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

Many studies show defective immune responses in patients diagnosed with cancer. Most of the diverse nonspecific approaches used to stimulate the immune system to recognize and destroy abnormal tumor cells have limited clinical utility. Attempts to identify tumor-specific antigens and to improve the antigen presentation were equally disappointing. It appears that some of these failures can be explained by tumor-induced immunosuppression. A large number of cytokines, hormones, and other molecules secreted by tumors were demonstrated to have immunomodulating properties. The most extensively studied immunosuppressive molecules secreted by tumors are transforming growth factor-beta (TGF beta), interleukin 10 (IL-10), and prostaglandin E2 (PGE2). TGF beta in particular may play a key role in tumor-induced immunosuppression. It is the most potent immunosuppressor described to date, and it has been consistently isolated from variety of tumor cell lines and detected in plasma of tumor-bearing hosts. Level of TGF beta production by tumor cells correlates with their metastatic potential, and TGF beta neutralization not only prevents development of metastases, but also inhibits growth or completely eradicates tumors as diverse as breast cancer, melanoma, and malignant gliosarcoma in animal models. PGE2 may play significant role in early stages of tumor development, promoting the process of tumorigenesis in some tumors. Research on reversal of tumor-induced immunosuppression promises new, more powerful, and less toxic approaches to cancer therapy. Existence of molecule(s) consistently secreted by different types of tumors and responsible for tumor progression raises the possibility of a single, universal assay to monitor progression and recurrence in many malignancies, including those that currently do not have reliable plasma markers.
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PMID:Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. 918 55

We studied the expression and regulation of TIMP-3, a recently cloned member of the tissue inhibitor of the metalloproteinase family, during human fetal development and in various human tissues, with emphasis on epithelial structures. Expression of TIMP-3 mRNA was detected by in situ hybridization in developing bone, kidney, and various mesenchymal structures. At 16 weeks of gestation, ectoderm-derived cells of hair germs expressed TIMP-3 mRNA, and beginning from the twentieth week consistent expression was detected in epithelial outer root sheath cells of growing hair follicles. In normal adult human skin, expression of TIMP-3 mRNA was limited to hair follicles, starting at the early anagen (growing) phase and vanishing at the catagen (regressing) phase. TIMP-3 mRNA was not detected in benign hair follicle-derived tumors but was present in tumor cells of infiltrative basal cell carcinomas and in surrounding stromal cells in squamous cell carcinomas. Human primary keratinocytes in culture expressed TIMP-3 mRNAs, the levels of which were upregulated by transforming growth factor-beta (TGF-beta), whereas interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) had no effect. Our results suggest a role for TIMP-3 in connective tissue remodeling during fetal development, hair growth cycle, and cancer progression.
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PMID:Human TIMP-3 is expressed during fetal development, hair growth cycle, and cancer progression. 952 89

To analyze transforming growth factor-beta (TGF-beta) response during MCF-7 cell progression, early passage (MCF-7E, < 200 passage) and late passage (MCF-7L, > 500 passage) cells were compared. MCF-7E cells showed an IC50 of approximately 10 ng/ml of TGF-beta1, whereas MCF-7L cells were insensitive. MCF-7E cells contained approximately threefold higher levels of TGF-beta receptor type II (TbetaRII) mRNA than MCF-7L, but their TbetaRI levels were similar. MCF-7E parental cells showed higher TbetaRII promoter activity than MCF-7L cells, which could be attributed to changes in Sp1 nuclear protein levels. Receptor cross-linking studies indicated that the cell surface receptor levels parallel mRNA levels in both cell lines. Limiting dilution clones of MCF-7E cells were established to determine the heterogeneity of TbetaRII expression in this cell line, and they showed varying degrees of TbetaRII expression. Fibronectin was induced at higher levels in cells expressing higher TbetaRII levels. All three TGF-beta isoforms were detected in limiting dilution clones and parental cells, but TGF-beta1 was more abundant relative to TGF-beta2 or 3, and no correlation between TGF-beta isoform profile with TGF-beta sensitivity was found. MCF-7L cells were tumorigenic and formed xenografts rapidly and progressively, whereas MCF-7E parental and limiting dilution clonal cells showed transient tumor formation followed by regression. These results indicate that decreased TbetaRII transcription in breast cancer cells leads to a loss of TbetaRII expression, resulting in cellular resistance to TGF-beta which contributes to escape from negative growth regulation and tumor progression.
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PMID:Expression of transforming growth factor-beta receptor type II and tumorigenicity in human breast adenocarcinoma MCF-7 cells. 964 30

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including malignant melanomas, depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a dedifferentiated, malignant, highly invasive cellular immunophenotype (CIP) and distant metastases, as aspects of constant neoplastic progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during malignant melanoma (MM) related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 25 MMs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; +3 to +4) of EDG on endothelial cells was demonstrated in all MM cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. MMs, like most mammalian neoplasms, are characterized by extensive neovascularization, and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including MMs. The importance of TGF-beta in all of the various aspects of neoplastic transformation, as well as malignant disease progression should also be studied more extensively in the future.
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PMID:Immunocytochemical detection of endoglin is indicative of angiogenesis in malignant melanoma. 970 32

