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PubMed1998

[Tyrosine kinase: implications in tumor pathology and therapeutic perspectives].

The tyrosine kinase family includes growth factor receptor and cytoplasmic enzymes. It plays a key role in normal cell division and abnormal cell proliferation and differentiation. The most common tyrosine kinases are the epidermal-growth factor (EGFR) and platelet-derived growth factor (PDGF) receptors, and a chromosome Philadelphia product, the Bcr-abl oncogene. Many studies have attempted to correlate clinical evolution of tumors with tyrosine kinase expression. However, clinical application of these new prognostic factors has not yet been demonstrated. More recently, tyrosine-phosphorylation inhibitors (tryphostin) have been developed in phase I studies. Results that were obtained show some objective responses in patients with glioblastoma and polymetastatic cancer. Another approach to block tyrosine kinase expression is the use of monoclonal antibodies. Trials using such antibodies have shown interesting preliminary results.

Antibodies, Monoclonal↗
PubMed2000

Expression of p16/INK4a in posttransplantation lymphoproliferative disorders.

It was recently demonstrated that classification of posttransplantation lymphoproliferative disorders (PT-LPDs) into morphological and molecular categories is clinically relevant. It was also reported that PT-LPD not associated with Epstein-Barr virus (EBV) had a more aggressive course than most lesions associated with EBV. Because the cyclin-dependent kinase inhibitor p16/INK4a has been reported to be frequently inactivated in high-grade lymphomas, we evaluated 17 PT-LPD to determine whether p16/INK4a expression could be correlated to morphology, EBV detection, and a Ki-67 labeling index. We demonstrated that tumors with no p16/INK4a expression (n = 8) had a predominantly monomorphic appearance, and most were EBV negative (respectively, 7/8 and 5/8), whereas lesions with p16/INK4a expression (n = 9) were mostly polymorphic PT-LPD (6/9) (P = 0.049) and associated with EBV (9/9) (P = 0.015). In particular, strong p16/INK4a expression was observed in atypical immunoblasts and Reed-Sternberg-like cells. Furthermore, the proliferation index was significantly higher in tumors lacking p16/INK4a expression than in other lesions (P = 0.0008). In conclusion, down-regulation of p16/INK4a was mostly observed in PT-LPD lesions known to follow more aggressive courses: monomorphic tumors and EBV-negative PT-neoplasms. Conversely, overexpression of p16/INK4a was associated with EBV-positive PT-LPD. While p16/INK4a might play a role in the proliferative rate of LP-LPD, further investigations are needed to assess the clinical relevance of p16/INK4a expression in predicting the evolution of tumors and to explain how EBV could favor p16/INK4a protein accumulation in lesions.

Adult↗
PubMed1987

Evolution of acute lymphoblastic leukemia in mice treated with carrier-bound methotrexate and levamisole.

The cytotoxic and antitumoral activities of free or bound to bovine serum albumin (BSA) methotrexate (MTX) and the influence of levamisole (LMS) on these were assayed on murine leukemia. Whereas the in vitro cytotoxic action of MTX was reduced by its conjugation to BSA, in vivo a single dose of 15 mg/kg MTX, which lacked therapeutic effect on tumor-bearing mice, increased the mean survival time (MST) of the animals when given as MTX-BSA. Levamisole slightly increased the MST of the tumor-bearing animals when administered as a 10 mg/kg single dose 7 days after the tumor inoculation. We were unable to achieve synergism between LMS and MTX-BSA when measuring MST and the tumor growth evolution.

Animals↗
PubMed2000

Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo.

