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-1/CXCR4 signaling may be a novel approach to inhibit metastasis in these patients. The
      development of SDF-1/CXCR4 system antagonists will provide opportunity to improve the
      survival rate.

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

January 2006

Completion Date

July 2006

Eligibility Criteria

        Inclusion Criteria:

          -  Oral 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 Hospita;

Verification Date

June 2005