[Behavior of the spleen and adrenal glands during the evolution of tumoral grafts in the rat].
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Acid Phosphatase↗
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Results for “tumor evolution”
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The origin and evolution of tumor viruses: implications for leukocyte differentiation and leukemia in man.
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Cell Transformation, Neoplastic↗
[Evolutive ovarian tumor in pregnancy. Difficulties in clinical and histological diagnosis].
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Female↗
[Eliocavography in the study of gynecological tumors. Its evolutive value].
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Female↗
Cysteine proteinases in tumor cell growth and apoptosis.
During their evolution tumor cells acquire and mobilize various mechanisms that crucially affect their capability of proliferation, invasiveness and metastasis. Recent findings provide evidence that tumor cell associated cysteine proteinases such as some lysosomal cathepsins and apoptotic caspases are fundamentally involved in specific developmental traits of tumor cell populations. Tumor cell exterior-associated cysteine cathepsins B and L promote tumor growth, invasion and metastasis through degradation of extracellular connective matrices and through endothelial cell growth-directed activities. On the other hand, caspases -3, -7 and -6, generated in tumor cell cytoplasm via a robust activation of their zymogens, suppress tumor cell growth, invasion and metastasis through proteolytic devitalizing and remodeling of tumor cells into readily phagocytable apoptotic corpses. Tumor cell variants that are deficient in expression of effector caspase zymogens or are capable to suppress the extrinsic and intrinsic activation mechanisms of effector caspase zymogens and the activity of effector caspases have a significant survival advantage in environments of various death stimuli. Advancements in pharmacological targeting of tumor associated pathogenic lysosomal cysteine cathepsins and in apoptotic caspases-oriented conditioning of tumor cells may substantially contribute to therapeutic control of tumor diseases.
Animals↗
A changing paradigm of glioma biology.
The past 30 years have witnessed a major paradigm shift in brain tumor research with the development of a wide variety of molecular biology techniques. These methods have permitted a better understanding of the pathogenesis of gliomas including the finding of neural stem cells that contribute to the establishment and continuous population of brain tumors. Molecular biology has contributed to our understanding of prognosis in these tumors with findings of genetic correlations to patient age, response to treatment, and outcome. Gene therapy has been made possible by molecular techniques that contribute to new treatment options. Nevertheless, if these advances are to make substantial clinical improvements, attention must be paid to issues of tumor evolution, local versus general pathogenesis, tumor heterogeneity, both general and regional, and the development of resistance to treatment. Appropriate clinical trials will be needed to test these new findings.
Brain Neoplasms↗
Genetic heterogeneity in ductal carcinoma of the breast.
Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones.
Breast Neoplasms↗
Selective inactivation of p53 facilitates mouse epithelial tumor progression without chromosomal instability.
We examined the selective pressure for, and the impact of, p53 inactivation during epithelial tumor evolution in a transgenic brain tumor model. In TgT(121) mice, cell-specific inactivation of the pRb pathway in brain choroid plexus epithelium initiates tumorigenesis and induces p53-dependent apoptosis. We previously showed that p53 deficiency accelerates tumor growth due to diminished apoptosis. Here we show that in a p53(+/-) background, slow-growing dysplastic tissue undergoes clonal progression to solid angiogenic tumors in all animals. p53 is inactivated in all progressed tumors, with loss of the wild-type allele occurring in 90% of tumors. Moreover, similar progression occurs in 38% of TgT(121)p53(+/+) mice, also with loss of at least one p53 allele and inactivation of p53. Thus, the selective pressure for p53 inactivation, likely based on its apoptotic function, is high. Yet, in all cases, p53 inactivation correlates with progression beyond apoptosis reduction, from dysplasia to solid vascularized tumors. Hence, p53 suppresses tumor progression in this tissue by multiple mechanisms. Previous studies of fibroblasts and hematopoietic cells show that p53 deficiency can be associated with chromosomal instability, a mechanism that may drive tumor progression. To determine whether genomic gains or losses are present in tumors that progress in the absence of p53, we performed comparative genomic hybridization analysis. Surprisingly, the only detectable chromosomal imbalance was partial or complete loss of chromosome 11, which harbors the p53 gene and is thus the selected event. Flow cytometry confirmed that the majority of tumor cells were diploid. These studies indicate that loss of p53 function is frequent under natural selective pressures and furthermore that p53 loss can facilitate epithelial tumor progression by a mechanism in addition to apoptosis reduction and distinct from chromosomal instability.