Women with breast cancer who have responded to initial hormonal therapy frequently experience additional remissions upon further endocrine manipulation. We postulate that hypersensitivity to estradiol (E2) may serve as a mechanistic explanation for these secondary responses. We previously provided evidence of hypersensitivity using an in vitro breast cancer model system and demonstrated the role of mitogen-activated protein kinase (MAP kinase) in the process of adaptation to long-term estradiol deprivation. In the present study, we wished to demonstrate that hypersensitivity to E2 could occur under more complex in vivo conditions and that MAP kinase activation is enhanced under these circumstances. We used an MCF-7 breast cancer model system involving long-term estradiol deprived (LTED) cells to produce xenografts in nude mice and an E2 clamp method to precisely control sex steroid levels. The E2 clamp was designed to maintain plasma E2 at a series of doubling doses from 1.25 pg/ml to 20.0 pg/ml in oophorectomized nude mice. As evidence of the validity of the clamp method, a uterine weight bioassay revealed an excellent, linear dose-response relationship between the predicted level of plasma E2 and stimulation of uterine weight. As evidence of hypersensitivity, we found that LTED xenograft tumors grew to a greater extent than wild-type in response to E2 concentrations of 1.25 pg/ml (P = 0.003) and 2.5 pg/ml (P = 0.0002). At the 10.0 and 20.0 pg/ml plasma concentrations, the LTED tumors were stimulated to a lesser extent than the wild-type. This pattern of increased growth at lower concentrations and reduced growth vs. the wild-type at higher concentrations mimics closely the pattern seen for LTED cells in vitro. All LTED cell tumors exhibited enhanced activation of MAP kinase ranging from 18 to 25%, and E2 did not increase this further. In contrast, E2 caused a linear increase in the percentage of activated MAP kinase positive cells (P < 0.0001) in wild-type tumors from basal levels of 2.66% to maximal levels of 6.40%. These observations suggest a dynamic interplay whereby activation of MAP kinase renders cells more sensitive to the proliferative effects of E2. The precise mechanisms for this interplay are unknown but, when further understood, could potentially provide insight into approaches to prevent the evolution of tumors to a hormone insensitive state.

Animals↗
PubMed2006

Application of two different clones of vimentin to the diagnosis of salivary gland tumors.

With the evolution of IHC techniques, a broad range of antibodies have become available to diagnostic immunohistology. The authors observed different expressions of vimentin in salivary gland tumors using two clones of this antibody. This study was undertaken to show these differences comparing the immunoexpression of two clones of vimentin (V9 and Vim 3B4, DAKO, Carpenteria, CA) using 10 pleomorphic adenomas, 10 adenoid cystic carcinomas, and 4 epithelial/myoepithelial carcinomas of the salivary glands. The V9 clone of vimentin was much more efficient in demonstrating the myoepithelial cells in the different tumors studied. The Vim 3B4 clone was capable of detecting some myoepithelial cells, the plasmacytoid or modified myoepithelial cells in the pleomorphic adenoma, but was very weak in epithelial/-myoepithelial carcinomas. The difference between the two clones studied is a warning that pathologists need to know the specificity and sensitivity of the reagent they are using.

Adenoma↗
PubMed1998

Protection of visual pathway in gamma knife radiosurgery for craniopharyngiomas.

Craniopharyngiomas present a major challenge to Gamma Knife radiosurgery (GKRS) due to their proximity to the optic apparatus. Based on observations of the evolving tumoral change on MRI and clinical results, an optimization of the treatment strategy and dose selection is possible. From March 1993 to September 1996, 21 patients with craniopharyngiomas were treated by GKRS. Every patient received stereotactic MRI exclusively for targeting and dose planning. The tumor and adjacent structures, including optic nerves, chiasm, and tracts were carefully identified and delineated on sagittal, coronal and axial films. The tumor volume ranged from 0.3 to 28 ml (average 9 ml). We purposefully apply multiple isocenters (average 9.1 shots) to create an isodose curve that covered the tumor optimally while sparing the optic pathway. The marginal dose prescribed was 9.5 to 16 Gy (50%). The maximal dose was 19 to 32 Gy. The maximal dose to the optic apparatus was 3.2 to 12.5 Gy. After GKRS, all patients were followed up clinically every month. MR studies were conducted every six months with the same techniques on the same scanner to investigate evolution of tumor volume and any adverse radiation effect. The follow-up period ranged from 6 to 40 months (mean: 18.4, median: 19). All patients were followed more than 6 months. Nineteen out of 21 cases (90.5%) achieved tumor control; that is, 18 tumor shrinkage (volume reduction: 15-95%) and 1 stabilized tumor growth. Among these 21 patients, 7 had improved visual acuity or visual field after GKRS, and the rest remained stable. Two patients developed mild T2 change on MRI without any endocrinological disturbance or visual impairment. Protection of the visual pathway can be secured by a sophisticated delineation on 3-dimensional stereotactic images with multiple-shot dose planning. Craniopharyngiomas with tumor volume up to 25 ml were treated safely and effectively, because the dose to the optic apparatus was kept as low as possiby this strategy. Further follow-up is needed to determine the highest tolerable dose to surrounding critical structures and the long-term outcome of tumor control.

