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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural killer (NK) cells may be important in the control of circulating tumor emboli. Because of this, the suppression of natural killer cell cytotoxicity (NKCC) observed with progressive tumor burden is a concern relative to the treatment of solid tumors. Our study examines the interplay between tumor progression, elaboration of metastases, and NKCC. Mice inoculated with Lewis lung carcinoma (3LL) cells developed visible primary tumors by day 6 of tumor bearing. This tumor burden appeared to be associated with a progressive decrease in NKCC beginning after day 6 of tumor bearing. Significant splenomegaly was observed beginning by day 12. Rapidly reproducing tumor cells take up 125I-labeled 5-iodo-2'-deoxyuridine (125I-IUDR) in lieu of thymidine more readily than normal cells. Intraperitoneal injection of the labeled IUDR allowed the identification of possible pulmonary metastatic activity earlier in the tumor progression sequence than has previously been possible using standard staining procedures. A significantly increased level of lung 125I-IUDR uptake was observed in the lung beginning after day 6 of tumor bearing; this increase in 125I-IUDR uptake began at the same time as the tumor burden impairment of NKCC. Successful implantation of tumor emboli may occur very early in experimental tumor burden systems, when measurable antitumor immune effector mechanisms are not yet massively suppressed. Antitumor immunotherapy programs may therefore need to be targeted to these earlier points of tumor bearing.
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PMID:Tumor burden impairment of murine natural killer cell cytotoxicity. 336 May 92

In previous studies we found that the immunosuppression seen in mice bearing Herpes virus type 2-transformed (H238) fibrosarcoma was likely to be due to tumor-derived transforming growth factor-beta (TGF-beta). In vitro experiments showed that interleukin-2 (IL-2) and antibodies against TGF-beta could significantly counteract TGF-beta-induced depression in lymphocytes. The present study was performed to determine if the administration of polyclonal anti-TGF-beta antibody and recombinant IL-2, alone or in combination, could inhibit H238 tumor progression in vivo and to investigate possible mechanisms of action. The tumor cells were injected s.c. at 1 x 10(6) cells/mouse and treatments were given 1-10 days post-injection. In phase I, a total of 25,000 units of IL-2 (5,000 units/injection) and/or 900 ng of anti-TGF-beta (100 ng/injection) were administered i.p. per animal. Phase II was conducted similarly, except that each mouse received a total of 127,500 units of IL-2, either with or without the same amount of antibody. No treatment-related toxicity was noted. Tumor volumes were monitored for 16-18 days after tumor implantation. The H238 tumors in treated mice from both both phases grew as rapidly as, or significantly faster than, in untreated controls. Significant enhancement of tumor growth was found in the groups given IL-2 as a single agent, regardless of total dose. The combination of the higher IL-2 dose with anti-TGF-beta resulted in more rapid tumor progression than in animals given the antibody alone. Relative spleen weights, peripheral blood leukocyte counts, and the chemiluminescent oxidative burst of phagocytes were significantly elevated in all tumor-bearing mice, whereas T cell response to mitogenic stimulation was depressed. However, the oxidative burst capacity of spleen (but not blood) cells and natural killer cell cytotoxicity were markedly lower in the treated groups compared to nontreated tumor-bearing controls. In contrast, plasma levels of tumor necrosis factor-alpha and IL-2 were substantially higher in the group given both modalities (phase II) compared to the other treated groups. These findings show that anti-TGF-beta antibody, both with and without low-dose IL-2 regimens, can be safely administered in vivo. However, tumor growth was not delayed by the treatment protocols used. The induction of hyporesponsiveness in certain cell types may account, at least partly, for the enhancement seen in tumor progression.
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PMID:Effects of anti-transforming growth factor-beta antibody and interleukin-2 in tumor-bearing mice. 780 55

Thirty-four dogs with histopathologically confirmed, measurable, nonresectable transitional cell carcinoma of the urinary bladder were treated with piroxicam (0.3 mg/kg PO sid) and were evaluated for tumor response and drug toxicity. Dogs were evaluated at the Purdue University Veterinary Teaching Hospital by means of physical examination, thoracic and abdominal radiography, cystography, complete blood count, serum biochemistry profile, and urinalysis. In selected cases, prostaglandin E2 (PGE2) concentrations in plasma and in supernatants of stimulated monocytes, and natural killer cell activity were quantified. Dogs were evaluated before therapy and at 28 and 56 days after initiation of therapy. Dogs with stable disease or remission at 56 days remained on the study and were evaluated at 1 to 2 months intervals. Tumor responses were 2 complete remissions, 4 partial remissions, 18 stable diseases, and 10 progressive diseases. The median survival of all dogs was 181 days (range, 28 to 720+ days), with 2 dogs still alive. Piroxicam toxicity consisted of gastrointestinal irritation in 6 dogs and renal papillary necrosis (detected at necropsy) in 2 dogs. Monocyte production of PGE2 appeared to decrease with therapy in dogs whose tumors were decreasing in size, and increased in dogs with tumor progression. A consistent pattern in natural killer cell activity was not observed. In vitro cytotoxicity assays against 4 canine tumor cell lines revealed no direct antitumor effects of piroxicam. In summary, antitumor activity, which was not likely the result of a direct cytotoxic effect, was observed in dogs with transitional cell carcinoma of the bladder treated with piroxicam.
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PMID:Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. 776 Mar 10

