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)

Cell adhesion receptors, including the integrin-type collagen receptors (alpha1beta1, alpha2beta1, alpha10beta1 and alpha11beta1) participate in cancer progression and invasion. Quantitative RT-PCR indicated that all 4 receptors are abundantly expressed in sarcoma-derived cell lines, whereas most carcinoma-derived cells express alpha1beta1 and alpha2beta1 only. This was surprising because alpha11beta1 has been connected previously to the progression of lung adenocarcinomas. To test the hypothesis that alpha11 expression may not persist in cultured cancer cells we analyzed fresh tissue samples of 104 total prostatectomies, keeping in mind that prostate cancer cell lines showed negligible alpha11 mRNA levels. In prostate alpha2 expression was significantly lower in poorly differentiated carcinomas when compared to benign lesions (p = 0.0331). In immunohistochemistry the protein levels of alpha2 integrin decreased significantly (p = 0.0001) and the protein levels of alpha11 subunit increased significantly (p = 0.029) with the increasing grade of carcinoma. Thus alpha11beta1 may replace alpha2beta1 during tumor progression. Our observations support the idea that alpha11beta1 may be expressed in tumors but the corresponding cell lines may lose the expression of this integrin. Previous studies have shown that in cell culture androgen receptor (AR) controls alpha2beta1 expression. We measured AR mRNA levels and the number of AR positive nuclei in the prostate samples and the results showed a significant correlation between alpha2beta1 and AR. Androgen receptors may control the mechanisms regulating integrin expression in prostate.
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PMID:Regulation of prostate cell collagen receptors by malignant transformation. 1615 94

Osteosarcoma cells are capable of extracellular matrix (ECM) synthesis. The ability of ECM to trigger the proliferation of a novel osteosarcoma cell line (OSCORT) was tested in this study in relation to a known tumor ECM, isolated from Engelbreth-Holm-Swarm (EHS) sarcoma (EHS-ECM). OSCORT was grown in monolayer, in EHS-ECM and in ECM deposited by the cells (OSCORT-ECM). Both EHS-ECM and OSCORT-ECM increased the proliferation and migration of OSCORT cells. Among the ECM biopolymers, heparan sulfate proteoglycan (HSPG) and fibronectin enhanced invasive growth, collagen type IV reduced it, while laminin had no effect. Among the ECM components HSPG and collagen IV increased both the synthesis and activation of collagenase type IV, and all the ECM components substantially increased beta1 integrin levels in the cells. The majority of ECM biopolymers decreased the level of topoisomerase I (except laminin) and elevated topoisomerase II (except fibronectin) in OSCORT. The switch in the ratio between the activities of topoisomerases I and II was mainly due to HSPG. The HSPG synthesized by OSCORT cells is described as agrin, which is a novel finding. The present study showed that HSPG (agrin) showed the most remarkable stimulatory action on the growth and migration of OSCORT cells. HSPG-induced topoisomerase II-induction deserves further experimentation, to discover its relevance to tumor progression.
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PMID:Invasive growth and topoisomerase-switch induced by tumorous extracellular matrix in osteosarcoma cell culture. 1624 75

The reports deals with the data on repeat large-scale dissection of soft-tissue sarcoma following non-radical removal in 23 patients (13 males and 10 females , aged 14-75; mean age 42+/-30.2 yrs). Repeat surgery was carried out 3-6 weeks after primary one. Tumor progression was registered in 8 (34.8%): local recurrences which required radical intervention 4 (17.4%), distant metastases - 6 (26.1%) (lung - 3; liver - 1; lung and mediastinal lymph nodes - 1; lung and lumbar vertebra - 1). During the study, 5 patients died of tumor progression; all of them revealed distant metastases while 2 had local recurrences. Overall 5-year survival in 23 patients was 78%; whereas disease-free one - 65%.
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PMID:[Results of repeat large-scale dissection of soft-tissue sarcoma following non-radical removal]. 1627 6