Adolescent↗
PubMed1992

Aging and cancer: plasma antioxidants and lipid peroxidation in young and aged breast cancer patients.

The relationship between aging and cancer is complex because the intrication takes place at the cell, the organism and the environment levels. On the other hand, carcinogenesis is a multi-step process, and different mechanisms may be involved in each step. For example, oxidants and antioxidants may play a different role depending upon the phase considered. Tumors in older patients are generally described as slow growing. The difference in tumor aggressiveness between young and older patients is especially obvious in breast cancer patients. The age specificity of some breast risk factors suggests that breast cancer which has been diagnosed in an aged woman was induced late in her life. We address the question whether the characteristics of a senescent organism with regards to oxidant-antioxidant status could be causally related to the slow evolution of tumors in old patients.

Adenocarcinoma↗
PubMed1998

p53 mediates apoptosis induced by c-Myc activation in hypoxic or gamma irradiated fibroblasts.

Deregulated c-Myc expression leads to a cellular state where proliferation and apoptosis are equally favored depending on the cellular microenvironment. Since the apoptotic sensitivity of many cells is influenced by the status of the p53 tumor suppressor gene, we investigated whether the induction of apoptosis by DNA damage or non-genotoxic stress are also influenced by the p53 status of cells with altered c-Myc activity. Rat-1 fibroblasts expressing a conditional c-Myc allele (c-MycER), were transfected to express an antisense RNA complimentary to p53 mRNA. Expression of antisense p53 RNA decreased p53 protein levels and delayed p53 accumulation following c-Myc activation. Under hypoxic or low serum conditions, cells expressing antisense p53 were substantially more resistant to c-Myc-induced apoptosis than were control cells. c-Myc activation also sensitized Rat-1 cells to radiation-induced apoptosis. Rat-1 cells expressing antisense p53 RNA were more resistant to apoptosis induced by the combined effects of c-Myc activation and gamma irradiation. In a similar manner, apoptosis induced by c-Myc in serum starved, hypoxic or gamma irradiated fibroblasts was also inhibited by Bcl-2. These data indicate that p53 is involved in c-Myc-mediated apoptosis under a variety of stresses which may influence tumor growth, evolution and response to therapy.

Animals↗
PubMed1982

[Congenital intraspinal neuroblastomas. A propos of 7 cases treated surgically].

Neuroblastomas appear to be one of the most frequent congenital solid tumors. Nevertheless, intraspinal congenital neuroblastomas are uncommon. The authors report seven cases of congenital intraspinal neuroblastomas operated on in the "Service de Neurochirurgie des Enfants-Malades" from 1970 to 1980. Their study and that of 16 cases published in the literature allows to stress several points (7, 12). The dumb-bell intraspinal neuroblastomas present a large extension. They usually determine a severe and definitive paraplegia. They probably have a long prenatal evolution. The tumoral prognosis of these congenital neuroblastomas is good. Success should be expected in nearly 80% of the cases. Surgery, in two steps, intra and extra spinal, remains compulsory even though the neurological prognosis is poor. It is useless to operate upon the neuroblastomas as emergencies, when neurological involvement is total at birth. The complementary treatment, X ray-therapy or chemotherapy is not without any danger on newborns. It necessary is not proved.

Female↗
PubMed2006

A stochastic model in tumor growth.

A stochastic model of solid tumor growth based on deterministic Gompertz law is presented. Tumor cells evolution is described by a one-dimensional diffusion process limited by two absorbing boundaries representing healing threshold and patient death (carrying capacity), respectively. Via a numerical approach the first exit time problem is analysed for the process inside the region restricted by the boundaries. The proposed model is also implemented to simulate the effects of a time-dependent therapy. Finally, some numerical results are obtained for the specific case of a parathyroid tumor.

Cell Division↗
PubMed1981

Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms.

The metastatic stability of clones, which were derived from the murine UV-2237 fibrosarcoma and which exhibit low or high metastatic potential, was examined after 60-72 days of continuous growth in vitro and in vivo. Subclones of the high metastatic clone exhibited a 140-fold variation in the production of experimental pulmonary metastases after intravenous injection into syngeneic C3H- mice. In contrast, subclones from the low metastatic clone varied only slightly (8-fold). Using cloned cells from three mouse tumors with differing metastatic potential, we determined the spontaneous mutation rates of cells with low or high metastatic capacities with respect to the selective genetic markers, 6-thiopurine resistance or ouabain resistance, or both. In all cases, cells with high metastatic potential had a 3- to 7-fold increase in the rate of mutation (per cell generation) at both genetic loci, as compared with their low metastatic but tumorigenic cell controls. These results support the hypothesis that the evolution of tumors from the benign to the malignant state could be the consequence of acquired genetic instability in the neoplastic cells.