Studies about the function of mucin molecules as surface molecule of adenocarcinoma of gastrointestinal tract had just started, and several important function of mucins had been revealed. In the process of the malignant transformation, class of the expressed mucin core protein and content of glycochain of mucin molecule was changed. Changes of glycoprotein of mucin molecule during transformation affect immunogenesity, tumorigenesity, metastatic ability and sensitivity for anti-cancer drugs. Glycosylated mucin acts important roles during metastatic sequence and prognosis of the gastrointestinal cancer was collerated with expression of immatured mucin of cancer cells. A type of mucin with immature type of glycochain, MUC1, had a protective function for cytotoxicity, e.g. natural killer cell and cytotoxic T-cell, and deglycosilation of MUC1 sensitize cancer cells for cytotoxicity. And MUC1 reduce sensitivity for anti-cancer drugs and MUC1 was glycosilated during process to get resistance for anti-cancer drug. The functions of mucin molecules is not fully revealed, but further studies will indicate importance of mucin molecules in tumor progression.
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PMID:[Functions of mucin molecules in gastrointestinal cancer]. 863 44

TGF-beta s and their receptors are expressed ubiquitously, and they act as key regulators of many aspects of cell growth, differentiation, and function. Steroid action on target tissues is often associated with increase in TGF-beta isoforms. Regulation of TGF-beta expression and activation is crucial for normal development and growth control. The loss of responsiveness of different tumor cells to the antiproliferative effects of TGF-beta is a common feature in carcinogenesis. Multiple changes are required for the cells to gain complete resistance to TGF-beta growth inhibition (Fynan and Reiss, 1993; Kimchi et al., 1988; Samuel et al., 1992). Although many tumor cells are not growth inhibited by TGF-beta, they respond to TGF-beta treatment by changes in the expression of matrix components and enhanced proteolytic activity (KeskiOja et al., 1988). Agents that induce TGF-beta production in target tissues can have a chemopreventive or chemotherapeutic value for the management of epithelial malignancies. Conversely, data supporting a positive role for TGF-beta in established tumor progression are beginning to emerge (Arteaga et al., 1993a,b; Barrett-Lee et al., 1990; Arrick et al., 1992 ; E. A. Thompson et al., 1991). In later stages of tumor development, cell proliferation is often not inhibited by TGF-beta, and tumor cells secrete large amounts of this growth factor (Fynan and Reiss, 1993). In vivo TGF-beta secreted by tumor or stromal cells can influence host responses such as a natural killer cell function and thus indirctly support tumor cell viability (Arteaga et al., 1993b). TGF-beta may also affect tumor growth indirectly by stromal effects and promotion of angiogenesis. TGF-beta may also be involved in the progression of breast tumors from the steroid-sensitive to steroid-insensitive state (King et al., 1989). Understanding of the net effect of TGF-beta in different stages of tumor development is critical for the evaluation of its therapeutic value in cancer treatment.
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PMID:Transforming growth factor-beta system and its regulation by members of the steroid-thyroid hormone superfamily. 890 54

Recently there has been considerable conjecture in the literature concerning a possible relationship between stress, depression and bereavement, and carcinoma. We shall propose a causal model in which the relationship between stress, depression and carcinoma is clarified. This relationship is grounded on dysregulation of the inflammatory cytokines in stress and depression. Stress is associated with increased expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), and reduced expression of IL-2, interferon-gamma (IFN-gamma), major histocompatability complex (MHC) class II molecules and natural killer cell activity (NKA). Depression is associated with elevated IFN-gamma and IL-1 beta, downregulated IL-2, and reduced NKA. Most organ-related carcinomas are associated with elevated TNF-alpha, which inhibits the activity of protein tyrosine phosphatase (PTPase), the enzyme that initiates activation of the MHC class I pathway. Sustained elevation of TNF-alpha inhibits the activity of PTPase which results in diminished expression of the MHC class I antigen on the cell surface and thus, malignant cells escape immune surveillance. Therefore, stress and depression can foster tumor progression by means of inhibiting the expression of MHC class I and II molecules and through the reduction of NKA.
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PMID:An immunological model connecting the pathogenesis of stress, depression and carcinoma. 982 37

