|Year : 2014 | Volume
| Issue : 7 | Page : 125-130
The clinical value of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression in patients with oral tongue squamous cell carcinoma
Junjie Yan1, Yinhua Jiang1, Min Ye1, Weidong Liu1, Liang Feng2
1 Department of Stomatology, The People's Hospital of Lishui, Lishui 323000, Zhejiang, China
2 Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang, China
|Date of Web Publication||29-Nov-2014|
Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang
Source of Support: None, Conflict of Interest: None
Background: Oral tongue squamous cell carcinoma (OTSCC) is an oral carcinoma prone to lymphatic metastasis. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) as important adhesion molecules play roles in regulating cell-cell adhesion and tumor cells metastasis.
Materials and Methods: Lymphatic vessel density (LVD) was evaluated by immunohistochemistry using anti-human D2-40 antibody. The expression of ICAM-1 or VCAM-1 in lymphatic vessels were measured by double immunofluorescence staining. Then both of the LVD and the expression of ICAM-1 or VCAM-1 were compared between in normal tongue and in OTSCC lymphatic vessels. In OTSCC, statistical analyses were performed to determine the prognostic correlation of ICAM-1 or VCAM-1 levels.
Results: LVD and expression of ICAM-1 or VCAM-1 in OTSCC lymphatic vessels was higher than those in normal tongue lymphatic vessels (LVD: 21.454 ± 7.022, 8.498 ± 1.679; ICAM-1: 30.241 ± 5.639%, 5.050 ± 1.227%; VCAM-1: 33.134 ± 5.127%, 2.113 ± 0.446%, in OTSCC, normal tongue tissues, respectively). High LVD and high ICAM-1 or VCAM-1 expression in lymphatic vessels was significantly associated with lymphatic node metastasis. Overall survival was significantly shorter in patients with high LVD and ICAM-1 or VCAM-1 expression in lymphatic vessels.
Conclusions: LVD and expression of ICAM-1 or VCAM-1 in OTSCC was higher than that in normal tongue lymphatic vessels. Monitoring changes in the expression of ICAM-1 or VCAM-1 in lymphatic vessels may be a useful technique for assessing prognoses in OTSCC patients.
Keywords: Immunohistochemistry, intercellular adhesion molecule 1, lymphatic vessel density, oral tongue squamous cell carcinoma, prognosis, vascular cell adhesion molecule 1
|How to cite this article:|
Yan J, Jiang Y, Ye M, Liu W, Feng L. The clinical value of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression in patients with oral tongue squamous cell carcinoma. J Can Res Ther 2014;10, Suppl S3:125-30
|How to cite this URL:|
Yan J, Jiang Y, Ye M, Liu W, Feng L. The clinical value of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 expression in patients with oral tongue squamous cell carcinoma. J Can Res Ther [serial online] 2014 [cited 2019 Aug 26];10:125-30. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/125/145827
| > Introduction|| |
Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer diagnosed in the oral cavity comprising 25-40% of oral carcinoma.  Patients with OTSCC have a significantly worse prognosis than those at other oral cavity sites.  A rich lymphatic network and highly muscularized structure make OTSCC more frequently associated with metastasis to draining lymph nodes. 
Lymphangiogenesis has been found in many types of primary tumor tissues, including in oral squamous carcinoma. ,,, The large amount and the immaturely and dysfunctionally structural characteristics of the new vessels may facilitate tumor cell's metastasis. , Although the mechanism of tumor cell's migration into lymphatic vessels has not been fully illustrated, alteration in cell-cell adhesion is essential during the metastatic pathway. ,, Adhesion molecules commonly play a central role in cell-cell adhesion, in which intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are the most effective molecules and are most widely studied.
Intercellular adhesion molecule 1, also called CD54, is a cell surface glycoprotein typically expressed on endothelial cells and immune system cells. ICAM-1 is a ligand for LFA-1 (integrin), a receptor found on leukocytes.  VCAM-1, or known as CD106, is a cell surface sialoglycoprotein. VCAM-1 is an endothelial ligand for VLA-4 (or α4 β1 integrin) and α4 β7 integrin.  CAMs, including ICAM-1 and VCAM-1, physiologically have the similar function. In inflammation or immune response, activated leukocytes can bind to endothelial cells via ICAM-1/LFA-1 or VCAM-1/VLA-4, then transmigrate into inflammatory tissue sites. ,
Until now, there have no reports of ICAM-1 and VCAM-1 expression on lymphangiogenesis vessels in OTSCC. In this study, first we measured lymphatic vessel density (LVD), then focusing on the expression of ICAM-1 and VCAM-1 in lymphatic endothelium, to investigate their relationship with OTSCC cell' s migration and clinicopathologic parameters, in order to determine if these results can be used to assess risk of lymphatic metastasis and prognosis in patients.
