AFP-producing Gastric Cancers Research Articles

Epigenetic regulation of GATA4 expression by histone modification in AFP-producing gastric adenocarcinoma

AFP-producing adenocarcinoma is a variant of adenocarcinoma with high malignancy. Production of AFP suggests enteroblastic or hepatoid differentiation of cancer cells. GATA4 is a key molecule involved in the prenatal development of the stomach and liver. GATA4 is epigenetically silenced by hypermethylation of primer region in many types of cancers including gastric cancer. The aim of this study is to investigate the expression and epigenetic regulation of GATA4 in AFP-producing adenocarcinoma. Immunohistochemical analysis revealed that GATA4 was positive in 3/8 cases of AFP-producing gastric adenocarcinomas and in 28/30 cases of common type adenocarcinomas. Epigenetic modification of GATA4 promoter region was investigated with 3 AFP-producing and 4 common-type gastric cancer cell lines. GATA4 mRNA was detected in 1/3 of AFP-producing and 2/4 of common-type gastric cancer cell lines by RT-PCR. Methylation-specific PCR revealed no GATA4 methylation in any of the AFP-producing gastric cancers, whereas methylation was consistent with GATA4 expression in the common-type gastric cancers. Chromatin immunoprecipitation assay for AFP-producing gastric cancers revealed that histones H3 and H4 were hypoacetylated in the GATA4-negative cells, while they were hyperacetylated in the GATA4-positive cells. Treatment with trichostain A, an inhibitor for histone deacetylase, induced acetylation of histones H3 and H4, and tri-methylation of lysine 4 of histone H3, which was associated with the active transcription of GATA4 in GATA4-negative AFP-producing cells. These results indicated that histone deacetylation is a silencing mechanism for GATA4 expression in AFP-producing gastric cancer cells. Differences between AFP-producing gastric cancer and common-type gastric cancer in terms of the mechanism of GATA4 regulation may be reflected in the phenotypic deviation of AFP-producing gastric cancer from common-type gastric cancer.

C-Met expression in a gastric cancer cell line producing alpha-fetoprotein.

We previously reported a higher frequency of c-Met protein expression and high proliferative status in gastric cancers producing alpha-fetoprotein (AFP) than in those not producing AFP. To investigate this further, we established an AFP-producing gastric cancer cell line, designated as AME-1, from the primary tumor of a patient with AFP-producing gastric cancer. alpha-Fetoprotein production in the AME-1 cell line was confirmed at the protein level by immunocytochemistry and at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR). A high amount of AFP was also detected in the supernatant of cultured AME-1. The AME-1 cell line expressed c-Met both at the mRNA and protein levels. A semiquantitative RT-PCR method indicated that AME-1 had a higher amount of c-Met mRNA than well-known gastric cancer cell lines (MKN-28, MKN-45) with strong c-Met expression. Hepatocyte growth factor (HGF), a ligand for the c-Met receptor, was not detected in the mRNA or protein of AME-1. The AME-1 cell line showed a proliferative response to exogenous HGF treatment in a dose-dependent manner, but the activity of migration was not stimulated by exogenous HGF. The AME-1 cell line may be a useful model for elucidating aggressive behavior, especially related to regulation of the c-Met/HGF system, in AFP-producing gastric cancers.

Clinicopathologic Features of Gastric Cancers Producing Alpha-Fetoprotein

Background: Patients with gastric cancers producing alpha-fetoprotein (AFP) were reported to have a poor prognosis with high rates of liver metastasis. The purpose of the present study was to clarify the clinicopathological features of AFP-producing gastric cancers, in particular characteristics of liver metastasis, and to evaluate treatment of these cancers. Methods: In 27 of the 29 cases with elevated preoperative serum AFP levels among a total of 974 primary gastric cancers, AFP production was confirmed in gastric cancer cells by immunohistochemistry. These cases were included in the AFP-positive gastric cancer group (AFP(+), 2.7%). The remaining 945 cases with normal serum AFP levels were designated the AFP-negative gastric cancer group (AFP(–)). Results: There was a higher incidence of lymph node metastasis, a deeper invasion of the gastric wall, a higher frequency of advanced stage, a more marked lymphatic invasion and a higher rate of liver metastasis in the AFP(+) group than in the AFP(–) group. The patients received curative resection in AFP(+) group had a significantly worse survival rates in comparison to that in AFP(–) group. With respect to liver metastasis (n = 17) in AFP(+) group, of 3 cases who received curative hepatic resection, 1 patient survived more than 3 years, while the remaining 2 died in less than 3 years due to multiple liver recurrence. The patients (n = 5) who received palliative resection for liver metastasis followed by transarterial continuous infusion chemotherapy all died in less than 1 year. Conclusion: AFP-producing gastric cancers had aggressive behavior and their clinical or biological features were quite different from the common AFP-negative gastric cancers. Surgical resection of liver metastasis from AFP-producing gastric cancers was unsatisfactory. The development of a novel multimodal therapy against AFP-producing gastric cancers is needed.

