Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant expression of the Evi1 (ecotropic virus integration site 1) proto-oncogene has been associated with hematopoietic malignancies in both mice and man. To determine the effect of enforced expression of Evi1 in vivo, we developed a transgenic mouse model utilizing the murine Sca-1 (Ly-6E.1) promoter. Here, we describe the generation and analysis of three independent lines of Evi1 transgenic mice. Transgenic animals of two founder lines developed normally. These mice did not show any obvious hematological abnormalities but showed a significant reduction in the number of bone marrow colony-forming unit erythroid (CFU-E)-derived colonies. This implies a defect of normal erythroid hematopoiesis affecting relatively late erythroid progenitor cells. We also show that when newborn Evi1 transgenic mice of these two lines were infected with Cas-Br-M MuLV, tumor incidence was greatly enhanced in comparison with nontransgenic littermates, indicating an increased susceptibility for leukemia development. Interestingly, analysis of a third founder line revealed that all male progeny consistently displayed severely impaired erythropoiesis with major defects in the bone marrow, spleen and peripheral blood. Taken together, our results present the first evidence of Evi1 disturbing normal erythropoiesis in vivo and provides evidence for cooperative potential of Evi1 in tumor progression.
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PMID:Erythroid defects and increased retrovirally-induced tumor formation in Evi1 transgenic mice. 1106 22

Patients with secondary myelodysplasias and acute myeloid leukemias (MDS/AML) frequently exhibit interstitial deletions of the chromosome-5q resulting in hemizygous loss of the transcription transactivator Smad5. Smad5 is a member of the signal transducer family conveying the pleiotropic TGF-gb/BMP cytokine signals with roles in development, cell growth control, and tumor progression. Here we present a study of the Smad5 expression and its functional role in leukemia cell lines as well as in primary CD34+ progenitors of MDS/AML patients and healthy individuals. Consistent Smad5 gene expression in these cell types and the gradual increase in its mRNA and protein levels in a model of induced erythroid differentiation of murine erythroleukemia (MEL) cells suggest a role of the gene in hematopoiesis. We show that bone morphogenetic protein 4 (BMP4) directs Smad5 activation in human hematopoietic cells, as monitored at the levels of protein phosphorylation, nuclear translocation, and specific transcription response. In vitro induction of normal human CD34+ cells by BMP4 results in significantly increased proliferation of erythroid progenitors (BFU-E) and formation of glycophorin-A+ cells, whereas perturbation of Smad5 expression by antisense oligonucleotides causes significantly decreased rates of BMP4-induced erythroid differentiation. We have not detected any effects of Smad5 inhibition on BMP4-stimulated progenitors of the granulocyteNmacrophage lineage. We propose that the BMP4/Smad5 signal transduction pathway activates hematopoietic differentiation programs that may be impaired in anemia manifestations in MDS and AML patients with Smad5 haploinsufficiency.
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PMID:Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. 1206 18

Capecitabine is a novel fluoropyrimidine carbamate which is selectively activated after oral administration to 5-fluorouracil (5-FU) by a sequential triple enzyme pathway in liver and tumor cells. The cytotoxic activity of the metabolized 5-FU depends on thymidylate synthase (TS) inhibition, leading to defective DNA synthesis. Capecitabine has shown promising activity in all tumor types sensitive to 5-FU and is therefore investigated in many clinical trials. Since we observed an increase of mean corpuscular volume (MCV) of red blood cells under therapy with capecitabine, the current investigation aimed to quantitate this effect and to elucidate the underlying mechanisms. A total of 154 patients suffering from advanced cancer received capecitabine (2500 mg/m2/day for 14 days every 21 days) either as monotherapy, or in combination with other antineoplastic agents or biological response modifiers. During 3 consecutive cycles of therapy a complete blood cell count including the red cell indices MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was performed before each application of capecitabine. In addition, vitamin B12, folic acid and homocysteine were determined to define their role in increasing MCV. Restaging was performed after 9 weeks. Within 9 weeks, a statistically significant increase of MCV (without other hematologic abnormalities or clinical symptoms) could be observed (p<0.0001). Vitamin B12, folic acid and homocysteine levels did not change significantly during the observation period. When comparing the different increases of MCV during 9 weeks (deltaMCV) with respect to tumor response, deltaMCV tended to higher values in patients with tumor remission or stable disease than in patients with tumor progression. We conclude that serum levels within the normal range rule out severe deficiencies of vitamin B12, folic acid or homocysteine as an account of macrocytemia. We therefore hypothesize that an increased MCV (without concomitant anemia) in patients receiving capecitabine might be due to the 5-FU-induced TS inhibition also in erythroid precursor cells. Whether this increase in MCV might serve as a surrogate marker for tumor response has to be evaluated in further investigations.
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PMID:Capecitabine treatment results in increased mean corpuscular volume of red blood cells in patients with advanced solid malignancies. 1256 98

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.
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PMID:Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. 1275 37