Hepatoblastoma (HBL), a major childhood malignant neoplasm, represents the most frequent malignant liver tumor in childhood. Recent reports have shown the CTNNB1 coding beta-catenin protein to be frequently mutated or deleted at hot-spot regions involving exon 3 in HBL. We investigated the genetic alterations of the CTNNB1 coding beta-catenin protein and expression of several genes downstream of Wnt signals in 4 benign and 17 malignant pediatric liver tumors (PLTs) consisting of 15 HBL, 1 hepatocellular carcinoma, and 1 hepatic immature sarcoma. Of 17 malignant PLTs, 10 (56%) revealed pathogenic alterations of the CTNNB1 gene, including 4 with missense mutations at codons 28, 32, 34 or 44, and 6 with interstitial deletions that partially or totally affected exon 3. All 6 deletions were in-frame deletions without a frame shift. The high frequency without any correlation to histological type indicates that the CTNNB1 gene alteration is a crucial event in the tumorigenesis of malignant PLTs. The immunohistochemical studies in 17 malignant PLTs demonstrated the nuclear/cytoplasmic accumulation of beta-catenin to be positive in all tumor specimens except for one hepatic sarcoma. A histological examination revealed all HBL cases involving tumors without detectable CTNNB1 gene alterations to show high expression of beta-catenin, thus indicating the accumulation of beta-catenin to be a common event in malignant PLTs, including HBL and hepatocellular carcinoma. Among the Wnt signal genes downstream of beta-catenin, E-cadherin is expressed in all malignant PLTs, while cyclin D1 expression was significantly detected in malignant PLTs with an advanced stage of disease. An immunohistological examination of nuclear accumulation of beta-catenin may thus be useful for diagnosing malignant PLTs. On the other hand, the expression of cyclin D1, a gene downstream of beta-catenin, might play a role in tumor progression.
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PMID:Diagnostic and prognostic impact of beta-catenin alterations in pediatric liver tumors. 1646 11

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
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PMID:Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. 1647 53

Human telomerase reverse transcriptase (hTERT) is a telomerase catalytic subunit that regulates telomerase activity. Telomerase is expressed in many human cancers and cell lines and is thought to contribute to their immortality. Little is known about the expression of telomerase in non-epithelial tumors. The objective of this study was to evaluate hTERT expression in a wide range of soft tissue sarcomas. A total of 154 cases of different types of soft tissue sarcoma (54 low-grade, 40 intermediate-grade, and 60 high-grade cases) were evaluated for hTERT expression using immunohistochemistry on tissue microarrays. hTERT immunoexpression was detected in 59% of cases; it was observed in 46%, 58%, and 72% of low-grade, intermediate-grade, and high-grade sarcoma cases, respectively. The intensity of staining positively correlated with the grade of the sarcomas: diffuse strong positive nuclear staining was identified in 6, 8, and 30 cases of low-grade, intermediate-grade, and high-grade sarcomas, respectively. These results suggest that telomerase expression is more often detected in highly malignant tumors than in low-grade sarcomas and thus may be a critical mechanism in tumor progression.
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PMID:Immunohistochemical detection of hTERT protein in soft tissue sarcomas: correlation with tumor grade. 1678 90

B-cell functions in antitumor immunity are not well understood. In this study, we evaluated the role of B cells in the development of antitumor immunity using Friend murine leukemia virus gag-expressing mouse EL-4 (EL-4 gag), D5 mouse melanoma, or MCA304 mouse sarcoma cells. To screen tumors for susceptibility to B-cell-deficient immune environments, spleen cells from naive C57BL/6 [wild-type (WT)] and B-cell knockout (BKO) mice were cultured with irradiated tumor cells in vitro. When cells were stimulated with EL-4 gag or D5 (but not MCA304 tumors), IFN-gamma production from CD8 T cells and natural killer cells was markedly decreased in WT compared with BKO cultures. IFN-gamma production was correlated with CD40 ligand expression on the tumor and inversely with interleukin-10 (IL-10) production by B cells. Sorted WT B cells produced more IL-10 than CD40 knockout (CD40KO) B cells when cocultured with EL-4 gag or D5 (but not MCA304). IFN-gamma production by BKO cells was reduced by the addition of sorted naive WT B cells (partially by CD40KO B cells) or recombinant mouse IL-10. In vivo tumor progression mirrored in vitro studies in that WT mice were unable to control tumor growth whereas EL-4 gag and D5 tumors (but not MCA304) were eliminated in BKO mice. Robust in vivo antitumor CTLs developed only in BKO tumor-challenged mice. Our studies provide the first mechanistic basis for the concept that B-cell depletion could therapeutically enhance antitumor immune responses to certain tumors by decreasing IL-10 production from B cells.
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PMID:Inhibitory effects of B cells on antitumor immunity. 1751 Apr 42

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, yet the genetic changes causing this disease are poorly understood. The Fos protein, a major component of the AP-1 transcription factor, is essential for osteoclast differentiation, acts as an oncogene, potentiates transforming signals and controls invasive growth and angiogenesis during tumor progression. To genetically investigate a potential interaction between the p53 and Fos pathways, Trp53/Fos double knock-out mice were generated. These mice develop highly proliferative and invasive rhabdomyosarcomas of the facial and orbital regions with more than 90% penetrance at 6 months of age. Expression of Fos in Trp53/Fos mutant rhabdomyosarcoma cell lines established from primary tumors is associated with enhanced apoptosis and downregulation of Pax7 expression. Our results show that Trp53/Fos double knock-out mice recapitulate major aspects of human rhabdomyosarcoma development and therefore provide a mouse model for the human disease. Furthermore, this study identifies a novel and unexpected tumor suppressive function of the Fos proto-oncogene.
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PMID:[Rhabdomyosarcoma development in Trp53/fos mutant mice: tumor suppressor functions of the Fos protooncogene]. 1689 56

