الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Squamous cell carcinoma (SCC) accounts for more than 90% of all oral cancers. The conventional management of oral squamous cell carcinoma (OSCC) fails to increase the 5 years survival rate which remains as low as 50%. This mandates the development of new treatment strategies including immunotherapy. Toll- like receptors (TLRs) are evolutionarily conserved proteins and a major type of receptors involved in both innate and adaptive immunity. They are expressed in both immune as well as tumor cells and are suggested to have a role in cancer immunotherapy.
Ten TLRs are identified in human, among them TLR4 is the subject of the present study. Studies involving the use of TLR4 agonists as a possible option for cancer treatment are still ongoing with contradicting results. Monophosphoryl lipid A (MPLA) is a TLR4 agonist derived from lipopolysaccharide (LPS) and shares the lipid A component as the active part. MPLA is successfully used as an adjuvant to many vaccines nowadays including those for the prevention of cancer, for example the Cervarix™ vaccine against cervical cancer. However, to the best of our knowledge, this is the first study investigating the possible therapeutic role of MPLA in OSCC.
The aim of the present work was to study the therapeutic effect of MPLA on a human OSCC cell line (SCC-4) in terms of cytotoxicity, cytokine release in addition to the expression of proteins related to cancer cell apoptosis and proliferation. Moreover, it aimed to compare this effect against the conventional chemotherapeutic drug, cisplatin.
The expression levels of TLR4 in 50 patient samples of OSCC as well as 10 samples of normal oral mucosa were assessed immunohistochemically using anti-TLR4 antibody. Assessment of TLR4 expression in SCC-4 cell line was performed by enzyme-linked immunocytochemistry using light microscopy and by fluorescence immunohistochemistry using confocal laser scanning microscopy. SCC-4 cells were treated with different doses of cisplatin (positive control), MPLA as well as MPLA/INF-β combination for
Summary
48 hrs. The cytotoxic effect of these treatments on SCC-4 cells was assessed using CCK8 as a cell viability assay. Flow cytometric analysis using Annexin V-FITC/PI staining for the detection of apoptosis and Ki67 for the detection of proliferation followed. Finally, functional expression of TLR4 through the evaluation of IL-8 release was assessed using ELISA.
The results of the present study revealed an overexpression of TLR4 in OSCC tissue specimens compared to the normal oral mucosa with the highest expression detected in the moderately differentiated SCC. TLR4 expression was verified in SCC-4 cells. The CCK8 cell viability assay revealed a dose dependent cytotoxic effect upon treatment with MPLA for 48 hrs which was not as efficient as cisplatin. A combination of MPLA and INF-β resulted in a decrease in SCC-4 cell viability comparable to cisplatin. Treatment with MPLA alone showed 38.96% apoptotic cell population compared to 41.37% when the cells were treated with a combination of
MPLA and INF-β. Incubation with MPLA and MPLA/INF-β for 48 hrs also resulted in a decrease in the proliferation of SCC-4 cells. IL-8 secretion was detected in the supernatants of SCC-4 cells after treatment with MPLA denoting TLR4 activation.
The current study suggests an antitumor effect of MPLA that was enhanced when combined with INF-β. However, the underlying molecular mechanisms are yet to be studied and explored. More studies to further elucidate the role of MPLA as a TLR4 agonist in OSCC are recommended.