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is one representative of the natural matrix metalloproteinase (MMP) inhibitor family, encompassing four members. It inhibits all MMPs, except several MT-MMPs, and a disintegrin with a metalloproteinase domain (ADAM)-10 with Kis < nM. Unexpectedly, its upregulation was associated to poor clinical outcome for several cancer varieties. Such finding might be related to the growth-promoting and survival activities of TIMP-1 for normal and cancer cells. In most cases, such properties are MMP-independent and binding of TIMP-1 to an unknown receptor system can trigger JAK (or FAK)/PI3 kinase/Akt/bad-bclX2 (erythroid, myeloid, epithelial cell lines) or Ras/Raf1/FAK (osteosarcoma cell line) signaling pathways. The relationship between viral infection and TIMP-1 expression is here underlined. Thus, TIMP-1 might display a dual influence on tumor progression; either beneficial by inhibiting MMPs as MMP-9 and by impairing angiogenesis or detrimental by favoring cancer cells growth or survival. We consider that the proMMP-9/TIMP-1 balance is of critical importance in early events of tumor progression, and might show promise as diagnostic and prognostic marker of malignancy.
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PMID:Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. 1578 25

Protein farnesyltransferase (FTase) is an enzyme responsible for posttranslational modification of proteins carrying a carboxy-terminal CaaX motif. Farnesylation allows substrates to interact with membranes and protein targets. Using gene-targeted mice, we report that FTase is essential for embryonic development, but dispensable for adult homeostasis. Six-month-old FTase-deficient mice display delayed wound healing and maturation defects in erythroid cells. Embryonic fibroblasts lacking FTase have a flat morphology and reduced motility and proliferation rates. Ablation of FTase in two ras oncogene-dependent tumor models has no significant consequences for tumor initiation. However, elimination of FTase during tumor progression had a limited but significant inhibitory effect. These results should help to better understand the role of protein farnesylation in normal tissues and in tumor development.
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PMID:Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development. 1583 21

The role of macrophages in modulating the systemic response to hypoxia and oxidative stress is emerging from basic biological processes, such as the regulation of red blood cell production, and from analysis of tumor progression, as a key factor determining whether cells survive, proliferate or differentiate under micro-environmental pressures. Our recent work identified a novel role for macrophages in promoting expansion of erythroid progenitors in vitro while confirming previous data that macrophages are not required for red cell enucleation. This work emerged from analyses of hypoxia and cell death in the Rb null fetal liver where we demonstrated that defects in erythropoietic islands were due to deterioration in the fetal liver microenvironment that disrupted heterotypic interactions of macrophages with erythroblasts and not to intrinsic defects in Rb null macrophages. The significance of these findings for the effect of hypoxia on macrophage interactions and activity during tumor progression is also discussed.
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PMID:Effects of hypoxia on heterotypic macrophage interactions. 1787 23

Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radiotherapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.
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PMID:Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. 1954 71

The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed.
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PMID:Targeting drug-metabolizing enzymes for effective chemoprevention and chemotherapy. 2023 42

Adverse effects of erythropoietin (EPO) on tumor progression and survival were observed in recent phase 3 oncology trials. However, mechanisms remain poorly understood. We tested the effects of exogenous EPO on murine B16F10 melanoma growth in a subcutaneous tumor transplant model, and for the first time, in a model of spontaneous tumor formation within autochthonous epithelial tissues using murine mammary tumor virus promoter polyoma virus middle T antigen (MMTV-PyMT) transgenic mice. EPO receptor (EPOR) messenger RNA (mRNA) was detectable in both B16F10 tumors and mammary tumors from MMTV-PyMT mice but was 0.12 +/- 0.02% and 1.3 +/- 0.91% of the EPOR mRNA level in murine erythroid HCD-57 cells, respectively. B16F10 tumor growth rates in mice treated for 3 weeks with 30 microg/kg per week of darbepoetin alpha, 0.41 inverse days (range, 0.05-0.69 inverse days; n = 16), were similar to tumor growth rates observed in mice treated with PBS, 0.42 inverse days (range, 0.10-0.69 inverse days; n = 17). In contrast, darbepoetin alpha raised hematocrit levels to 0.593 (maximum, 0.729) compared with 0.448 (maximum, 0.532) in PBS-treated mice (P = .0004). In MMTV-PyMT mice, the weights of tumor-bearing mammary glands in mice treated for 6 weeks with 30 microg/kg per week of darbepoetin alpha, 3.37 g (range, 1.94-5.81 g; n = 27), did not significantly differ from the weights in PBS-treated mice, 3.76 g (range, 2.30-6.33 g; n = 26). In contrast, darbepoetin alpha raised hematocrit levels to 0.441 (maximum, 0.606) compared with 0.405 (maximum, 0.492) in PBS-treated mice (P = .05). Thus, effects of exogenous EPO on tumor growth were not recapitulated in these murine tumor models.
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PMID:Limitations of a murine transgenic breast cancer model for studies of erythropoietin-induced tumor progression. 2056 59


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