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Results for “tumor evolution”

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At least 289 records · Page 16Linked to original sources
PubMed2006

Targeted deletion of MKK4 in cancer cells: a detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss.

Tumor-suppressors have commanded attention due to the selection for their inactivating mutations in human tumors. However, relatively little is understood about the inverse, namely, that tumors do not select for a large proportion of seemingly favorable mutations in tumor-suppressor genes. This could be explained by a detrimental phenotype accruing in a cell type-specific manner to most cells experiencing a biallelic loss. For example, MKK4, a tumor suppressor gene distinguished by a remarkably consistent mutational rate across diverse tumor types and an unusually high rate of loss of heterozygosity, has the surprisingly low rate of genetic inactivation of only approximately 5%. To explore this incongruity, we engineered a somatic gene knockout of MKK4 in human cancer cells. Although the null cells resembled the wild-type cells regarding in vitro viability and proliferation in plastic dishes, there was a marked difference in a more relevant in vivo model of experimental metastasis and tumorigenesis. MKK4(-/-) clones injected i.v. produced fewer lung metastases than syngeneic MKK4-competent cells (P = 0.0034). These findings show how cell type-specific detrimental phenotypes can offer a paradoxical and yet key counterweight to the selective advantage attained by cells as they experiment with genetic null states during tumorigenesis, the resultant balance then determining the observed biallelic mutation rate for a given tumor-suppressor gene.

Animals↗
PubMed1989

[Clinical model concept of the evolution of malignant tumors: implication for hormone therapy of breast cancer].

An analysis is made of current concepts about heterogeneity, instability and autonomy of tumor cells which accounts for the clinical course of incurable, late-stage malignant disease which as such is characterized by a growing independence from growth control mechanisms of the host, by progressive metastatic spread and by unpredictable malignancy associated events. Increasing heterogeneity, instability and autonomy are best demonstrated by the development of resistance phenomena and are potentially reversible processes. This reversibility can be exploited using biological response modifiers. Understanding this triad also helps explain certain clinical phenomena such as qualitative differences in remissions and mixed responses, early vs. late stage disease, and the potential therapeutical hazards which can lead to further tumor heterogeneity. On the breast cancer example further clinical implications are illustrated, namely receptor heterogeneity, autocrine autonomy, and combination therapy with hormones. The concepts discussed are the basis for the development of non-toxic tumor therapies which are aimed less at tumor cell kill than at stabilization.

Breast Neoplasms↗
PubMed2001

Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is detected in ischemic brain cells in experimental animal models and is believed to play an important role in apoptosis. However, the natural expression of TNF-alpha during human stroke is not known. METHODS: We examined TNF-alpha immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in brain samples of stroke victims (n=16) after variable survival (15 hours to 18 days). Systemic TNF-alpha content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed. RESULTS: Neuronal TNF-alpha was demonstrated from 0.6 to 5.4 days after the onset of stroke symptoms, peaking bilaterally during days 2 and 3. Bilateral glial TNF-alpha immunoreactivity was detected during the acute phase, with the astrocytic TNF-alpha expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-alpha immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-alpha levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-alpha staining overlapped, although not completely, during the first days. CONCLUSIONS: The data support the hypothesis that TNF-alpha may be involved both in the acute propagation of inflammatory processes and cell death and possibly in the more delayed reconstitutive processes of human ischemic stroke.

Adult↗
PubMedDate not supplied

Genetic instability and the evolution of angiogenic tumor cell lines (review).

Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established.

Animals↗
PubMedDate not supplied

[Intraventricular glial tumor. in the evolution of Bourneville tuberous sclerosis: ultrastructural study].

Ultrastructural study of an intraventricular tumour in a child with Bourneville tuberose sclerosis showed the presence of marked glial astrocytic proliferation. All the tumour cells were undoubtedly of astrocytic type, as shown by the presence of gliofilaments and beta-type glycogenic particles. They were also characterized by an abundant ergastoplasm of an original type (lamellar stacking of the saccules), a well developed Golgi apparatus, a multitude of mitochondria and numerous dense lysosomic bodies, indicative of metabolic hyperactivity. On the basis of these morphological date, the tumour may be defined as an astrocytoma, the blastic tendency of which cannot be affirmed, other than on the basis of the presence of mitotic figures.

Astrocytoma↗
PubMedDate not supplied

[Evolution of myeloplaxic tumors. Apropos of 21 cases].

21 cases of giant cells tumors were observed. Two were malignant primarily. Twelve cases treated by curetage produced 7 recurrences, one being malignant. Seven cases treated by resection produced no recurrence. The authors believe that the prognosis and the indications are based more on clinical and radiological features than on histologic grading studies.

Adolescent↗
PubMedDate not supplied

An experimental model for oncogene activation during tumor progression in vivo.

Tumor progression usually involves a complex pattern of molecular alterations. In many human tumors oncogene amplification or activation has been associated with advanced stages of cancer. Transfection studies have demonstrated the ability of several cellular oncogenes to induce a more malignant phenotype in transformed cells. We have examined the role of c-myc in tumor progression in rat tracheal cell culture, and in rat skin tumors induced by ionizing radiation. In the latter in vivo model, c-myc amplification was found to occur as a function of tumor size. Serial biopsies of growing tumors confirmed the trend toward increased gene copy number with time and stage of progression. This effect was specific for the c-myc gene, in epithelial tumors. Evidence was found for a role of tumor heterogeneity and evolution of tumor cell subpopulations in determining the oncogene activation profile of individual tumors.

Animals↗
PubMed1988

Unusual evolution of Wilms tumor in a patient with Wiedemann-Beckwith syndrome.

A very unusual case of Wilms tumor in a child with Wiedemann-Beckwith syndrome is presented. The patient had his first metastasis after a disease-free interval longer than three years. Later, he developed spinal epidural involvement. Both data emphasize the oncogenic potential of Wiedemann-Beckwith syndrome in children and support the contention that Wiedemann-Beckwith syndrome worsens the prognosis of Wilms tumor. Patients with Wilms tumor associated to Wiedemann-Beckwith syndrome should receive intensive therapy as well as close and prolonged follow-up in spite of apparent tumor remission.

Antineoplastic Combined Chemotherapy Protocols↗