High Frequency of c-Met Expression in Gastric Cancers Producing Alpha- Fetoprotein

Gastric cancers producing α-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(–)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(–) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.

α-Fetoprotein–producing gastric cancer: histochemical analysis of cell proliferation, apoptosis, and angiogenesis

OBJECTIVE: α-Fetoprotein (AFP)-producing gastric cancer has been associated with a poor prognosis. In the present study, the cell proliferation, apoptosis, and angiogenesis of this cancer were studied histochemically to determine its malignant potential. METHODS: Tissue samples were taken from four patients with AFP-producing gastric cancer and 26 patients with AFP-negative gastric cancer. Cell proliferation was evaluated by Ki-67 immunostaining, and the Ki-67 labeling index (LI) was determined. Apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling method, and the apoptotic index was determined. Angiogenesis was evaluated by measuring the microvessel density using factor VIII immunostaining, and immunostainings for vascular endothelial growth factor and thymidine phosphorylase were performed. RESULTS: The Ki-67 LI of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers ( p < 0.01). The apoptotic index of the AFP-producing gastric cancers was significantly lower than that of the AFP-negative gastric cancers ( p < 0.01). The microvessel density of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers ( p < 0.01). Vascular endothelial growth factor expression was observed in all four of the AFP-producing gastric cancers, whereas thymidine phosphorylase was not expressed in any of the AFP-producing gastric cancers. CONCLUSIONS: These results suggest that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. These biological characteristics of AFP-producing gastric cancer reflect the aggressive behavior and the poor prognosis of patients with this type of cancer.

Alpha-fetoprotein-producing gastric cancer: histochemical analysis of cell proliferation, apoptosis, and angiogenesis.

Alpha-fetoprotein (AFP)-producing gastric cancer has been associated with a poor prognosis. In the present study, the cell proliferation, apoptosis, and angiogenesis of this cancer were studied histochemically to determine its malignant potential. Tissue samples were taken from four patients with AFP-producing gastric cancer and 26 patients with AFP-negative gastric cancer. Cell proliferation was evaluated by Ki-67 immunostaining, and the Ki-67 labeling index (LI) was determined. Apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling method, and the apoptotic index was determined. Angiogenesis was evaluated by measuring the microvessel density using factor VIII immunostaining, and immunostainings for vascular endothelial growth factor and thymidine phosphorylase were performed. The Ki-67 LI of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers (p < 0.01). The apoptotic index of the AFP-producing gastric cancers was significantly lower than that of the AFP-negative gastric cancers (p < 0.01). The microvessel density of the AFP-producing gastric cancers was significantly higher than that of the AFP-negative gastric cancers (p < 0.01). Vascular endothelial growth factor expression was observed in all four of the AFP-producing gastric cancers, whereas thymidine phosphorylase was not expressed in any of the AFP-producing gastric cancers. These results suggest that AFP-producing gastric cancers have high malignant potential (high proliferative activity, weak apoptosis, and rich neovascularization) compared with that of AFP-negative gastric cancers. These biological characteristics of AFP-producing gastric cancer reflect the aggressive behavior and the poor prognosis of patients with this type of cancer.