| > Materials and Methods|| |
Patients and tumor specimens
Tissue samples were collected from 80 OTSCC patients diagnosed and treated at Harbin Medical University Stomatological Hospital, Harbin, China and The People's Hospital of Lishui, Zhejiang 323000, China, from the year 2000-2006. Before treatment, informed consent for the scientific use of tissue materials was obtained from the patients that were approved by the Local Ethics Committee. All patients underwent potentially curative surgery without preoperative therapy. [Table 1] presents the clinical and pathological characteristics of these patients. Normal oral mucosa group were obtained from each of the tissue 2.0-2.5 cm away from the primary tumor,  and the organization were graded according to the tissue morphology. All patients were staged according to the 1997 UICC tumor node metastasis (TNM) Classification of Malignant Tumors.  After treatment, all patients were followed-up until death or for at least 60 months.
|Table 1: Relationship between LVD, expression of ICAM-1, VCAM-1 in lymphatic endothelium and clinicopathologic parameters (n=80) |
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All specimens were fixed routinely in 10% formalin and embedded in paraffin. Consecutive 4-μm-thick sections were cut and deparaffinized with xylene, rehydrated in a graded alcohol series. One section from each tumor was stained with hematoxylin and eosin to reevaluate the histologic diagnosis according to Anneroth's classification,  and the other sections were used for immunohistochemistry. The grade of tumor differentiation was determined using the criteria proposed by the World Health Organization. 
Monoclonal antibodies against D2-40 were used as lymphatic endothelial marker to evaluate LVD in a conventional method. The D2-40 antibody can detect a fixation-resistant epitope on podoplanin, which is a selective marker for lymphatic endothelium, allowing the recognition of lymphatic vessels in formalin-fixed, paraffin-embedded tissues. Monoclonal D2-40 (ZM-0465) antibodies was purchased from Zhongshan Goldenbridge Biotechnology (Beijing, China). Monoclonal ICAM-1 (BA0541), VCAM-1 (BA0406) antibodies and fluorochrome-conjugated secondary antibodies (BA1101, BA1032) were purchased from Wuhan Boster Biotech (Wuhan, China). The antibody was diluted with an antibody diluent.
For immunohistochemistry, sections were pretreated for antigen retrieval by microwave at 98°C for 10 min (pH 6.0). To block endogenous peroxide activity, 3% H 2 O 2 was applied, and nonspecific reactions were blocked with 1% bovine serum albumen (BSA). Sections were incubated at 4°C overnight with the primary antibody (1:100 dilution) with phosphate buffered saline (PBS). The following day sections were incubated with corresponding secondary antibody (PV 6000, Zhongshan Goldenbridge Biotechnology, Beijing, China) for 30 min. Immunolabeling was visualized by using diaminobenzidine chromogen (Zhongshan Goldenbridge Biotechnology, Beijing, China). All the slides were counterstained with hematoxylin. The sections were dehydrated through ethanol and xylene before mounting. Negative control staining consisted of substituting nonimmune goat serum for the primary antibody.
Double immunofluorescence staining was performed in normal and OTSCC tissues referencing to Mason et al.  Sections were retrieved by microwave and then treated with 1% BSA to block nonspecific reactions. Incubate sections with the mixture of two primary antibodies (rabbit monoclonal antibody against human ICAM-1 and mouse monoclonal antibody against human D2-40, 1:100 dilution for both) in 1% BSA overnight at 4°C. The next day sections were incubated with the mixtures of two secondary antibodies (goat anti-mouse IgG and goat anti-rabbit IgG, both were 1:200 dilution) in 1% BSA for 1 h at room temperature in dark. Decant the mixture of the second antibody solution and wash three times with PBS for 5 min each in dark. Labeling was visualized on a conventional fluorescence microscope immediately. Negative control for primary monoclonal antibodies used in this study was confirmed with matched isotype immunoglobulin. Similar process was performed to examine the co-expression of VCAM-1 (1:00 dilution) and D2-40 (1:100 dilution).
