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

Monocyte transformation by the v-myc oncogene has been used to study myelomonocytic tumor progression in vitro. Murine monocytes transformed by a recombinant retrovirus containing MC29 v-myc were found to exhibit a proliferative burst to day 28-40 post-infection. There-after growth slowed and cell number remained relatively static to day 80-90 post-infection. During both the proliferative and quiescent periods, the cells were dependent on the myelomonocytic growth factor CSF-1 for growth and viability. Analysis of this transformation revealed that the initial transformants were polyclonal, non-immortal, and non-tumorigenic in syngeneic mice. At day 80-90 post infection, a fresh round of cellular proliferation occurred and, in contrast to the initial burst, growth was sustained allowing the establishment of cell lines. These lines were found to be monoclonal, immortal, growth factor independent and, in certain cases, tumorigenic in syngeneic mice. Associated with the establishment of growth factor independent cell lines was the constitutive synthesis of the myelomonocytic growth factor, CSF-1. Proto-oncogene screening of the initial transformants and the cell lines also revealed the expression of c-raf and the CSF-1 receptor, c-fms. Our results indicate that, following transformation by v-myc, monocytes can progress in vitro to become growth factor independent and immortal and that both monocyte transformation and immortalization can be dissociated from tumorigenicity.
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PMID:Tumor progression following transformation of murine monocytes by v-myc: acquisition of immortalization and tumorigenicity. 171 Nov 91

The ovarian surface epithelium (OSE) takes part in the lysis and repair of the ovulatory site. It also forms invaginations and cysts that give rise to the majority of ovarian epithelial carcinomas. In the present study, we investigated the capacity of cultured human OSE to secrete cytokines that may contribute to the regulation of ovarian functions and may influence ovarian carcinogenesis. Bioassays, combined with antibody neutralization experiments, showed that OSE cells in short-term culture secrete bioactive interleukin-1 (IL-1), interleukin-6 (IL-6), macrophage colony-stimulating factor (CSF-1), granulocyte colony-stimulating factor (G-CSF), and limited granulocyte-macrophage colony-stimulating factor (GM-CSF). There was a tendency for these factors to be absent or secreted in reduced amounts in SV40-immortalized OSE lines and in two ovarian carcinoma lines. No IL-2, IL-3, or IL-4 was detected. The results show that normal OSE cells secrete factors that are known to have regulatory effects on follicular growth and differentiation, ovulation, and the distribution of intraovarian cells of the immune system. In addition, the results suggest that the secretion of cytokines by ovarian carcinomas represents the retention of normal precursor cell properties, rather than new characteristics acquired as a result of neoplastic progression.
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PMID:Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium. 769 Nov 94

A leukemoid reaction occurs after inoculation of L1210 leukemic cells into recipient mice and the degree of granulocytosis is correlated with tumor progression. It was found that the sera of leukemic mice contained elevated levels of colony stimulating activity (CSA) when compared with normal mouse sera. Media conditioned by L1210 cells in vitro (L1210-CM) contained CSA which stimulated normal bone marrow myeloid colony growth and an auto-stimulatory activity (ASA) which stimulated L1210 cell proliferation. We studied the effects of trans-retinoic acid (RA) and 1,25 dihydroxyvitamin D3 (VD3) on the production of growth substances by L1210 cells. When L1210-CM was prepared in the presence of RA and VD3, the CSA and ASA were markedly inhibited. A combination of the two agents was more effective than either agent. Mice inoculated with 1 x 10(5) L1210 suspension culture cells treated with either agent or both combined survived significantly longer than controls. Mice inoculated with L1210 cells treated with the two agents combined survived longest. By using antibodies, preliminary analysis of growth substances generated in L1210-CM showed that it contains primarily GM-CSF and M-CSF-like activities which were distinct from ASA. Combination antibody titer assays revealed that ASA was not significantly inhibited with anti-GM-CSF and anti-M-CSF antibodies, while CSA was inhibited by between 61 and 84%. We conclude that RA and VD3 synergistically inhibit the release of growth-enhancing substances by L1210 cells which may reduce the growth advantage of leukemic cells and the resulting leukocytosis in lymphocytic leukemia.
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PMID:Modulation of growth supportive and oncogenic properties of murine leukemia cells. 802 3

