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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Senescence of the lympho-haemopoietic system is associated with an increased incidence of neoplasia, autoimmune diseases and infections. Myelosuppression, either in the context of cancer chemotherapy or in the face of severe infections, commonly manifests as pancytopenia, and has an adverse impact on the prognosis of the elderly cancer patient by increasing infection and bleeding-related morbidity. The physiological basis of this blunted haemopoietic response is unclear, and has been ascribed to age-related deficits in marrow progenitor cell numbers, changes in the marrow microenvironment, decreased production of regulatory growth factors, or a combination of these mechanisms. These age-related deficits tend to be subtle and are only of clinical importance either when present cumulatively or under conditions of extreme haemopoietic stress. Furthermore, some of these deficits can be circumvented with the use of haemopoietic growth factors (HGFs). Thus, the availability in the clinic of various HGFs has had a tremendous impact on the care of the elderly cancer patient. The HGFs currently approved for use are: granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and epoetin-alpha (recombinant human erythropoietin). However, we still need to better elucidate age-related changes in the early stages of haemopoiesis. The question of haemopoietic exhaustion, particularly under prolonged growth factor stimulation, is real and still unanswered.
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PMID:Aging and haemopoiesis. Implications for treatment with haemopoietic growth factors. 881 84

Aged persons frequently manifest declining parameters of those immune functions which protect the young against disease. Longitudinal studies are beginning to show that number, type and function of T cells may be associated with longevity, morbidity and mortality in free-living elderly humans. Multi-faceted alterations in the ability of T cells from old donors to respond to stimulation are being dissected, and pathways which are compromized in the elderly compared to the young are being defined. Successful immune responses depend upon waves of rapid and extensive clonal expansion to combat primary infection, followed by death of most T cells, survival of memory cells and their later reactivation and further expansion. This implies that the finite replicative potential of T cells might impose a critical limiting factor on the maintenance of immune responses in the face of thymic involution and drastically reduced capacity to generate new naive T cells. This type of 'clonal exhaustion' can readily be studied in vitro using human T cell clones and the findings can be applied to the in vivo situation. Understanding the processes of replicative senescence in such in vitro models may shed light not only on some of the underlying mechanisms of immunosenescence but also in situations of chronic antigenic stimulation in vivo. Moreover, it might begin to indicate how the system could be manipulated on the one hand to prevent or reverse T cell senescence without nullifying the control mechanisms of tumor suppression, and on the other hand, to reconstitute possibly faulty suppression, for example in autoimmune disease.
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PMID:The T cell in the ageing individual. 908 69

One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen. An explanation for this phenomenon could be that different T cell clones react to the normal graft and the malignant cells, respectively, and only the tumor-reactive clonotypes may be affected by the growing tumor. To test this hypothesis, we used a T cell receptor transgenic mouse in which essentially all CD8(+) T cells are specific for a closely related set of self-peptides presented on the MHC class I molecule Ld. We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected. Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected. Therefore, systemic T cell exhaustion or anergy was not responsible for the growth of the antigenic cancer cells. Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established. Thus, the failure of established tumors to attract and activate tumor-specific T cells at the tumor site may be a major obstacle for preventive or therapeutic vaccination against antigenic cancer.
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PMID:Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. 922 52

Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21(CIP1/WAF1)-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.
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PMID:Sonic hedgehog opposes epithelial cell cycle arrest. 1050 56

Fatigue is a frequent symptom in tumor patients. Although the phenomenon is well known, there is no homogeneous definition. Decreased quality of life, exhaustion, fatiguability, tiredness, malaise and asthenia are synonymous or overlapping terms used for this syndrome. Validated fatigue questionnaires show that fatigue and exhaustion are present in at least 75% of all tumor patients. Fatigue and exhaustion are enhanced by chemo-, radiation- and immunotherapy as well as surgery. Fatigue in tumor patients has many reasons and comprises physical, mental and emotional facets. The expression exhaustion should be applied for physical fatigue in order to differentiate this form from mental or emotional fatigue. Tumor anemia, atrophy of the skeleton muscles and tumor cachexia are the decisive factors for exhaustion. Treatment of fatigue improves quality of life in tumor patients and enhances their compliance. This paper gives an overview about the different types of fatigue and demonstrates various forms of treatment.
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PMID:[Fatigue and exhaustion in tumor patients. Etiology, diagnosis and treatment possibilities]. 1114 41

The significant factors of risk for bone marrow involvement in Hodgkin's disease included age over 40 yrs, such unfavorable histological features as lymphoid exhaustion and nodular sclerosing stage II, symptoms of intoxication, an ESR of more than 50 mm/h, increased fibrinogen (> 5.0 g/l), blood-plasma alkaline phosphatase (> 130 units), leukocyte concentration (> 10,000 per min) and decreased hemoglobulin (< 100 g/l). Despite the reliable correlation between bone marrow involvement and said factors, relevant data did not provide a similarly reliable basis for accurate prognosis of tumor dissemination. However, our findings pointed to two categories of Hodgkin's disease patients characterized by minimal risk of tumor dissemination--patients under 20, with stage I-II AB and IIIA tumors,--and patients with similar tumors and such favorable histological patterns of major pathology as high lymphocytic ratio and nodular sclerosing stage I.
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PMID:[Risk factors for bone marrow involvement in Hodgkin's disease]. 1131 33

