Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression.
(17/11529)
Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1alpha (IL-1alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1alpha by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1alpha. The short-term expression of IL-1alpha persists in the malignant T cells for a few days (approximately 3-6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1alpha in a short-term manner, manifested reduced tumorigenicity: approximately 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1alpha, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1alpha in activated tumor cells may allow its improved application in the treatment of malignancies. (+info)
Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation.
(18/11529)
Bombesin-like peptides such as gastrin-releasing peptide (GRP) have been shown to play a role in cancer as autocrine growth factors that stimulate tumor growth through specific receptors. To search for potential clinical indications for GRP analogues, it is important to identify human tumor types expressing sufficient amounts of the respective receptors. In the present study, we have evaluated the expression of GRP receptors in human nonneoplastic and neoplastic prostate tissues using in vitro receptor autoradiography on tissue sections with 125I-Tyr4-bombesin as radio-ligand. GRP receptors were detected, often in high density, in 30 of 30 invasive prostatic carcinomas and also in 26 of 26 cases of prostatic intraepithelial proliferative lesions, corresponding mostly to prostatic intraepithelial neoplasias. Well-differentiated carcinomas had a higher receptor density than poorly differentiated ones. Bone metastases of androgen-independent prostate cancers were GRP receptor-positive in 4 of 7 cases. Conversely, GRP receptors were identified in only a few hyperplastic prostates and were localized in very low density in glandular tissue and, focally, in some stromal tissue. In all of the cases, the receptors corresponded to the GRP receptor subtype of bombesin receptors, having high affinity for GRP and bombesin and lower affinity for neuromedin B. These data demonstrate a massive GRP receptor overexpression in prostate tissues that are neoplastically transformed or, like prostatic intraepithelial neoplasias, are in the process of malignant transformation. GRP receptors may be markers for early molecular events in prostate carcinogenesis and useful in differentiating prostate hyperplasia from prostate neoplasia Such data may not only be of biological significance but may also provide a molecular basis for potential clinical applications such as GRP-receptor scintigraphy for early tumor diagnosis, radiotherapy with radiolabeled bombesin-like peptide analogues, and chemotherapy with cytotoxic bombesin analogues. (+info)
Fas/Fas ligand interaction in human colorectal hepatic metastases: A mechanism of hepatocyte destruction to facilitate local tumor invasion.
(19/11529)
This study demonstrates a novel role for the Fas pathway in the promotion of local tumor growth by inducing apoptotic cell death in normal hepatocytes at the tumor margin in colorectal hepatic metastases. Our results show that >85% of lymphocytes infiltrating colorectal liver cancer express high levels of Fas-ligand (Fas-L) by flow cytometry. Using immunohistochemistry of tumor tissue we showed strong Fas expression in noninvolved hepatocytes, whereas Fas-L expression was restricted to tumor cells and infiltrating lymphocytes at the tumor margin. Apoptosis was observed in 45 +/- 13% of the Fas(high) hepatocytes at the tumor margin whereas only 7 +/- 3% tumor cells were apoptotic (n = 10). In vitro, primary human hepatocytes expressed Fas receptor and crosslinking with anti-Fas antibody induced apoptosis in 44 +/- 5% of the cells compared with 4. 6 +/- 1.0% in untreated controls (P = 0.004). Both tumor-infiltrating lymphocytes (TIL) and human metastatic colon cancer cells cells are able to induce Fas-mediated apoptosis of primary human hepatocytes in coculture cytotoxic assays. TIL induced apoptosis in 47 +/- 9% hepatocytes compared with control 4.3 +/- 1. 0% (P = 0.009) and this effect was reduced by anti-human Fas-L mAb (18.7 +/- 1.3%, P = 0.009). SW620 cells induced apoptosis in 26 +/- 2% hepatocytes compared with control 5.6 +/- 1.7% (P = 0.004) and this was reduced to 11.2 +/- 1.8% (P = 0.004) in the presence of anti-human Fas-L mAb. These data suggest that the inflammatory response at the margin of colorectal liver metastases induces Fas expression in surrounding hepatocytes, allowing them to be killed by Fas-L-bearing TIL or tumor cells and facilitating the invasion of the tumor into surrounding liver tissue. (+info)
Histopathologic features and expression of Bcl-2 and p53 proteins in primary gastric lymphomas.
(20/11529)
The aim of this study is to present a histopathologic and immunohistochemical analysis of primary gastric lymphomas which were reclassified according to the concept of mucosa associated lymphoid tissue (MALT). The resected specimens from 41 patients with primary gastric lymphoma were investigated retrospectively. Immunohistochemical study was done to analyze the immunophenotype and bcl-2 and p53 proteins expression. Twenty three of the cases had tumors mainly located in the antrum. Histologically, 12 were low grade and 20 were high grade B-cell lymphoma of MALT, 9 other B-cell nonHodgkin's lymphomas. Helicobacter pylori was identified in 72% of the cases. According to Musshoff's modification, most of the MALT lymphoma cases had stage I or II disease. There was significant difference between low and high grade cases, in respect to depth of invasion in gastric wall. Immunohistochemically, the neoplastic cells in all MALT lymphomas expressed B-cell phenotype. Bcl-2 protein was found to be expressed in 59% and p53 protein expression was detected in 72% of cases. Among the B-cell lymphoma of MALT, bcl-2 positivity decreased and p53 positivity increased significantly as the histological grade advanced. So, an inverse correlation was observed between the expression of bcl-2 and p53. In conclusion, most primary gastric lymphomas are low or high grade B-cell MALT lymphomas and appear to arise in MALT acquired as a reaction to Helicobacter pylori infection. Expression of bcl-2 and p53 in gastric lymphomas may be associated with transformation from low-grade to high-grade disease. (+info)
p53 and p16INK4A mutations during the progression of glomus tumor.
