Trial Information

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 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-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 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-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.