Antagonistic pleiotropy, the evolutionary theory of senescence, posits that age related somatic decline is the inevitable late-life by-product of adaptations that increase fitness in early life. That concept, coupled with recent findings in oncology and gerontology, provides the foundation for an integrative theory of vertebrate senescence that reconciles aspects of the 'accumulated damage' 'metabolic rate', and 'oxidative stress' models. We hypothesize that (1) in vertebrates, a telomeric fail-safe inhibits tumor formation by limiting cellular proliferation. (2) The same system results in the progressive degradation of tissue function with age. (3) These patterns are manifestations of an evolved antagonistic pleiotropy in which extrinsic causes of mortality favor a species-optimal balance between tumor suppression and tissue repair. (4) With that trade-off as a fundamental constraint, selection adjusts telomere lengths--longer telomeres increasing the capacity for repair, shorter telomeres increasing tumor resistance. (5) In environments where extrinsically induced mortality is frequent, selection against senescence is comparatively weak as few individuals live long enough to suffer a substantial phenotypic decline. The weaker the selection against senescence, the further the optimal balance point moves toward shorter telomeres and increased tumor suppression. The stronger the selection against senescence, the farther the optimal balance point moves toward longer telomeres, increasing the capacity for tissue repair, slowing senescence and elevating tumor risks. (6) In iteroparous organisms selection tends to co-ordinate rates of senescence between tissues, such that no one organ generally limits life-span. A subsidiary hypothesis argues that senescent decline is the combined effect of (1) uncompensated cellular attrition and (2) increasing histological entropy. Entropy increases due to a loss of the intra-tissue positional information that normally regulates cell fate and function. Informational loss is subject to positive feedback, producing the ever-accelerating pattern of senescence characteristic of iteroparous vertebrates. Though telomere erosion begins early in development, the onset of senescence should, on average, be deferred to the species-typical age of first reproduction, the balance point at which selection on this trade-off should allow exhaustion of replicative capacity to overtake some cell lines. We observe that captive-rodent breeding protocols, designed to increase reproductive output, simultaneously exert strong selection against reproductive senescence and virtually eliminate selection that would otherwise favor tumor suppression. This appears to have greatly elongated the telomeres of laboratory mice. With their telomeric failsafe effectively disabled, these animals are unreliable models of normal senescence and tumor formation. Safety tests employing these animals likely overestimate cancer risks and underestimate tissue damage and consequent accelerated senescence.
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PMID:The reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair. 1190 79

Cellular senescence or replicative senescence is a state of irreversible growth arrest that somatic cells enter as a result of replicative exhaustion. This can be mimicked by culture manipulations such as Ras oncogene overexpression or treatment with various agents such as sodium butyrate and 5-azacytidine. It is believed that cellular senescence is one of the protective mechanisms against tumor formation. Genetic analyses of cellular senescence have revealed that it is dominant over immortality because whole cell fusion of normal with immortal cells yields hybrids with limited division potential. Only four complementation groups for indefinite division have been identified from extensive studies fusing different immortal human cell lines with each other. The senescence-related genes for three of the complementation groups B-D have been identified on human chromosomes 4, 1, and 7, respectively, by microcell-mediated chromosome transfer, though the existence of senescence-related genes on other chromosomes has been suggested. MORF4 was cloned as the senescence-related gene on human chromosome 4 and is a member of a new gene family, which has multiple transcription factor-like motifs. This gene family may affect cell division by modulating gene expression. Study of this novel gene family should lead to new insights regarding the mechanisms and function of cellular senescence in aging and immortalization.
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PMID:Genetics of cellular senescence. 1204 41

Spontaneous tumors frequently express antigens that can be recognized by the immune system but nevertheless manage to evade immune surveillance. To better understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting against a subcutaneously growing tumor, modified to express influenza hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen-specific CD8 T cells was sufficient to protect against challenge with 1x10(6) tumor cells, while larger numbers of T cells rejected established tumors. HA-specific CD4 T cells could not reject tumors on their own but helped rejection by CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded antigen-specific CD8 and CD4 T cells, while a failing anti-tumor response was accompanied by transient expansion followed by rapid elimination of antigen-specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance because of an insufficient number of tumor-specific T cells and antigen overload, resulting in exhaustion of the immune response. In this scenario, adoptive immunotherapy rather than vaccination promises successful treatment.
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PMID:Visualizing the course of antigen-specific CD8 and CD4 T cell responses to a growing tumor. 1261 1

Fatigue in tumor patients is caused both by the tumor and/or its treatment, and is accompanied by loss of drive, lack of energy, depressive mood and loss of vitality; it is unresponsive to rest and sleep. A differentiation is made between mental fatigue, drive fatigue and psychological fatigue. In particular cytokines produced by the cancer cells, but also by the immune system, play a pathophysiological role. Such cytokines as interferon gamma and interleukin are also involved in the development of cachexia in tumor patients, and may also lead to changes in sleep pattern. An additional factor contributing to the loss of performance and exhaustion in cancer patients is the frequently deficient oxygen supply to the muscles, as also anemia, which is often seen in advanced tumor disease. Mental fatigue is also closely associated with depressive mood as well as the noxious influences of cytostatic agents, steroids and painkillers on the CNS. The causes of fatigue should always be investigated before appropriate causal treatment can be instituted.
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PMID:[Fatigue--when cancer patients are consistently without drive and energy. Determine the etiology!]. 1268 92


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