Prognostic value of overexpression of p53 in human ovarian carcinoma patients receiving cisplatin

A major obstacle to the treatment of ovarian carcinoma is intrinsic/acquired resistance to cisplatin-based chemotherapy. The clinical significance of p53 overexpression in patients with ovarian carcinoma is still controversial. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with ovarian carcinoma who are treated with cisplatin. We retrospectively examined the overexpression of p53 in primary ovarian carcinoma, and its association with chemotherapeutic efficacy. One hundred and thirty four ovarian carcinomas were surgically removed from patients who received adjuvant cisplatin-based chemotherapy. Immunohistochemical analysis of p53 was performed using a DO7 antibody against the p53 protein in 134 ovarian carcinomas. The significance of p53 in the prognosis of patients with ovarian carcinomas was also examined by a survival analysis of mortality follow-up data covering the period from 1988 to 2001. Thirty-three tumors (25%) exhibited p53 overexpression. Overexpression of p53 in grade 2/grade 3 tumors was significantly higher than that seen in grade 1 tumors (P=0.0088, 0.0229). Patients with tumors who also showed overexpression of p53 had a significantly inferior response to chemotherapy compared with the patients with p53-negative tumors (P=0.04). Cox regression analysis revealed that p53 overexpression was prognostic for poor disease outcome after adjustment for FIGO stage, grade and residual tumor. These findings suggest that overexpression of p53 in ovarian carcinoma is associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, detection of p53 overexpression using the DO7 antibody may be considered as a predictive marker of chemoresistance for cisplatin in patients with ovarian carcinoma.     

Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer

Heat shock proteins (Hsp) 70 and Hsp 40 are stress proteins that cooperate as chaperones in mammalian cells. We determined the expression of Hsp 70 and Hsp 40 in 81 gastric cancers. Immunoreactivities to Hsp 70 and Hsp 40 were detected in 67.9 and 22.2% of tumors, respectively. Immunohistochemical analysis showed enhanced Hsp 70 and Hsp 40 expression in gastric tumor tissue, relative to the surrounding normal tissue. Overexpression of Hsp 70 and Hsp 40 was also confirmed by immunoblotting. Among various clinicopathological parameters, low histopathological differentiation was associated with reduced expression of both proteins.     

A case of para-aortic lymph node recurrence of gallbladder cancer completely responding to single drug (UFT) chemotherapy

A 67-year-old man with gallbladder cancer was treated by cholecystectomy and extrahepatic bile duct resection with regional lymph node dissection. At 10 months after surgery, CT demonstrated para-aortic lymph node recurrence. Single drug chemotherapy of UFT at 400 mg was started. After one month, the lymph node recurrence could not be detected by CT. UFT may be the primary candidate for chemotherapy for lymph node recurrence of gallbladder cancer.     

Alpha6beta1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells

ErbB2 and alpha6 integrin have been implicated in malignancy of breast cancer cells. Here we have determined the influence of alpha6beta1 integrin on erbB2 signaling in anchorage-independent growth, using MDA-MB435 breast cancer cells. Firstly, we transfected the cells with erbB2 cDNA, and isolated cells with high or low levels of alpha6beta1 integrin by cell sorting (alpha6H-ErbB and alpha6L-ErbB). We found that an erbB ligand, heregulin beta1, enhanced growth activity of alpha6L-ErbB cells, but not alpha6H-ErbB cells. Secondly, we established cells expressing a beta4 integrin deletion mutant (beta4-deltacyt), which selectively inhibited alpha6beta1 integrin expression and adhesion to laminin-1. Again, heregulin beta1 enhanced the growth of erbB2 cDNA-transfected beta4-deltacyt cells, but not mock cells. Western blot analysis revealed that heregulin beta1 stimulated phosphorylation of Akt and its downstream molecules, GSK3beta and p70S6kinase, and that the extent of phosphorylation was greater in ErbB2/beta4-deltacyt cells than ErbB2/mock cells. Furthermore, we found that the erbB2 cytoplasmic domain was truncated in ErbB2/mock cells, which was independent of ligand stimulation and adhesion, and was suppressed by proteasome inhibitors. These results suggest that alpha6beta1 integrin inhibits erbB2 signals by inducing proteasome-dependent proteolytic cleavage of the erbB2 cytoplasmic domain, and may thereby contribute to the regulation of tumor growth.     