Animals↗
[Cellular immunity in an experimental ascites tumor: tumor immunostimulation mediated by splenic lymphocytic cells].
The authors consider three successive phenomena in the experimental Ca H tumor evolution. A first stage of tumor resistance due to cytotoxic cells in the presence of some suppressor cells; a second stage when suppressor activity is predominantly observed, and a final stage of lymphocyte-mediated immunostimulation. Vasodilatation and angiogenesis are probably important during third stage.
Animals↗
Testicular seminomas are aneuploid tumors.
BACKGROUND: Distinct ploidy patterns of germ cell tumors and aneuploidy of classic seminoma are of central importance in a current concept designating seminoma as a stage in tumor evolution preceding all nonseminomatous germ cell tumors. Whereas cytogenetic studies almost constantly revealed numerical chromosomal aberrations in seminomas in line with this pathogenetic model, ploidy determination by DNA cytometry yielded highly controversial results on the frequency of diploid seminomas. EXPERIMENTAL DESIGN: Twenty-two classic seminomas were investigated in a comparative manner by DNA flow and DNA image cytometry on nuclei isolated from fresh as well as formalin-fixed tumors. The cellular composition of the tumors, i.e., the number of neoplastic, interstitial, and lymphoid cells was quantified in each case. RESULTS: Irrespective of the tissue preparation and fixation method, all of the tumors that were analyzed were aneuploid by image cytometry. Diploid cases were only found by flow cytometry. Thus, 1/22 cases from paraffin-embedded and 4/11 cases of native tumors showed a single diploid stemline by flow cytometry, however, they exhibited aneuploidy by image cytometry. The quantity of tumor infiltrating lymphocytes was clearly correlated with false diploidy detected by flow cytometry. CONCLUSIONS: Classic testicular seminomas are aneuploid tumors. Previous reports on diploid cases detected by flow cytometry have most likely been caused by extensive lymphocytic infiltration.
Aneuploidy↗
[Long-term effects on recurrence and mortality in superficial urothelioma of the bladder treated with endovesical chemotherapy].
BACKGROUND: To evaluate as the natural history of superficial bladder tumors is modified by intravesical chemotherapy and if the behavior of treated tumors allows to forecast subsequent tumoral evolution. METHODS: 125 patients with superficial bladder tumor Ta and T1 were submitted to transurethral resection (TURB) and additional chemotherapy for one year. Mean follow-up was of 92.2 +/- 39.8 months and all patients were observed for four years at least. RESULTS: Efficacy of treatment was according to the literature: the median of recurrence was estimated about the 10th year (increase of free interval); the percentage of patients free from recurrence after 14 years of follow-up was 35 +/- 19.9, instead that of specific survival was 87.1 +/- 11.8 (inefficacy in a long period); the percentage of tumor related deaths was of 10.4 (inefficacy to avoid the progression). Regarding the risk factors present on the beginning, there was a significance for the T1 that relapsed in the 56.6% versus the 30.9% of the Ta (p = 0.012) and for the multiple tumors that relapsed in the 64.4% versus the 38.7% of the single one (p = 0.009). Also the time and the T category of the first recurrence were interesting factors for the subsequent evolution of disease. In fact, in the 47 patients at beginning T1 that relapsed, there was a 43.4% of tumor related deaths if the recurrence occurred in the first year of follow-up, versus the 12.5% if the recurrence occurred after the first year (p = 0.017). Furthermore the 61.9% of patients "non Ta" (T1 or Tis) to the first recurrence died for tumor but no one if the first recurrence was Ta (p = 0.000). CONCLUSIONS: Intravesical chemotherapy is still reliable. It is able to increase the free interval of recurrence after TURB. Moreover it can offer a useful criterion to recognize patients with chemoresistant tumors at higher risk of progression.
Administration, Intravesical↗
Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.
Animals↗
Lessons from past experience in cancer immunotherapy and their application to cancer and AIDS treatment and prophylaxis.