EIGHT CASES OF AFP-PRODUCING GASTRIC CANCER AT THE HOSPITAL-A CLINICOPATHOLOGICAL STUDY-

A series of eight cases of AFP-producing gastric cancer experienced at the hospital in a recent 5-year period were clinicopathologically studied. Preoperative AFP levels in the subjects ranged from 50.31 ng/ml to 144, 5100 ng/ml. Six of these eight cases were of advanced cancer, and five out of the six cases had a Bormann type 3 carcinoma. It was histopathologically peculiar that seven cases had ly3 and all of them had severe lymphatic invasion. Histologically, four cases had porlmainly, and hepatocyte like tumor cells were confirmed in five cases. As to lymph node metastases, there were no case of n0, three cases of n1, and remaining cases of n2 or more; all cases had metastatic foci. Five of the eight patients had hepatic metastasis and died within one year. It is suggested that AFP-producing gastric cancers are liable to metastasize to the liver and the hepatic metastasis itsefl is an important factor determining the prognosis of the patient. From the above, it is indicate that AFP-producing gastric tumors have a biologically potent malignancy and need treatments including extended lymph nodes dissection and indwelling of a reservoir for the liver metastasis in an early stage.

Roles of Histological Findings and Serum AFP Levels in the Prognosis of AFP-producing Gastric Cancers

We investigated the roles of histological findings and serum AFP levels in the prognosis of gastric cancers which produce AFP. We considered the typical features of such gastric cancers to be the medullary growth of undifferentiated cancer cells with clear, or slightly eosinophilic, abundant cytoplasm and pleomorphic large round nuclei, forming either papillary clear carcinomas or hepatoid carcinomas. Seventeen patients with AFP-producing gastric cancers were observed in the period, 1979-1991. They were divided into two groups: those with (n 5) and those without (n 12) the typical histological features mentioned above. Their clinicopathological findings and prognoses were compared. Both groups showed a male dominance, gross Borrmann's type 2 or 3 appearances, diagnoses made at an advanced stage and metastatic involvements of the liver. The patients with the typical histological features showed a significantly higher AFP serum level and a significantly shorter survival. The patients who lacked the typical findings, and with serum AFP levels > or = 100 ng/ml, had poorer prognoses, while those lacking the typical histological features, and serum AFP levels < 100 ng/ml had better prognoses. The combination of histological findings and serum AFP level appeared to be useful in predicting the prognosis of AFP-producing gastric cancers. Intensive adjuvant therapy, e.g., chemotherapy administered via hepatic arterial infusion, may be indicated for patients at a high risk of recurrence following curative surgery.

TWO CASES OF AFP-PRODUCING GASTRIC CANCER CONFIRMED IMMUNOHISTOLOGICALLY

Recent development of the radioimmunoassay technique has been enabled to measure the low level of serum alphafetoprotein (AFP). A various kinds of malignant tumors, which show elevated serum AFP except hepatic cell carcinomas and embrionic cancers, have been reported. Those are mainly consisted of gastric cancers and cholangiomas, pancreatic and colorectal cancers have been really reported. Prognosis of AFP-producing gastric cancers is poor, because of rapid growing, and easily metastasis of the liver and lymphnodes. Intensive chemotherapy should be recommended for treatment perioperatively. The measurement of serum AFP level may contribute to make diagnosis and to evaluate therapeutic effects. In this report, we emphasize the importance of strict postoperative follow-up, using regular check of serum AFP, CT scan and ultrasonogram.

FOUR CASES OF ALPHA-FETOPROTEIN PRODUCING GASTRIC CANCER SUGGESTIVE OF MULTIPLE DIFFERENTIATION

Clinical and histological characteristics of alpha-fetoprotein (AFP) producing gastric cancers were studied. Four (3.8%) among 104 cases of gastric cancer experienced in the last eight years were AFP-producing gastric cancer. in addition to AFP, the coexistence of carcinoembryonic antigen, ferritin or carbohydrate antigen 199 were found in the tumor cells by immunohistochemical methods. It is suggested that AFP-producing tumor cells might have an ability to differentiate into various forms. Clinically, most of AFP-producing gastric cancers belonged to Borrmann type 2 or type 3. As they were already markedly advanced and with a high frequency of hepatic metastasis during surgery, the prognosis was very poor. In cases of AFP-producing gastric cancer, serum AFP values were found to show a good correlation with the clinical course. It may be useful in predicting the prognosis such as recurrence or liver metastasis.