Antitumor effect by interleukin-11 receptor alpha-locus chemokine/CCL27, introduced into tumor cells through a recombinant adenovirus vector

In this study, we examined antitumor activity of a mouse CC chemokine ILC/CCL27 and a mouse CX(3)C chemokine fractalkine/CX(3)CL1 in vivo. We generated recombinant adenovirus vectors with a fiber mutation, encoding mILC (Ad-RGD-mILC) and mFKN (Ad-RGD-mFKN). We confirmed tumor cells infected with Ad-RGD-mILC and Ad-RGD-mFKN to express and release these chemokines. Tumor rejection experiments in vivo were carried out by inoculating OV-HM cells infected with Ad-RGD-mILC or Ad-RGD-mFKN into immunocompetent mice. mILC significantly suppressed the tumor growth, whereas no such significant effect was observed by mFKN. The antitumor activity induced by mILC was T cell dependent, involving both CD4(+) and CD8(+) T cells. Immunohistochemical analysis revealed accumulation of both CD3(+) lymphocytes and NK cells in the tumor tissue transduced with mILC and mFKN. However, there was a significant difference in the distribution of infiltrating cells. Furthermore, mFKN appeared to have an angiogenic activity, which might have masked its tumor suppressive activity. Collectively, ILC/CCL27 may be a good candidate molecule for cancer gene therapy.     

A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer

Alterations of the HER-2 (erbB-2/neu) proto-oncogene have been associated with carcinogenesis and poor prognosis of certain cancers. A single nucleotide polymorphism (Ile/Val, A/G) in the transmembrane domain was reported to be associated with a risk of breast cancer. In our study, we examined the association between the HER-2 polymorphism and gastric carcinoma. The Ile/Ile, Ile/Val and Val/Val genotypes were found in 146 (68.9%), 56 (26.4%) and 10 (4.7%) of 212 gastric cancer patients and in 234 (81.5%), 48 (16.7%) and 5 (1.8%) of 287 control subjects, respectively. The Ile/Val or Val/Val genotype was significantly more frequent in patients than in controls (p = 0.005 and 0.033, respectively). The OR of Val/Val genotype then revealed a significantly enhanced risk of 3.25 (95% CI 1.09-9.70) compared to Ile/Ile genotype; heterozygous Ile/Val genotype showed an intermediate risk of 1.97 (1.27-3.06). In patients, carcinomas of advanced stage were significantly more frequent in patients with Ile/Val or Val/Val genotype than those with Ile/Ile genotype (p < 0.001). The logistic regression analysis for tumor invasion, lymph node metastasis and distant metastasis revealed that lymph node metastasis was most closely associated with the HER-2 genotype. These results suggest that this nucleotide polymorphism in the transmembrane domain-coding region of HER-2 could be associated with development of gastric carcinoma and may serve as a predictor of risk for a malignant phenotype of gastric cancer. The association of HER-2 genotype with clinicopathologic characteristics of gastric cancer was also suggested, which has to be confirmed with a larger sample size.     

Identification of the antigens predominantly reacted with serum from patients with hepatocellular carcinoma

BACKGROUND: To identify antigens specifically recognized by the immune surveillance system in patients with hepatocellular carcinoma (HCC), the authors examined two complementary DNA (cDNA) libraries of moderately differentiated HCC by serologic analysis of recombinant cDNA expression libraries (SEREX). METHODS: The libraries were screened with autologous patients' sera, and sequences of the reacted clones were determined. To study the immunoreactivity of the antigens, sera from 20 patients with HCC, from 20 healthy volunteers, and from 16 patients with chronic viral hepatitis were examined. RESULTS: Twenty-seven antigens were identified. They included SART1, p57Kip2, ROCK-1, gamma-catenin, and heat shock proteins, which are classified as tumor-associated genes. Three of 27 antigens-Tat-binding protein-1 (TBP-1), beta4 integrin-binding protein (p27[BBP]), and ribosomal protein L30 (rpL30)-were reacted predominantly with sera from patients with HCC (55% of patients, 45% of patients, and 20% of patients, respectively). Patients in the control group had no antibodies against these three antigens. Seventy percent of patients with HCC had the antibody against at least one of these antigens. CONCLUSIONS: Disease specific humoral immune response against TBP-1, p27(BBP), and rpL30 was induced in patients with HCC, and the antibodies against these antigens also may be used as tumor markers.     