IFN-gamma is a pleiotropic cytokine that plays an important role in regulating the growth of primary tumors. Although numerous studies of the effects of IFN-gamma on primary-solid-tumor growth have been performed and several potential mechanisms for its efficacy have been proposed, it remains unclear how IFN-gamma modulates tumor progression and whether it exerts its effects indirectly via host cells or directly by interacting with tumor cells. Using the well-characterized mouse metastatic mammary carcinoma 4T1 in a postsurgery setting, IFN-gamma-deficient mice were found to have significantly shorter survival time relative to wild-type mice, demonstrating that IFN-gamma is also a critical component in regulating innate immunity to metastatic disease. Experiments quantifying lung and liver metastasis indicate that decreased survival of IFN-gamma-deficient mice is attributable to increased metastatic disease. To determine whether IFN-gamma is acting directly on the tumor cells, IFN-gamma-nonresponsive 4T1 cells were generated by transfection (4t1/IRt). Metastasis experiments with 4T1/IRt demonstrated that IFN-gamma mediates its effects via host-derived cells, rather than by directly affecting tumor growth. To identify the population of cells responsible for IFN-gamma efficacy, perforin-deficient, T-cell subset-depleted, natural killer cell-depleted, or carrageenan-treated phagocytic cell-depleted mice were inoculated with 4T1 and assessed for primary tumor growth and metastatic disease. None of the conditions altered primary tumor growth; however, the carrageenan treatment significantly increased metastatic disease in the liver and lungs. Survival experiments in 4T1-inoculated, carrageenan-treated mice confirmed that the elimination of phagocytic cells significantly reduces survival time and yields a survival phenotype comparable with IFN-gamma deficiency. Therefore, IFN-gamma is a critical component of innate immunity to metastatic mammary carcinoma that probably mediates its effects via host-derived phagocytic cells.
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PMID:Interferon-gamma-dependent phagocytic cells are a critical component of innate immunity against metastatic mammary carcinoma. 1215 47

In addition to natural killer (NK) cells, T cells expressing natural killer cell markers, CD56 or CD57 (NK type T cells), have been considered to play an important role in antitumor immunity. We examined the proportion of NK cell and NK type T cell subsets in the peripheral blood from patients with gastric cancer. The IFN-gamma production capacity and population of cytoplasmic perforin positive cells in peripheral blood mononuclear cells (PBMC) were evaluated. Peripheral blood samples were obtained from 56 patients with gastric cancer and 21 healthy volunteers. The proportion of CD56- CD57+ T cells (CD57+ T cells) was significantly higher in advanced gastric cancer patients than those in healthy volunteers and patients with early stage gastric cancer, whereas no correlation was observed between the proportion of CD56+ T cells or NK cells and tumor progression. Furthermore, a significant decrease of CD8+ CD57+ T cells was found in patients with advanced gastric cancer. The proportion of CD57+ T cells did not correlate with interferon-gamma (IFN-gamma) production from PBMC in gastric cancer patients, although a significant correlation was found between them in healthy volunteers. The proportion of perforin positive CD57+ T cells, especially CD8+ CD57+ T cells, in patients with gastric cancer was markedly lower than that in healthy volunteers. Collectively, although the proportion of CD57+ T cells in PBMC was found to increase with tumor progression, their function in antitumor immunity is impaired in patients with gastric cancer.
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PMID:The increase of CD57+ T cells in the peripheral blood and their impaired immune functions in patients with advanced gastric cancer. 1288 21

Experimental and epidemiologic studies have demonstrated that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers. Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2, a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli, growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2-catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms: (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form reactive oxygen species that can directly induce the oxidation of DNA or instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX-2-mediated arachidonic acid metabolism, exhibits several biologic actions that have been shown to promote tumorigenesis and tumor progression. These actions include increased cell proliferation, promotion of angiogenesis, and the elevated expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases natural killer cell activity and alters immune surveillance. In vitro experimental studies find that COX-2 inhibitors decrease cellular proliferation, increase apoptosis, and modulate genes involved in cell cycle regulation. Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP) prevention. Population-based studies have observed a reduced incidence of CaP among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before the sixth or seventh decade of life, any strategy to delay or lengthen the time to development of clinically evident CaP, such as chemoprevention strategies, would greatly impact the natural history of this disease. Recent progress and critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and CaP prevention will be presented.
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PMID:The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma. 1504 Aug 74

There is a persuasive body of evidence suggesting that tissue factor (TF) is a major determinant of tumor progression. In addition to its "traditional" function as the initiator of hemostasis, TF may support tumor progression through signaling mechanisms involving either direct signal transduction through the TF cytoplasmic domain or TF:F VIIa-mediated and TF/F VIIa/F Xa-mediated activation of protease-activated receptors. Whereas TF-mediated signaling events uncoupled from hemostasis may play an important role in tumor dissemination in some contexts, TF-mediated thrombin generation appears to be the major mechanism linking tumor cell-associated TF to metastasis. At least one mechanism coupling thrombin generation to metastatic potential involves the most distal components of the hemostatic system (i.e., platelets, fibrinogen, and factor XIII) and leads to a restriction in natural killer cell-mediated lysis of newly formed micrometastases. A detailed understanding of the mechanisms linking TF and circulating hemostatic system components to tumor progression may lead to novel therapeutic targets for cancer treatment.
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PMID:Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. 1864 20


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