Original Research ArticleHigh Fas expression in gastric carcinoma cells as a factor correlating with the occurrence of metastases to regional lymph nodes
Introduction
Formation and progression of neoplasm is strictly connected with the processes of an abnormal cell proliferation and disturbances of apoptosis, a natural defense mechanism.
Two main apoptosis pathways can be found: external (membranous) and internal (mitochondrial). The former occurs due to stimulation of Fas membrane receptor while the latter to a great extent depends on proteins from Bcl-2 family. The final effect in all cases involves cell death due to activation or particular enzymes.
Stimulation of cell membrane receptors from the TNF family, which contains Fas receptor (Apo-1, CD95) takes place after the receptor binds a part of a specific ligand – Fas protein – ligand (Fas-L) [1], [2]. For instance, cytotoxic T-lymphocytes which have a Fas-L particle on their surface – act by means of Fas–Fas-L interaction. Cytotoxic lymphocytes, after identification of cells which should be removed (e.g. neoplastic cells or those infected with viruses) bind with their cell membrane Fas receptor and begin the programmed cell destruction. The structure of Fas receptor comprises the so-called death domain (DD) on the cell cytoplasm side. Binding Fas receptor with Fas-L results in the activation of its death domain which binds with FADD (Fas associated death domain)–intermediate protein in the caspase activation process [3]. The Fas–FADD complex, by means of its DED domain (Death effector domain) – activates procaspase 8 (the so-called FLICE–FADD-like protein interleukin 1 beta converting enzyme). Caspase 8 (FLICE) activates the effector protein of the apoptosis process – caspase 3 [3]. There is another apoptosis model through cell membrane receptors – through secondary intracellular messengers responsible for apoptosis. The final product is a ceramide created from sphingomyelin influenced by sphingomyelinase. Its activation depends on the stimulation of cell membrane receptor for TNF and Fas/APO-1. As a result, death protein – FADD/Mort 1 and RIP are created (after stimulation of the Fas receptor). These proteins influence sphingomyelinase which exerts an impact on sphingomyelin. The latter participates in the formation of a ceramide which causes caspase activation [1], [4], [5].
Although the knowledge on apoptosis is constantly expanded, the following questions have remained unanswered: which of the apoptosis pathways and to what extent is disturbed during neoplastic transformation and how do these disturbances influence the formation process of various cancers and metastases via circulatory and lymphatic pathways.
The aim of the study was to evaluate the influence exerted by Fas and Fas-L expression in gastric carcinoma cells on the occurrence of metastases to regional lymph nodes. Moreover, the impact of the following factors on the occurrence of metastases to regional lymph nodes was analyzed: age, gender, carcinoma histological form (macroscopic classification, Lauren, Kubo, Goseki), tumor topical stage (pT), malignancy grade (G) and carcinoma location in the stomach.
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Patients
The study included 89 patients treated surgically for gastric carcinoma at 2nd Clinical Department of General and Gastroenterological Surgery of the Medical University of Bialystok (Poland) between 2000 and 2006 (Table 1). The procedure involved gastrectomy (complete or subtotal depending on neoplasm histological type and its location in the stomach) as well as excision of greater omentum and regional lymph nodes (D2 or non-standard D3 in the case of macroscopically changed lymph nodes). The
Results
The reaction of Fas and Fas-L was observed in cytoplasm. (Fig. 1, Fig. 2). A statistically significant relationship between the expression of Fas protein in gastric carcinoma cells and the number of metastases to regional lymph nodes was observed. In the case of patients with a positive expression of this protein, the number of lymph nodes affected by gastric carcinoma metastases was increasing (p < 0.01) (Table 2 and Fig. 3).
No such dependency was observed in the case of Fas-L protein expression
Discussion
The stage of carcinoma at the point of the diagnosis is the most crucial predictor as it enables the choice of the optimum treatment [8], [9], [10], [11], [12], [13]. The presence of remote metastases excludes a radical surgical treatment. However, affected regional lymph nodes require lymphadenectomy of a broader scope.
Disturbances of the membrane apoptosis pathway, which includes Fas and Fas-L proteins, are critical in the formation of numerous neoplasms of the digestive tract. They are
Conclusions
Our present study failed to confirm the theory of immunological escape of cancerous cells with positive Fas-L expression which could result in a more frequent metastasis occurrence. However, the study confirmed the thesis on the impact exerted by the disturbances of the Fas-dependent apoptosis on the occurrence of gastric carcinoma of different aggressiveness. Higher Fas expression in gastric cancerous cells would be connected with the form of cancer which gives metastases to regional lymph
Conflict of interest
The authors declare no conflict of interest.
Financial disclosure
The study was financed within statutory actions no. 3-37774, by the Medical University of Bialystok, Poland.
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