Characteristics of normal stromal components and their correlation with cancer occurrence in human prostate

Prostate cancer is one of the most common age-related malignancies. The occurrence frequency of prostate cancer is very different according to prostate zones. The prostate stroma is an important element in growth and differentiation of the normal prostate and also has a close relationship to the occurrence of benign prostatic hypertrophy and cancer. We examined 14 cases of normal prostate tissues obtained at autopsy and 11 cases of prostate cancer tissues at radical prostatectomy specimens with cancers for clarifying the characteristics of stromal components in the normal prostate and the correlation between the stroma and the occurrence of prostate cancers. Stromal cells, such as smooth muscle cells, myofibroblasts and fibroblasts were identified by immunohistochemistry (IHC). Connective tissue fibers were detected by Elastica van Gieson and also IHC stain. Quantitative analysis of the smooth muscle tissue and connective tissue fibers were performed using a computer image analyzer system. In the normal prostate, stromal components varied in each zone. Every zone of the prostate contained smooth muscle cells, myofibroblasts, fibroblasts and collagen fibers. Elastic fibers were clearly visible in the transition zone. Smooth muscle cells were the main stromal component but less numerous in the frequent occurrence zone (peripheral zone) of prostate cancer (p<0.05). Myofibroblasts and fibroblasts were found either in normal or cancer tissues, although a few in number. The increase of collagen fibers accompanied decrease of smooth muscle cells as prostate cancer grade increased (p<0.05). The characteristics of stromal components and their amounts in the normal prostate appear to correlate with a distinct predilection for cancer occurrence in the peripheral zone and a weak stromal reaction in prostate cancers.     

Vasorelaxant activity of caffeic acid derivatives from Cichorium intybus and Equisetum arvense

The vasorelaxant activities of chicoric acid (Compound 1) from Cichorium intybus and dicaffeoyl-meso-tartaric acid (Compound 2) from Equisetum arvense L. in isolated rat aorta strips were studied. Compound 1 is a diester composed of (S,S)-tartaric acid and caffeic acid, and 2 is composed of its meso type. Both 1 and 2 showed slow relaxation activity against norepinephrine (NE)-induced contraction of rat aorta with/without endothelium. These compounds did not affect contraction induced by a high concentration of potassium (60 mM K+), while they inhibited NE-induced vasocontraction in the presence of nicardipine. These results show that the inhibition by 1 and 2 of NE-induced vasocontraction is due to a decrease in calcium influx from the extracellular space caused by NE. In addition, dicaffeoyl tartaric acids showed vasorelaxant activity, regardless of their stereochemistry.     

CD34-positive stromal cells in primary lung carcinomas

To investigate the phenotypes of stromal cells in primary lung carcinomas, we examined the distribution of CD34-positive stromal cells in primary lung carcinomas, with special reference to histological types. In total 26 surgically resected primary lung carcinomas (13 adenocarcinomas, 10 squamous cell carcinomas, 2 large cell carcinomas, and 1 small cell carcinoma and their normal tissues were examined. CD34-positive stromal cells were observed in connective tissue adjacent to the bronchiolar and bronchial epithelium in normal lung tissues. Nine of the 13 adenocarcinomas had CD34-positive stromal cells in the tumor stroma, whereas none of the other histological type tumors examined had CD34-positive stromal cells. These results suggest that CD34-positive stromal cells are specific in the stroma of primary lung adenocarcinomas, and there is a possibility that CD34-positive stromal cells may play a supportive role in primary lung adenocarcinomas.