Macrophage colony-stimulating factor (M-CSF) is a hematopoietin whose actions are essential for growth and survival of macrophages, placental development, ramification of microglia and tumor progression. The expression of the receptor for macrophage colony-stimulating factor (c-fms) is regulated by two distinct promoters: distal and proximal. The distal promoter is active in trophoblasts during embryogenesis and the proximal promoter directs expression to the cells of myeloid lineage. Here we report the generation of transgenic mice expressing beta-galactosidase under the control of the human proximal c-fms promoter and demonstrate the promoter activity in astrocytes, cells of neurological origin that partially take over the role of the macrophages in the central nervous system. Enzymatic activity of beta-galactosidase was detected in homogenated spleen, bone marrow and brain and in the cell extracts from peritoneal macrophages of transgenic mice. Immunohistochemical staining of brain showed the presence of beta-galactosidase in astrocytes. We hypothesize that M-CSF released by astrocytes, upon stimulation by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha) or interleukin-1 (IL-1), regulates the expression of its own receptor.
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PMID:The promoter of macrophage colony-stimulating factor receptor is active in astrocytes. 914 89

Colony stimulating factor (CSF-1) and its receptor (CSF-1R, product of c-fms proto-oncogene) were initially implicated as essential for normal monocyte development as well as for trophoblastic implantation. However, recent findings have suggested that CSF-1 and CSF-1R might have additional roles in mammary gland development during pregnancy and lactation. Studies with osteopetrotic (op-/op-) mice, which bear a specific mutation that inactivates the CSF-1 gene, demonstrated that op-/op- mothers are incapable of normal milk production due to the incomplete development of their mammary glands during pregnancy. Also, significant increases in the levels of CSF-1 and CSF-1R proteins are observed in the epithelial cells of mammary gland during pregnancy and lactation. In vitro studies investigating the effect of the three major lactogenic hormones (prolactin, insulin, and glucocorticoids) on the expression of CSF-1 and CSF-1R have demonstrated that expression of CSF-1 can be regulated by prolactin and insulin whereas CSF-1R expression is regulated by glucocorticoids. This apparent role for CSF-1/CSF-1R in normal mammary gland development is very intriguing because this receptor/ligand pair has also been found to be important in the biology of breast cancer, where they regulate tumor cell invasion by a urokinase-dependent mechanism. This review aims to summarize recent findings on the role of CSF-1 and its receptor in normal and neoplastic mammary development which may elucidate potential relationships of growth factor-induced biological changes in the breast during pregnancy and tumor progression.
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PMID:The role of CSF-1 in normal and neoplastic breast physiology. 989 62

Here, we report the functional expression of CD40 on human malignant melanomas (MMs). Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression. CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative. CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-gamma and tumor necrosis factor-alpha but not by interleukin (IL)-1beta or CD40 triggering. CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up-regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor-a, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor kappaB. Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone. Finally, CD40 ligation induced growth inhibition and apoptosis in MM. These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs.
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PMID:Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis. 1009 61

Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) and/or their receptors are increasingly detected in solid human tumors, although little is known about their function in tumor growth and invasion. We analyzed RNA and protein expression of both factors and their receptors in 22 human gliomas (WHO grade II, III, and IV) and derived cell cultures. G-CSF, GM-CSF, and/or their receptors were expressed in all tumors and derived cell cultures, but coexpression of both factors and receptors was almost exclusively found in grade IV glioblastomas and thus correlated with advanced tumor stage. The functional significance of G-CSF and GM-CSF as regulators for glioma cells was demonstrated by 1) stimulation of proliferation and migration in tumor cells expressing one or both receptors by the corresponding factor; 2) inhibition of growth and migration of glioma cells expressing G-CSF, GM-CSF, and their receptors by neutralizing antibodies to both factors. These results indicate a significant role for both factors in the autocrine regulation of growth and migration in late-stage malignant gliomas and suggest a shift from paracrine to autocrine regulation with tumor progression. The implication of G-CSF and GM-CSF in glioblastoma growth regulation could make these factors further prognostic indicators and raises questions concerning their use in cancer therapy.
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PMID:Autocrine growth regulation by granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor in human gliomas with tumor progression. 1055 Mar 13