All samples were reviewed by two independent investigators who were blinded to the clinical outcomes of the patients. LVD was measured according to Weidner's method.  First, all slides were screened using a low-magnification objective lens to identify the areas containing the highest number of positively stained vessels (hot spots). Then the number of vessels was counted in three fields in the hot spots using a ×200 magnification lens. The single, brown-stained cell or cluster of endothelial cells that clearly was separated from the adjacent microvessels, tumor cells and other connective tissue elements was considered positive. From three fields, the mean number of vessels per mm square area was defined as LVD.
Immunofluorescent microscopy was performed using an Olympus fluorescent microscope. Composite images were created using Photoshop software (Adobe systems, Inc., Mountain View, CA, USA).To evaluate the expression of ICAM-1 in lymphatic vessels, number of ICAM-1(+) lymphatic vessels in random three fields (×100) were manually counted, and the number of total lymphatic vessels were collected in the same three fields simultaneously. The percentage of ICAM-1(+) lymphatic vessels of the total number of lymphatic vessels was calculated as a result. The number of ICAM-1(+) lymphatic vessels were determined only if the lymphatic endothelium expression of ICAM-1 could be clearly delineated. The percentage of VCAM-1(+) lymphatic vessels in total lymphatic vessels was calculated in the same method.
All statistical analyzes were performed using SPSS 19.0 (SPSS linc, Chicago, IL, USA). "Probability" P < 0.05 means there is statistical significance.
| > Results|| |
Expression of D2-40 in normal tongue and oral tongue squamous cell carcinoma tissues
D2-40 staining was mainly located in the cytoplasm or cell membrane of the lymphatic endothelial cells. D2-40-positive lymphatic vessels were detected in all cases, while the tumor cells and blood vessel endothelium had no D2-40 staining. In normal oral mucosal tissue, the lymphatic vessels were relative small and evenly distributed in the underling superficial lamina propria. In OTSCC samples, lymphatic vessel's distributing pattern unevenly depended on the location, and lymphatic vessels were mostly observed in the peri-tumoral area. And they were more elongated and dilated with open lumina compared with the lymphatic vessels in normal tissue samples [Figure 1].
|Figure 1: Lymphatic vessels staining pattern using D2-40 antibody (magnification, ×400). (a) Staining of lymphatic vessels in normal tongue tissue, (b) staining of lymphatic vessels in oral tongue squamous cell carcinoma|
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Expression of intercellular adhesion molecule 1, vascular cell adhesion molecule 1 in lymphatic vessels
The expression of ICAM-1 or VCAM-1 was mainly located in the blood or lymphatic endothelium. In OTSCC tissues, there were some sporadic ICAM-1 or VCAM-1 positive staining points. In normal tongue tissues, the mean percentage of ICAM-1 or VCAM-1 positive staining lymphatic vessels were 5.0% and 2.1%, respectively. While in OTSCC tissues, the mean percentage of ICAM-1(+) or VCAM-1(+) staining were 30.2% and 33.1%, respectively [Figure 2].
|Figure 2: Expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 in normal tongue and oral tongue squamous cell carcinoma lymphatic vessels (magnification, ×200)|
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In OTSCC lymphatic vessels were identified by immunofluorescent staining of D2-40 (A, D, in green). ICAM-1 and VCAM-1 were showed in image B, E, respectively (in red). Merged images C and F indicate ICAM-1 or VCAM-1 expression in OTSCC lymphatic vessels (in yellow), respectively. Merged images G and H show the expression of ICAM-1 or VCAM-1 in normal tissue lymphatic vessels, respectively.
Statistic analysis results
Lymphatic vessel density in OTSCC tissue samples (mean = 21.454 ± 7.022) was significantly higher than LVD in normal tongue tissues [mean = 8.498 ± 1.679, [Figure 3]. There was a significant higher mean expression of ICAM-1 or VCAM-1 in OTSCC lymphatic vessels (30.241 ± 5.639%, 33.134 ± 5.127%, respectively) than in normal tongue tissues [5.050 ± 1.227%, 2.113 ± 0.446%, respectively, [Figure 3]. In OTSCC, LVD values were correlated significantly with higher scores of TNM classification [P < 0.01, [Figure 1], lymph node involvement [P = 0.000, [Table 1]. Expression of ICAM-1 or VCAM-1 in lymphatic vessels was associated with TNM classification and lymphatic metastasis (P = 0.000, respectively) [Table 1].
