Lapatinib inhibits the growth of esophageal squamous cell carcinoma and synergistically interacts with 5-fluorouracil in patient-derived xenograft models.

Lapatinib is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) tyrosine kinase domains. To explore the potential utility of lapatinib for the treatment of esophageal squamous cell carcinoma (ESCC), we examined the expression profiles of EGFR and HER2 in tumor tissues and in paired adjacent non-neoplastic tissues from patients with ESCC. We evaluated the antitumor effects of lapatinib alone or in combination with oxaliplatin or 5-fluorouracil (5-FU) on a panel of primary ESCC cells in vitro with various levels of EGFR and HER2 expression. The in vivo effect of lapatinib alone or in combination with oxaliplatin or 5-FU was evaluated using a primary ESCC xenograft model. EGFR was overexpressed in 80.9% (76/94) of the ESCC samples, while 24.5% (23/94) of the samples overexpressed HER2. EGFR and HER2 co-overexpression was detected in 22.3% of samples (21/94). In vitro, the primary ESCC cells were more sensitive to lapatinib combined with 5-FU or oxaliplatin than to lapatinib alone. Lapatinib in combination with 5-FU had more potent antitumor effects in the primary ESCC xenograft model, and markedly reduced the phosphorylation of EGFR and HER2, compared with lapatinib alone or in combination with oxaliplatin. These data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC primary cells, and that lapatinib in combination with 5-FU may be a promising treatment strategy for patients with ESCC.

Loss and reduced expression of PTEN correlate with advanced-stage gastric carcinoma.

Phosphatase and tensin homolog (PTEN) is a tumor suppressor involved in multiple cell processes. To investigate the role of PTEN in the development of gastric carcinoma, we determined the expression pattern of PTEN in primary gastric carcinoma and in paired adjacent non-neoplastic tissue. We also determined the correlation of PTEN expression with clinicopathological characteristics and patient survival. Overall, 159 gastric carcinomas and 151 paired adjacent non-neoplastic tissues were used in the present study. PTEN expression was determined using tissue microarrays and immunohistochemistry. The clinical sensitivity and specificity of PTEN expression were calculated using receiver operator characteristic curves. Results showed that the loss of cytoplasmic PTEN was significantly more frequent in carcinoma tissue compared with adjacent non-neoplastic tissue (62 vs. 5%, respectively; P<0.0001). PTEN expression was markedly downregulated in carcinoma tissues compared with adjacent non-neoplastic tissues. The loss of cytoplasmic PTEN expression was positively correlated with histological stage (P=0.016). The loss of nuclear or total PTEN, and downregulation of total PTEN expression, was significantly different between American Joint Committee on Cancer tumors of stage I and stages II-IV. A low cytoplasmic or total PTEN expression showed high clinical sensitivity and specificity for gastric carcinoma. However, PTEN expression was not significantly associated with overall or 3-year survival rates. The findings of the present study indicated that PTEN expression may be a molecular diagnostic marker for gastric cancer. Thus, the loss or reduced expression of PTEN potentially correlate with advanced stages of gastric carcinoma.

High overexpression of fatty acid synthase is associated with poor survival in Chinese patients with gastric carcinoma.

Fatty acid synthase (FAS) is the key enzyme regulating de novo biosynthesis of fatty acids. FAS overexpression has been found in many types of tumors and is associated with poor survival. However, the expression of FAS and its relationship with prognosis in Chinese patients with gastric carcinoma are still unknown. Therefore, in this study, we examined the expression of FAS using tissue microarrays and determined its correlation with clinicopathological characteristics and prognosis of gastric carcinoma in Chinese patients. FAS overexpression was graded as S (T/A) <1, ≥1 to <2, ≥2 to <3 or ≥3 in 35 (38.9%), 20 (22.2%), 9 (10%) and 26 (28.9%) patients, respectively. High FAS overexpression [S (T/A) ≥3] was significantly correlated with poor prognosis (log-rank test, P= 0.0078) and with decreased 3-year survival rate (χ(2) test, P=0.0023). FAS overexpression was not significantly associated with other clinicopathological characteristics. In conclusion, our results suggest that FAS expression might be a potential prognostic marker for gastric carcinoma in Chinese patients.

Combined phosphatase and tensin homolog (PTEN) loss and fatty acid synthase (FAS) overexpression worsens the prognosis of Chinese patients with hepatocellular carcinoma.

We aimed to investigate the expression pattern of phosphatase and tensin homolog (PTEN), to evaluate the relationship between PTEN expression and clinicopathological characteristics, including fatty acid synthase (FAS) expression, and to determine the correlations of PTEN and FAS expression with survival in Chinese patients with hepatocellular carcinoma (HCC). The expression patterns of PTEN and FAS were determined using tissue microarrays and immunohistochemistry. The expression of PTEN was compared with the clinicopathological characteristics of HCC, including FAS expression. Receiver operator characteristic curves were used to calculate the clinical sensitivity and specificity of PTEN expression. Kaplan-Meier survival curves were constructed to evaluate the correlations of PTEN loss and FAS overexpression with overall survival. We found that the loss of PTEN expression occurred predominantly in the cytoplasm, while FAS was mainly localized to the cytoplasm. Cytoplasmic and total PTEN expression levels were significantly decreased in HCC compared with adjacent non-neoplastic tissue (both, p < 0.0001). Decreased cytoplasmic and total PTEN expression showed significant clinical sensitivity and specificity for HCC (both, p < 0.0001). Downregulation of PTEN in HCC relative to non-neoplastic tissue was significantly correlated with histological grade (p = 0.043 for histological grades I-II versus grade III). Loss of total PTEN was significantly correlated with FAS overexpression (p = 0.014). Loss of PTEN was also associated with poor prognosis of patients with poorly differentiated HCC (p = 0.049). Moreover, loss of PTEN combined with FAS overexpression was associated with significantly worse prognosis compared with other HCC cases (p = 0.011). Our data indicate that PTEN may serve as a potential diagnostic and prognostic marker of HCC. Upregulating PTEN expression and inhibiting FAS expression may offer a novel therapeutic approach for HCC.