Tumor growth is associated with neutrophilia, thrombocytosis, and extramedullar hematopoiesis. The mechanism(s) accounting for these phenomena is unclear, although granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or granulocyte colony-stimulating factor (G-CSF) released by tumor cells have been involved. We studied whether CSF released by Ehrlich tumor (ET) may play a role. A comparative study was performed with two cell variants (ET and ET/0) growing in euthymic, nude, and SCID mice. Extramedullar hematopoiesis was assessed in the spleen by scoring organ enlargement, wheat germ agglutinin ve+ cells, and interleukin 3-dependent granulocyte-macrophage colony-forming unit (GM-CFU). Both cell lines showed the same cytokine profile by reverse transcriptase polymerase chain reaction, including GM-CSF, G-CSF, and macrophage colony-stimulating factor (M-CSF); yet, only ET cells produced detectable colony-stimulating activity in vitro, mainly due to GM-CSF. No differences in tumorigenicity were noted between ET and ET/0 cells inoculated to normal or immunodeficient mice. An increase in extramedullar hematopoiesis, accompanied by neutrophilia and thrombocytosis, was associated with tumor progression irrespective of the cell line. A strong correlation was obtained between the increase in splenic GM-CFU and tumor mass (r = 0.96, p < 0.0001) that was independent on the tumor cell line, strain of mice, or stage of tumor development. The results point against CSF released by tumor cells and/or reactive host T cells as the only factors involved in the extramedullar hematopoiesis in this tumor model. The remarkable correlation between splenic GM-CFU and the tumor mass still suggests that a factor(s) of tumor origin may play a critical role.
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PMID:Ehrlich tumor stimulates extramedullar hematopoiesis in mice without secreting identifiable colony-stimulating factors and without engagement of host T cells. 1064 93

In human breast carcinomas, overexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) correlates with poor prognosis. To establish if there is a causal relationship between CSF-1 and breast cancer progression, we crossed a transgenic mouse susceptible to mammary cancer with mice containing a recessive null mutation in the CSF-1 gene (Csf1(op)) and followed tumor progression in wild-type and null mutant mice. The absence of CSF-1 affects neither the incidence nor the growth of the primary tumors but delayed their development to invasive, metastatic carcinomas. Transgenic expression of CSF-1 in the mammary epithelium of both Csf1(op)/Csf1(op) and wild-type tumor-prone mice led to an acceleration to the late stages of carcinoma and to a significant increase in pulmonary metastasis. This was associated with an enhanced infiltration of macrophages into the primary tumor. These studies demonstrate that the growth of mammary tumors and the development to malignancy are separate processes and that CSF-1 selectively promotes the latter process. CSF-1 may promote metastatic potential by regulating the infiltration and function of tumor-associated macrophages as, at the tumor site, CSF-1R expression was restricted to macrophages. Our data suggest that agents directed at CSF-1/CSF-1R activity could have important therapeutic effects.
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PMID:Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. 1125 44

Tumor-stroma interactions are of primary importance in determining the pathogenesis of metastasis. Here, we describe the application of sensitive competitive polymerase chain reaction (PCR) techniques for detection and quantitation of human breast cancer cells (MDA-MB-231) in an in vivo mouse model of experimental metastasis. Human-specific oligonucleotide primers in competitive PCR reactions were used to quantify the amount of MDA-MB-231 cells per tissue per organ. Using this species-specific (semi)quantitative PCR approach, gene expression patterns of (human) tumor cells or (mouse) stromal cells in metastatic lesions in the skeleton or soft tissues were investigated and compared. In all metastatic lesions, MDA-MB-231 cells express angiogenic factors (vascular endothelial growth factors [VEGFs]; VEGF-A, -B, and -C) and bone-acting cytokines (parathyroid hormone-related protein [PTHrP] and macrophage colony-stimulating factor [M-CSF]). In these metastases, PECAM-1-positive blood vessels and stromal cells of mouse origin are detected. The latter express angiogenic factors and markers of sprouting vessels (VEGF receptors flt-1/flk - 1/flk-4 and CD31/PECAM-1). Strikingly, steady-state messenger RNA (mRNA) levels of VEGF-A and -B and the major bone resorption stimulators PTHrP and M-CSF by tumor cells were elevated significantly in bone versus soft tissues (p < or = 0.05, p < or = 0.0001, p < or = 0.001, and p < or = 0.05, respectively), indicating tissue-specific expression of these tumor progression factors. In conclusion, MDA-MB-231 breast cancer cells express a variety of factors in vivo that have been implicated in metastatic bone disease and that correlate with poor survival of patients with breast cancer. We hypothesize that the observed up-regulated expression of angiogenic and bone-resorbing factors by the breast cancer cells in the skeleton underlie the clinically observed osteotropism of breast cancer cells and pathogenesis of osteolytic bone metastases. The application of the species-specific competitive PCR-based assay in vivo can provide new information concerning the involvement of gene families in tumor progression and metastatic disease and greatly facilitates the study of tumor-stroma interactions in cancer invasion and metastasis.
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PMID:Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. 1139 85


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