A weakly tumorigenic cell clone (QR-32) derived from a murine fibrosarcoma (BMT-11) grew lethally in 6 out of 10 syngeneic C57BL/6 mice after co-implantation with gelatin sponge. All six cell lines (QRsP) established from the arising tumors from QR-32 had enhanced tumorigenicity and/or pulmonary metastatic ability in vivo, indicating that those QRsP cell lines acquired progressed phenotypes as compared with those of QR-32 cells. In contrast, the frequency of tumor progression was suppressed to 50% (3/6) in the cell lines (QRsP/PSK) established from those arising in the mice treated with an immunopotentiating protein-bound polysaccharide, PSK. The enhanced metastatic ability was accompanied by enhanced expressions of a tumor-associated transcription factor, E1AF and by increased production of matrix metalloproteinase (MMP) in five lines of QRsP and two lines of QRsP/PSK. It was found that administration of PSK augmented the production of an antioxidative enzyme, manganese superoxide dismutase (Mn-SOD), in the tumor tissues co-implanted with gelatin sponge. PSK administration also brought about up-regulation of interferon-gamma (IFN-gamma)-expression and down-regulation of transforming growth factor-beta (TGF-beta)-expression in the tumor tissues, which were examined by RT-PCR on day 7, 14 and 21 after the co-implantation. Other inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) were expressed equally both in PSK-treated and untreated tumor tissues. In vitro experiments proved that although IFN-gamma did not increase the production of Mn-SOD by itself, concomitant treatment with both IFN-gamma and TNF-alpha enhanced the Mn-SOD-production in QR-32 cells greatly. On the contrary, TGF-beta treatment lowered the Mn-SOD level in QR-32 cells. PSK-treatment did not induce Mn-SOD in cultured QR-32 cells directly. These results indicated that PSK inhibits the malignant progression of QR-32 cells promoted by co-implantation with gelatin sponge, most possibly through elevating the Mn-SOD level in QR-32 cells via modulation of the production of inflammatory cytokines, that is, increasing IFN-gamma and decreasing TGF-beta at the site of tumor growth.
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PMID:[Induction of manganese superoxide dismutase by an immunopotentiator as a mechanism of inhibiting of malignant progression of murine tumor cells]. 984 81

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including breast carcinomas (BCs), depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases, as aspects of tumor progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during mammary carcinoma-related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PM) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 15 BCs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; ++ + to ++ ++) of EDG on endothelial cells was demonstrated in all 15 BC cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. BCs, as most mammalian neoplasms, are characterized by extensive neovascularization and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including BCs.
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PMID:Over-expression of endoglin (CD105): a marker of breast carcinoma-induced neo-vascularization. 985 49

Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.
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PMID:Cyclosporine induces cancer progression by a cell-autonomous mechanism. 1002 62

To determine the incidence of microsatellite instability (MSI) and its relationship with both clinicopathologic parameters and patient survival, 101 cases of breast cancer were investigated. In addition, transforming growth factor-beta (TGF-beta) receptor type II (RII) gene mutation was also examined to clarify the relation to MSI in breast cancer development. MSI and RII gene mutation were screened by single strand conformation polymorphism (SSCP). The mutations of the RII gene were confirmed by a direct sequence. An association between the MSI status and the clinicopathological features was examined to assess the potential of the MSI status as a prognostic indicator in sporadic breast cancer cases. MSI was detected in 12 of 101 (11.9%) breast cancer cases. The positive MSI breast cancer cases showed relatively more advanced disease than negative MSI cases, and also exhibited relatively poorer prognoses. No RII gene mutations were observed in any of the breast cancer cases. Our data suggest that the MSI status may thus be a useful indicator for the prognosis of sporadic breast cancer cases. However, the breast seems to be an infrequent target organ for cancer development through RII gene mutations. As a result, tumor progression through this pathway appears to be related to organ specificity. For positive MSI breast cancers, other target genes therefore still need to be identified.
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PMID:Analyses of microsatellite instability and the transforming growth factor-beta receptor type II gene mutation in sporadic breast cancer and their correlation with clinicopathological features. 1020 70

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has enabled better characterization of the molecular mechanisms underlying iodide transport, thus opening the way to clarifying its role in thyroid diseases. Several studies, at both the mRNA and the protein expression levels, have demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS gene expression and NIS protein abundance, both in vitro and in vivo. However, other factors, including iodide, retinoic acid, transforming growth factor-beta, interleukin-1alpha and tumour necrosis factor alpha, may participate in the regulation of NIS expression. Investigation of NIS mRNA expression in different thyroid tissues has revealed increased levels of expression in Graves' disease and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in differentiated thyroid carcinomas, despite the expression of other specific thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to concentrate radioiodine, including salivary glands, stomach, thymus and breast. The production of specific antibodies against the NIS has facilitated study of the expression of the symporter protein. Despite of the presence of high levels of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of NIS protein, limited to the basolateral membrane of the thyrocytes. By immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic adenomas and reduced in thyroid carcinomas. Measurement of iodide uptake by thyroid cancer cells is the cornerstone of the follow-up and treatment of patients with thyroid cancer. However, radioiodide uptake is found only in about 67% of patients with persistent or recurrent disease. Several studies have demonstrated a decrease in or a loss of NIS expression in primary human thyroid carcinomas, and immunohistochemical studies have confirmed this considerably decreased expression of the NIS protein in thyroid cancer tissues, suggesting that the low expression of NIS may represent an early abnormality in the pathway of thyroid cell transformation, rather than being a consequence of cancer progression. The relationship between radioiodine uptake and NIS expression by thyroid cancer cells require further study. New strategies, based on manipulation of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy in the treatment of radiosensitive cancer, are also being investigated.
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PMID:Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. 1057 59


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