|Figure 3: (a) Comparation of lymphatic vessel density, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 between oral tongue squamous cell carcinoma and normal tongue tissues, and (b-d) survival curves in oral tongue squamous cell carcinoma|
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[Figure 3] use the paired-samples t-test to compare LVD, ICAM-1 and VCAM-1 between OTSCC and normal tongue tissues. The three parameters in OTSCC were significantly higher than the one in normal tongue tissues, P < 0.05. Use log-rank test to compare the survival rate of LVD, ICAM-1 and VCAM-1 between OTSCC and normal tongue tissues, there were all statistical significance (P < 0.05).
| > Discussion|| |
Oral tongue squamous cell carcinoma is an oral carcinoma prone to lymph node metastasis, which influence the tumor's recurrence and patient's prognosis. In cancer research most efforts were focused on distant metastasis, little is known about the early steps of metastasis. The process of tumor cell's lymphatic metastasis is similar to blood metastasis, consisting of several sequential steps in which the tumor cell's migration into lymphatic vessels acted as an initial step.  A large number of reports have mentioned lymphangiogenesis in oral carcinoma, which is believed to be associated with tumor cell's lymphatic metastasis, but its exact function remains ambiguous. In our study, firstly we conformed an association between LVD with tumor cell's lymphatic metastasis, which was accordance with most previous studies.  In peritumoral area, in addition to the increased account of vascularity, we also observed most of the structures of these lymphatic vessels were some irregular, with divided endothelium, which may contribute to tumor cell's migration.
CAMs' abnormal expression has been noted in many tumor types, while the effects of adhesion molecules are some controversial. ,,,,, A link between ICAM-1 expression and tumor progression was first demonstrated in melanoma cells in which ICAM-1 expression correlates with the risk of metastasis. , In breast cancer patients with CAMs-positive tumors had a better prognosis and overall survival rates. , There are not very much reports about the expression of CAMs in lymphatic endothelial cells until now. CAMs in lymphatic vessels may function similarly as to in blood vessels, physiologically playing a role in leukocytes or lymphatics migration from tissues into lymphatic vessels. Researchers have wondered if those adhesion molecules could be employed by tumor cells during their metastatic spread to regional lymph nodes and distant organs.  Some reports mentioned that some tumor cells may use adhesion molecules as guidance cues to enter the vessels, as an active process.  Using double-labeling immunofluorescence, we found a high expression of CAMs in lymphatic endothelium and conformed that it is associated with lymphatic metastasis. May we hypothesize that tumor cells might adhere to the lymphatic vessel regions where had a higher CAMs expression? In oral carcinoma, we also observed many tumor cells display CAMs positive-staining, and previous studies have reported VLA-4 expression in tumor cells.  Then another migration method may exist that tumor cells can utilize leukocytes as linkers to adhere to endothelium, especially at places with discontinuous endothelial monolayer and large gaps that expose the underlying extracellular matrix. ,, Previous studies have mentioned that OTSCC cells can digest interstitial matrix and basement membrane. , All of these findings contributed to establishing a microenvironment facilitating tumor cell's migration. We may conclude that these CAMs participated a role in the interaction between tumors and lymphatic vessels, directly or indirectly, promoting tumor cells migration into lymphatic vessels.
As to the impact of abnormal expression of CAMs to the immune system remains paradox, although some reports advise that over-expression of CAMs in lymphatic vessels may benefit for immune surveillance.  Another interesting possibility was that CAMs may make for a reverse migration of lymphatic cells from lymphatic luminal outside into tissues, performing a host-sefense immune role.  In our study, based on the finding that high expression of CAMs was associated to the tumor cells migration and bad prognosis, we cannot conform such a conclusion. However, we can't deny it as well as we actually found some lymphatic cells around tumor cells, but could not confirm they were from blood or lymphatic vessels. A possible explanation may be that the CAMs' anti-tumor immune efficiency was comparatively weak as to its pro-migration role.
| > Conclusion|| |
In oral squamous carcinoma, we find an obvious lymphangiogenesis than in normal tissues, simultaneously with a higher expression of ICAM-1 and VCAM-1 in lymphatic endothelium. CAMs' expression is associated with the incidence of lymph node metastasis and bad prognosis. The abnormal structure of lymphatic vessels and higher CAMs' expression in endothelial cells may facilitate tumor cell's migration into lymphatic vessels. The molecule mechanisms of CAMs' expression regulation and their exact effects in tumor cell's migration process may need further research. In the future, an effective anti-tumor strategy may preference to blocking metastatic progression during the initial step. Adhesion molecules as a promising treatment target may be able to be deserved more attention.
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[Figure 1], [Figure 2], [Figure 3]