Gene Expression Signatures of Lymph Node Metastasis in Oral Cancer: Molecular Characteristics and Clinical Significances

Abstract

Even though lymph node metastasis accounts for the vast majority of cancer death in patients with oral cancer (OC), the molecular mechanisms of lymph node metastasis remain elusive. Genome-wide microarray analyses and functional studies in vitro and in vivo, along with detailed clinical observations, have identified a number of molecules that may contribute to lymph node metastasis. These include lymphangionenic cytokines, cell adhesion molecules, basement membrane-interacting molecules, matrix enzymes and relevant downstream signaling pathways. However, defined gene signatures from different studies are highly variable, which hinders their translation to clinically relevant applications. To date, none of the identified signatures or molecular biomarkers has been successfully implemented as a diagnostic or prognostic tool applicable to routine clinical practice. In this review, we will first introduce the significance of lymph node metastasis in OC, and clinical/experimental evidences that support the underlying molecular mechanisms. We will then provide a comprehensive review and integrative analysis of the existing gene expression studies that aim to identify the metastasis-related signatures in OC. Finally, the remaining challenges will be discussed and our insights on future directions will be provided.

Knockdown of Sec6 improves cell–cell adhesion by increasing α‐E‐catenin in oral cancer cells

“…Metastasis of cancer cells involves a series of sequential and interdependent events that include initial growth, local invasion, angiogenesis, intravasation of invading cancer cells into the vasculature or lymphatic systems, extravasation, and subsequent deposition and proliferation at a second site [1]. In particular, the decrease in cadherin‐mediated cell adhesion is identified as an essential step of the metastatic process and tumor progression [1]. Downregulation of E‐cadherin‐mediated cell adhesion has been associated with the progression of various malignant tumors including oral cancers [4].…”

“…Oral cancer is the sixth most common malignancy in humans and occurs with an increasing frequency worldwide [1]. The increase in frequency of oral cancer may be related to greater general life expectancy, the increasing consumption of alcohol and tobacco [2], and the involvement of HPV infection [1]. Histologically, more than 90% of oral cancers are classified as squamous cell carcinoma and are derived from the epithelium lining of the oral cavity.…”

“…Histologically, more than 90% of oral cancers are classified as squamous cell carcinoma and are derived from the epithelium lining of the oral cavity. Despite recent advancements in surgery, radiation, and chemotherapy, treatment of oral squamous cell carcinoma still has a high failure rate, as many patients present with regional metastasis at the time of presentation or subsequently develop metastasis after initial diagnosis [1]. The five-year survival rate for patients with lymph node metastasis at presentation notably decreases to 25-40% from a rate of approximately 90% for patients without lymph node metastasis in oral cancers [3].…”

“…The five-year survival rate for patients with lymph node metastasis at presentation notably decreases to 25-40% from a rate of approximately 90% for patients without lymph node metastasis in oral cancers [3]. Metastasis of cancer cells involves a series of sequential and interdependent events that include initial growth, local invasion, angiogenesis, intravasation of invading cancer cells into the vasculature or lymphatic systems, extravasation, and subsequent deposition and proliferation at a second site [1]. In particular, the decrease in cadherin-mediated cell adhesion is identified as an essential step of the metastatic process and tumor progression [1].…”

Loss of NKX3-1 as a potential marker for an increased risk of occult lymph node metastasis and poor prognosis in oral squamous cell carcinoma

“…In addition, progression and metastasis of tumor cells and poor prognosis are also correlated with overexpressions of VEGFs (37)(38)(39)(40). VEGF-C is classified into lymphatic markers, which are desmoplakin, LYVE-1, PROX-1, VEGF-C, VEGF-D and VEGFR-3, and generally studied in the correlation with nodal metastasis of cancers (36,41). Therefore, up-regulation of VEGF-C is induced by reduction of NKX3-1 expression, resulting in driving lymphangiogenesis (13).…”