(21/11529)
Glomus tumors are significantly rare tumors of carotid body. The great majority of these tumors are benign in character. Here we present two brothers with hereditary glomus jugulare tumor who had consanguineous parents. Radiotherapy was applied approximately 8 and 10 years ago for treatment in both cases. Eight years later, one of these cases came to our notice due to relapse. The mutation pattern of p53, p57KIP2, p16INK4A and p15NK4B genes which have roles in the cell cycle, was analyzed in tumor samples obtained from the two affected cases in the initial phase and from one of these cases at relapse. The DNA sample obtained from the case in initial diagnosis phase revealed no p53, p57KIP2, p16INK4A or p15INK4B mutation. He is still in remission phase. Despite the lack of p53, p57KIP2, p16INK4A and p15INK4B mutation at initial diagnosis the tumor DNA of the other case in relapse revealed p53 codon 243 (ATG-->ATC; met-->ile) and p16 codon 97 (GAC-->AAC; asp-->asn) missense point mutations. No loss of heterozygosity in p53 and p16INK4A was observed by microsatellite analysis of tumoral tissues in these cases. P53 and p16INK4A mutations observed in relapse phase were in conserved regions of both genes. No previous reports have been published with these mutations in glomus tumor during progression. The mutation observed in this case may due to radiotherapy. In spite of this possibility, the missense point mutations in conserved region of p53 and p16INK4A genes may indicate the role of p53 and p16INK4A in tumor progression of glomus tumors. (+info)
Primary endometrioid carcinoma of fallopian tube. Clinicomorphologic study.
(22/11529)
Twenty cases of primary Fallopian tube endometrioid carcinoma (PFTEC) are presented in the paper. This accounts for 42.5% of all histologic forms of primary Fallopian tube carcinoma (PFTC) found in our Department. The youngest patient was 38, and the oldest 68 years (mean: 56 years). Seven patients were nulliparas. Only two cases were bilateral. According to FIGO staging, 13 cases were evaluated as stage I, 4 as II, and 3 as stage III. Due to the histologic grading, 8 tumors were classified as well, 7 as moderately, and 5 as poorly differentiated. In the time of preparation of the manuscript, 12 women were still alive, 2 of them with recurrent disease. The follow-up of patients without recurrence ranged from 4 to 120 months (median: 63). Eight patients had died (survival time: from 4 to 65 months; median: 26). Metastases were found in 8 patients, especially to ovaries. In 14/20 cases of PFTEC various forms of tubal wall invasion were observed. Blood or lymphatic vessels involvement was found in 9 patients. Six of them had died and one is alive with the symptoms of disease. Immunohistochemical detection of the mutant form of p53 protein and oncogene product, c-erbB-2, was studied in 17 cases. Nine patients exhibited simultaneous p53 protein accumulation and c-erbB-2 expression. 2/9 of these patients are alive with recurrent tumors and 4/9 died. Endometrioid carcinoma of the Fallopian tube can be characterized by a tendency to superficial invasion of tubal wall and in a half of the cases by invasion of vessels. The majority of these tumors were diagnosed at an early stage tumors. (+info)
Role of transforming growth factor-beta 1 in invasion and metastasis in gastric carcinoma.
(23/11529)
PURPOSE: Transforming growth factor-beta1 (TGF-beta1) is a major modulator of cellular proliferation and extracellular matrix formation. We determined the role of TGF-beta1 in invasion and metastasis in gastric cancer. MATERIALS AND METHODS: We detected TGF-beta1 expression in primary and lymph node metastatic lesions of gastric cancer, using an antibody and in situ hybridization. The plasma TGF-beta1 levels in the peripheral vein and in the tumor drainage vein were assayed. RESULTS: In the cytoplasm of cancer cells, TGF- beta1 was immunostained in 35.9% (78 of 217) of primary gastric carcinomas, and this expression was confirmed by in situ hybridization. Of 59 gastric carcinomas with a TGF-beta1-negative primary tumor, metastatic lymph nodes were positive for TGF-beta1 staining in 32 cases (54.2%). Positive staining of TGF-beta1 in gastric cancer tissues was closely related to serosal invasion, infiltrative growth, and lymph node metastasis. Multivariate analysis showed that the expression of TGF-beta1 was an independent risk factor for serosal invasion and infiltrative growth of the tumor. The plasma level of TGF-beta1 did not differ between TGF-beta1-negative and -positive groups. There were also no differences in plasma TGF-beta1 levels among each tumor stage, between the peripheral and the tumor drainage veins, and between preoperative and postoperative testings. CONCLUSION: Transforming growth factor-beta1 is closely related to the invasion and metastasis of gastric cancer, and production of TGF-beta1 in the tumor does not contribute to the total amount of TGF-beta1 in the blood circulation. We interpret our observations to mean that in a tumor microenvironment, TGF-beta1 alters the biologic behavior of the tumor. (+info)
Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility.
(24/11529)
The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed. (+info)