Animals↗
PubMed1994

Instability of short tandem repeats (microsatellites) in human gliomas.

OBJECTIVE: Microsatellite instability implying multiple replication errors (RER) characterizes a proportion of familial and sporadic carcinomas. The purpose of this report is to analyze whether microsatellite instability occurred during the development of human gliomas. EXPERIMENTAL DESIGN: We checked prospectively 16 central nervous system tumors, including 10 glioblastomas and 6 astrocytomas of different malignancy grades, for genetic microsatellite instability. Fifteen different microsatellites, located on 6 different chromosomes, were investigated. All microsatellites are dinucleotide CA, repeats except for D11S956,P23 (CTAT) and CYP 19, which are tetranucleotide repeats and P23 (GTTTT) which is a pentanucleotide repeat. The repeats were analysed by PCR amplification, followed by electrophoresis on denaturing 6% polyacrylamide gels. MEASURES: We looked for all kinds of microsatellite alterations. Only microsatellite shifts were considered to represent microsatellite instability. RESULTS: Three out of 10 glioblastomas showed mobility shifts on gel electrophoresis in tumor, compared to corresponding normal DNA samples. In contrast, no microsatellite instability was found in any of the astrocytomas. Besides the presence of larger or smaller alleles, an imbalance in the ratio between alleles was noticed in one astrocytoma and in one glioblastoma multiforme. In addition, loss of heterozygosity (LOH) is observed without a fixed pattern in 3 glioblastomas. CONCLUSIONS: We conclude that genetic instability of microsatellites may be demonstrated in high grade gliomas rather than in their low grade precursors and should be regarded as an evolution in tumor progression rather than as a new mechanism for tumor initiation in gliomas.

Astrocytoma↗
PubMed1987

Facilitation of emergence of multidrug-resistant state by alteration of tumor environment: implications from competitive ecology models.

The presence of multidrug-resistant (MDR) cells in a solid tumor constitutes a major problem in cancer therapy. Current thinking suggests that the resistant phenotype arises de novo during the tumor's evolution via somatic mutation mechanisms. The proportion of MDR cells, once established, may be enriched during therapy as a consequence of differential cell kill. Michelson et al have developed mathematical models of these phenomena to gain an insight into the dynamics of clonal subpopulation emergence in general and MDR emergence in particular, and I now show that one unexpected consequence of therapy may be the facilitation of MDR emergence due to damage inflicted on the host. The therapeutic damage to the host is modeled as a decreased ability to carry a specific tumor burden.

Antineoplastic Agents↗
PubMed1995

Sequence of the human invasion-inducing TIAM1 gene, its conservation in evolution and its expression in tumor cell lines of different tissue origin.

By means of proviral tagging in combination with in vitro selection for invasive T-lymphoma variants, we have previously identified the murine invasion- and metastasis-inducing Tiam1 gene. Tiam1 encodes a novel protein which shares a Dbl-homology (DH) domain with GDP dissociation stimulator-(GDS) proteins that activate Rho-like GTPases. We have cloned the human TIAM1 coding sequence and studied its evolutionary conservation and expression pattern. TIAM1 is highly conserved among vertebrates. The close similarity between human TIAM1 and the mouse homologue is indicated by 88% and 95% identity of nucleotides and predicted sequences, respectively. The murine gene is highly expressed in brain and testis and at low or moderate levels in almost all other normal tissues. Interestingly, Tiam1 transcripts were found in virtually all analysed tumor cell lines of human and rodent origin including B- and T-lymphomas, neuroblastomas, melanomas and carcinomas. The evolutionary conservation as well as the broad expression pattern of Tiam1 in most normal tissues, suggests a general function in cellular signaling processes presumably by activation of a Rho-like GTPase that regulates the cytoskeletal organization.

Amino Acid Sequence↗
PubMed2003

Glioblastomatous transformation of ganglioglioma: case report with reference to molecular genetic and flow cytometric analysis.