Passive immunotherapy which we attempted in 1957 using polyclonal antibodies from immunized donors aggravated tumor evolution: we suspected that blocking by Ig, tumor cell antigen epitopes which are necessary to enhance or even maintain the T-lymphocyte effector role in anti-cancer immunity could be the reason for this tumor aggravation by "specific" antibodies. Today the very limited results of monoclonal antibodies in cancer treatment favors this hypothesis. The aggravation of HIV by (some) antibodies suggests that the same phenomenon may also happen in this condition. In 1957, on the other hand, we described the therapeutically beneficial cytostatic targetting effect of polyclonal antibodies, an effect which has often been quoted and widely confirmed. Does the reason for the poor results of monoclonal antibody targetting in tumor treatment reside in cancer antigen heterogeneity? This is what an experiment we conducted with Olsson on AkR leukemia indicated, suggesting that several monoclonals should be simultaneously combined for most patients, to be determined by the antigenic study not only of each tumor but of each localisation. We shifted our cancer immunotherapy approach to an adoptive form in 1959; a), after establishing partial and transient, then total and permanent allogeneic marrow graft and chimerism in man; b), after describing the graft versus leukemia (GvL) action of the graft versus host (GvH) effect in leukaemic mice; c), and the same phenomenon in humans. Our observations on human allogeneic grafted bone marrow GvH and GvL were statistically confirmed in 1979 by the Seattle group. In the 1970s we attempted to induce strong GvL with weak GvH by replacing allogeneic bone marrow graft by allogeneic lymphocyte transfusions without host conditioning. Remarkable results were registered in mice, and in patients with acute leukaemia--5 complete remissions out of 7 patients who developed moderate GvH, and only 3 out of 70 in those who did not develop GvH. As we now know that CD4-, CD8+ lymphocytes are not all MHCl-restricted, we consider that the allogeneic CTL approach is worth trying as reinforcement treatment of (at least) severe hematopoietic malignancies. If it is indeed worthwhile in some severe neoplasias to include the adoptive form of immunotherapy in the multi-treatment program, the replacement of the patient's bone marrow by engrafted allogeneic stem cells has not been proven necessary, as the persistence in "ALL cured" chemotherapy patients of abnormally differentiated cells does not reduce the expectancy of cure.(ABSTRACT TRUNCATED AT 400 WORDS)
Acquired Immunodeficiency Syndrome↗
[Cancer-related bone pain in children].
Pain often discloses the existence of bone tumors in children. The complex physiopathology of pain in malignant bone tumors remains largely unknown and is currently investigated. Cancer-related bone pain is independent from the type and the location of the tumor, and from the number and size of the malignant lesions. It does not necessarily increase with tumor growth. Pain, which is the most common early symptom of bone cancer, may also be present at every step of the disease. It may arise from postsurgery injury, side effects of chemo- or radiotherapy, tumor evolution, secondary sequels of treatments, phantom pain. Tumor eradication using cancer therapeutic strategies is the major etiological treatment option for bone cancer pain. Symptom control requires multidisciplinary medical management with drugs effective against bone lysis, analgesics, drugs with anti-neuropathic activity, as well as non-pharmacological techniques and psycho-social management. This psycho-social management must be tailored to the specific needs of teenagers who are particularly prone to this pathological manifestation. Measures to prevent the occurrence of residual chronic pain must be implemented, whereas children and their family should be clearly informed of the risks and of analgesic options available.
Analgesics↗
[Neoplasm of the ovary as a cause of hyperamylasemia].
A case of hyperamylasemia produced outside the pancreas and of exceptional origin, is presented. The place of origin is an ovarian carcinoma whose first manifestation was acute abdominal pain. The blood level of amylase was slightly increased mainly in its salivary fraction detected by the chromogenic/inhibition technique. This level, followed the tumor evolution and decreased in parallel to the tumor's response treatment.
Aged↗
Utility and limits of an imaging follow-up in evaluation of response and evolution of cerebral tumors after radiotherapy.
CT scans of 110 patients with malignant gliomas treated with radiotherapy, postoperative or alone, were reviewed. Our aim was to assess the utility and limits of an imaging follow-up in evaluating tumor response to treatment and evolution. We have tried to define the densitometric parameters of tumors in various evolutive phases, with special emphasis on variations of contrast enhancement during time. CT scan findings were compared with clinical and therapeutic data.
Brain Neoplasms↗
Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.
UNLABELLED: Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. SIGNIFICANCE: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related commentary by Korsah, p. 1979.
Humans↗
Altered RB expression is a prognostic clinical marker involved in human bladder tumorigenesis.
We are now beginning to understand the development of bladder cancer at the molecular level. Tumor evolution involves the interaction of both oncogenes and tumor suppressor genes. One of the key tumor suppressor genes in this process is the retinoblastoma (RB) gene. Much has been learned recently about the role of this gene in the tumor progression and prognosis of bladder cancer, although several questions are still unanswered. The progress made on this subject in our laboratory as well as others will be the focus of this report.
Biomarkers, Tumor↗