The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma

Abstract

Objectives:Ninety percent of head and neck cancers are squamous cell carcinoma which develops in the oral cavity. Metastasis is the main causative factor for death in 90% of all cancer-related deaths and begins with the invasion of tumor cells through the walls of small blood vessels or lymph vessels. A growing body of evidence has shown that vasculogenic mimicry (VM) facilitates tumor growth and cancer metastasis. The current study aimed to present the role of vascular endothelial (VE)-cadherin, CD44, and vimentin in inducing VM and epithelial-mesenchymal transition (EMT) and to identify the cancer stem cell (CSC) niche in different grades of oral squamous cell carcinoma (OSCC).Materials and Methods:A total of 63 OSCC samples (21 samples each grade) were collected from the archive of Pathology Department of Besat educational hospital, Hamadan, Iran, from 2000 to 2015. VE-cadherin, CD44, and vimentin/periodic acid–Schiff (PAS) double-staining were used to validate VM. VM was identified by the detection of PAS-positive loops surrounded by tumor cells. Chi-square test was used to examine the differences between the variables. Significant level was set at 0.05. Pearson's correlation was used to assess the co-localization of the markers.Results:There were statistically significant differences between tumor grade and the expression levels of VE-cadherin, CD44, and vimentin (P = 0.000). In addition, significant differences were found between tumor grade and microvessel density (P = 0.000) and between tumor grade and VM (P = 0.000).Conclusion:Our results may disclose a definite relationship between VE-cadherin, CD44 and vimentin expression levels, VM formation, EMT, CSCs, and microvessel count in OSCC samples. For this reason, it is suggested that VE-cadherin, CD44, and vimentin are related to angiogenesis and VM formation in OSCC, therefore, in tumor progression and metastasis. Recently, antitumor angiogenic therapies have been challenged. The presence of VM may explain the failure of antiangiogenic treatments.

The role of CD44 in pathological angiogenesis

“…Cancer led to approximately 9.6 million deaths worldwide in 2018 and is the second leading cause of death. 33 CD44 is highly expressed in cancer cells and cancer-associated ECs, 3,[34][35][36] and its expression has been observed to be associated with poor prognosis for many cancer types, including colorectal carcinoma, infiltrating ductal carcinoma, gastric adenocarcinoma, bladder cancer, head and neck cancer. [37][38][39][40][41][42][43] Although CD44 is widely recognized as a cancer stem marker 3,44 and promotes cancer progression and metastasis by regulating cancer cell stemness, 3,44,45 survival, [46][47][48] proliferation, [47][48][49] and adhesive and invasive properties, [50][51][52][53] the protumorigenic effects of CD44, at least partially, rely on its tumor angiogenesis-promoting activities.…”

“…25 A number of studies have revealed a positive relationship between CD44 expression and microvessel density (MVD), which is a characteristic of angiogenesis, in human tumor samples. 35,36,38,[54][55][56][57][58][59][60] A parallel increase in CD44 expression and high MVD has been observed in a variety of cancer types, such as infiltrating ductal carcinoma, 38 renal cell carcinoma, 56 and oral squamous cell carcinoma 35 (summarized in Table 1). In the oral orthotopic carcinogenesis mouse model, CD44 expression becomes upregulated in perivascular area along with excessive blood vessel formation during cancer progression.…”

Endocan Expression Profile in Different Grades of Oral Squamous Cell Carcinoma

“…Therefore, it is urgent to understand the molecular mechanisms of OSCC tumorigenesis and metastasis. Several molecular signaling and pathways contribute to the development and metastasis of OSCC (8).…”

“…Tumor growth and metastasis are correlated to the function and the altered expression level of many proteins, as well as gene mutations (5,8,(22)(23)(24). In addition, cancer cell invasion and metastasis are correlated to the level of cancer cell differentiation.…”

“…Several molecules and signaling factors are involved in angiogenesis in cancers. Besides, in highly aggressive cancers, tumor cells form vascular-like channels lined by tumor cells instead of endothelial cells called vasculogenic mimicry (VM), which participates in tumor progression and metastasis (8,23,28). The head and neck area is rich in lymphatic vessels and lymph node metastasis is a common event in head and neck cancers (5,22,29,30).…”