Dermatofibrosarcoma protuberans is a superficial low-grade sarcoma that rarely evolves into a high-grade fibrosarcoma. Dermatofibrosarcoma protuberans is genetically characterized by the unbalanced chromosomal t(17;22)(q21;q13), usually in the form of a supernumerary ring chromosome. The product of this chromosomal translocation is the chimeric gene COL1A1-PDGFB (collagen type I alpha I-platelet-derived growth factor beta), which is amplified at low levels in the ring chromosome. The aims of this study were to evaluate (1) whether genomic gains of this fusion gene occur during the clonal evolution of dermatofibrosarcoma protuberans into fibrosarcomatous dermatofibrosarcoma protuberans and (2) whether there is a difference between the number of genomic copies of COL1A1-PDGFB between classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas associated with fibrosarcomatous dermatofibrosarcoma protuberans. Eleven cases of fibrosarcomatous dermatofibrosarcoma protuberans with both dermatofibrosarcoma protuberans and fibrosarcomatous areas and 10 cases of classic dermatofibrosarcoma protuberans were studied. Genomic copies of COL1A1-PDGFB were evaluated by fluorescence in situ hybridization using a custom designed probe for the PDGFB locus on 4 mum thick paraffin-embedded tissue sections. Genomic gains of the COL1A1-PDGFB gene were observed in six (of 10) fibrosarcomatous dermatofibrosarcoma protuberans in the fibrosarcomatous areas when compared to the dermatofibrosarcoma protuberans areas of the same tumor (2-7 gene copies (median PDGFB copy gain, 2.8) versus 1-3 gene copies (median PDGFB copy gain, 1.7), respectively, P=0.004). Four fibrosarcomatous dermatofibrosarcoma protuberans did not show genomic gains of COL1A1-PDGFB fusion gene between the two areas. Essentially no difference in the copy number of COL1A1-PDGFB fusion gene was observed between dermatofibrosarcoma protuberans areas of classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas of fibrosarcomatous dermatofibrosarcoma protuberans (median PDGFB copy gain of 1.8 versus 1.7, respectively, P=0.36). Genomic gains of COL1A1-PDGFB fusion gene is possibly an oncogenic mechanism that is identified in the clonal evolution of a subset of dermatofibrosarcoma protuberans that evolves into fibrosarcomatous dermatofibrosarcoma protuberans. Since this finding was not observed in all cases of fibrosarcomatous dermatofibrosarcoma protuberans, other oncogenic mechanisms may be operating in this form of tumor progression. Copy number of COL1A1-PDGFB fusion gene in the classic dermatofibrosarcoma protuberans areas does not seem to be a major predisposing mechanism for fibrosarcomatous transformation.
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PMID:Gains of COL1A1-PDGFB genomic copies occur in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. 1698 Sep 46

Emmprin is a transmembrane glycoprotein on tumor cells that stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMPs). Emmprin and the induced MMPs play a crucial role in tumor progression, invasion and metastasis of human carcinomas (epithelial malignancies). However, only a few reports have addressed its role in soft tissue sarcomas. This study investigated the expression and role of emmprin in epithelioid sarcoma (ES). Immunoblot studies of 2 ES cell lines showed that they express emmprin, and co-culture of these ES cells with dermal fibroblasts resulted in upregulation of gelatinase A (MMP-2) in fibroblasts, as shown by zymography, immunoblotting and enzyme immunoassay. This stimulation was inhibited by an activity-blocking peptide against emmprin and by antiemmprin antibody. In addition, in vivo, immunohistochemical analysis of 5 ES patient cases demonstrated diffuse emmprin expression in ES cells and MMP-2 expression in both ES cells and peritumoral fibroblasts. The histopathological findings that peritumoral fibroblasts that were not in direct contact with emmprin-expressing ES cells exhibit upregulated MMP-2 prompted us to look for a soluble form of emmprin. Soluble full-length emmprin released from ES cells was detected in conditioned medium and shown to stimulate MMP-2 production by fibroblasts. In conclusion, emmprin is expressed in ES in both membrane and soluble forms and stimulates MMP-2 production via interactions with fibroblasts, which could play a role in ES cell stromal invasion and vascular involvement.
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PMID:Emmprin in epithelioid sarcoma: expression in tumor cell membrane and stimulation of MMP-2 production in tumor-associated fibroblasts. 1713 22


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