Gangliogliomas generally behave as benign indolent tumors. However, gangliogliomas undergoing malignant transformation have also been reported. The molecular basis for the malignant transformation of gangliogliomas remains unclear. We describe a case of ganglioglioma, which had transformed to glioblastoma after the gross total resection of the original tumor, in a 4-year-old girl. The present case is unusual in four aspects: (i) it arose from a low-grade ganglioglioma in the absence of previous radiation or chemotherapy, which is the fourth reported case; (ii) the original tumor showed a high proliferative index on flow cytometry but a low Ki-67 labeling index, implying that the application of flow cytometry might play a certain role in predicting biological and clinical behavior of low grade gangliogliomas; (iii) p53 mutation and deletion appeared in the secondary glioblastoma, which was not shown in the original well-differentiated ganglioglioma; and (iv) the transformed glioblastoma showed p16 inactivation detected by methylation and deletion, which are relatively uncommon genetic events in secondary glioblastomas. This is the first report of a genetic alteration in glioblastoma arising from a well differentiated ganglioglioma prior to radiation or chemotherapy. Based on the above findings, irrespective of radiotherapy or chemotherapy, rare recurrence of malignant evolution, especially tumors of high S-phase fraction on flow cytometry, warrants long-term follow-up, even in a well-differentiated ganglioglioma.

Biomarkers, Tumor↗
PubMed1989

Characterization of cell lines derived from a multiply aneuploid human bladder transitional-cell carcinoma, UCRU-BL-13.

A series of cultured cell lines (designated UCRU-BL-13) has been established from different serial passages of a multiply aneuploid human bladder transitional-cell carcinoma xenografted in nude mice. Serial passage of the xenografts in vivo and of the cell lines in vitro was accompanied by shifts in the tumor ploidy, with dominance of different major peaks. Despite this, the expression of tumor markers remained constant, and consistent chromosomal markers were observed both in the 8th xenograft passage and in a subline in tissue culture established over a year apart. Chromosomal numbers reflected the predominant aneuploid peaks observed; consistent numerical and structural changes included a marker derived from chromosome 1, 8p-, -10, 11q+, and 17q+. The cell line derived from the initial xenograft comprised a mixture of transitional, adenocarcinoma and squamous carcinoma cells in early passage, but adenocarcinoma cells were absent from later passages. The lines expressed the B-blood-group antigen, histocompatibility antigens, receptors for transferrin and EGF, and reacted with a series of monoclonal antibodies (MAbs) directed to malignant human epithelial cell lines. These lines provide a model for studying the evolution of tumor heterogeneity and drug resistance in bladder carcinoma exhibiting multiple aneuploidy.

Aneuploidy↗
PubMed1997

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice.

Tumors derived from individuals with hereditary nonpolyposis colorectal cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also frequently exhibit MMR deficiency. In keeping with the role of MMR in the maintenance of genome integrity, mice deficient in MSH2 via gene targeting demonstrate a high incidence of thymic lymphomas and small intestinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lacI reporter gene for mutation detection were crossed with MSH2-/- mice. Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold elevations in spontaneous mutation frequency in DNA obtained from brain, small intestine, and thymus, respectively, as compared to heterozygous or wild-type mice. Mutations most frequently recovered from MSH2-/- mice were single base substitutions (77%), particularly base transitions (64%). Frameshifts occurred less frequently (19%) and fell within very short (3-5 bp) mononucleotide runs. Thus the number of key growth control genes potentially impacted by MMR deficiency extends beyond those containing repetitive sequences. These results highlight the capacity for MSH2 deficiency to serve as a potent driving force during the multi-step evolution of tumors.

Animals↗
PubMed1998

Evolution of immune surveillance and tumor immunity: studies in Xenopus.

We have developed a novel experimental model of cancer immunity in the frog, Xenopus, which may provide a useful alternative to murine tumor models and a way to assess whether the control of tumor development is a fundamental function of the immune system of vertebrates. In Xenopus, tumor immunity can be studied in two developmentally distinct immune systems. The larval immune system reflects characteristics of an ancestral system that appears to function without classical MHC class I antigen presentation and an efficient effector mechanism. The adult system appears more highly evolved in that it is remarkably similar to that of mammals and is able to generate a potent antitumor response. This amphibian model also provides a unique system with which to investigate a postulated role of heat shock proteins as components of an ancestral system of antigen presentation and/or immune surveillance that predates the antigen presentation pathway that exclusively involves MHC molecules.

Animals↗