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)

Although human breast tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumor suppressor genes, the identity of the genetic alterations that are critical in the early stages of the breast tumorigenic process remains obscure. A high frequency (27-41%) of loss of heterozygosity (LOH) occurrence has been shown at the MET locus on chromosome band 7q31 and this specific alteration is associated with poorer survival. Here, we report that restriction fragment length polymorphism (RFLP) analysis on 221 informative (heterozygous) primary breast tumors and 57 informative relapses (13 local recurrences and 44 distant metastases) revealed a similar frequency of 7q31 LOH as tumors progress from primary cancer to relapse, in marked contrast to other changes such as 11p15.5 LOH. This finding suggests that inactivation of a putative tumor suppressor gene located in 7q31 is a very early event in breast tumorigenesis. Our results also show that metastatic potential is an induced phenomenon that occurs at a relatively early stage, rather than a marker of tumor progression.
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PMID:Loss of heterozygosity on 7q31 occurs early during breast tumorigenesis. 753 86

Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
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PMID:Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. 763 32

Hepatocyte growth factor (HGF), secreted by mesenchymal cells, has pleiotropic biological activities on several cell types. HGF and its receptor, the c-met proto-oncogene product (c-MET) have been implicated in the genesis and progression of several carcinomas and sarcomas. It has been suggested that MET/HGF autocrine signaling may contribute to tumorigenesis in sarcomas. HGF has been recently found to be a mitogen for rat Schwann cells and to be present in neurofibromas in NF1 patients. In this investigation, we assessed the immunoreactive patterns of HGF and MET in benign and malignant peripheral nerve sheath tumors (PNST) using archival formalin-fixed tissue. The standard avidin-biotin-peroxidase method was used. All benign tumors were negative with HGF. Eight cases of MPNST were positive with both HGF and MET. In some malignant PNST, positivity with both ligand and the receptor may be indicative of an autocrine mediated signal transduction and may implicate HGF/MET in tumor progression. Immunoreactivity with MET was strikingly greater in MPNST in contrast to benign PNST; this finding may prove to be helpful in distinguishing some histologically low-grade MPNST from cellular and atypical benign PNST.
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PMID:Hepatocyte growth factor and c-MET in benign and malignant peripheral nerve sheath tumors. 930 31

Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.
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PMID:Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. 962 53

A unique series of epidermal cell lines representing different stages of malignant transformation were spontaneously derived from a single adult immunosuppressed individual. Four keratinocyte lines (PM1-4) established from forehead skin are here compared with 4 squamous cell carcinoma (SCC) lines (MET1-4) derived respectively from a primary cutaneous tumour, two local recurrences and a distant metastasis of invasive SCC. Despite altered growth properties, the PM lines retained many features of normal keratinocytes including keratin phenotype, differentiation capacity and non-tumorigenicity in athymic mice. In contrast, from early passage, the MET lines displayed markedly reduced growth requirements, abnormal differentiation, aberrant K18 expression and tumorigenicity in athymic mice. The abnormal keratin profile of individual MET lines closely reflected the keratin phenotype of the tumour of origin. Although unusual HPV types were identified in the original tissue, there was no evidence of persistent virus within any cell line and it appears that HPV is not critical for maintenance of the immortal phenotype. The PM lines were distinctly different from invasive SCC lines and are likely to be useful for studies of mutations important early in neoplastic progression. The SCC series represent primary, recurrent and metastatic carcinoma. Availability of such a series from the same individual will facilitate genetic analysis of the malignant process.
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PMID:Spontaneous keratinocyte cell lines representing early and advanced stages of malignant transformation of the epidermis. 1077 84

Changes in morphological features between the primary and metastatic sites in osteosarcoma and the role of nm23 protein and c-MET oncogene product have remained controversial. In addition to histological studies, we evaluated the expression of nm23, c-MET, p53, and MDM2 immunohistochemically using 25 osteosarcomas in which both primary and concordant metastatic specimens were available. Moreover, we assessed proliferative activity using the monoclonal antibody MIB-1. Among these 25 cases, 4 tumors that were osteoblastic type (16%) in the primary site had changed morphologically to MFH-like type in the metastatic site, whereas 2 MFH-like type and 1 small cell-type tumors had changed to osteoblastic type. MIB-1 LI was significantly higher in the metastatic site than in the primary site (primary, 20.02; metastatic, 26.72; P = .0209). Seventeen cases (68%) showed increased nm23 expression in the metastatic site, whereas 2 cases showed reduced expression. nm23 expression was significantly increased in the metastatic site, compared with the primary site (P = .0009). Seven cases (28%) showing negative reaction for c-MET in the primary site showed immunuoreactivity for c-MET in the metastatic site. Although there was no statistical significance, c-MET expression seemed to be more frequent in the metastatic site, compared with the primary site. Among the overall tumors, c-MET-positive tumors showed significantly higher MIB-1 LI, compared with c-MET-negative tumors (negative, 20.99; positive, 27.65; P = .0292). No significant change was observed regarding p53 and MDM2 between the primary and metastatic site. Our results suggest that rather than being a metastasis-suppressor gene, nm23 is in fact correlated with metastatic progression in osteosarcoma. Positive correlation between c-MET expression and proliferative activity also suggests that c-MET expression may play an important role in tumor progression in osteosarcomas.
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PMID:Comparison of histological changes and changes in nm23 and c-MET expression between primary and metastatic sites in osteosarcoma: a clinicopathologic and immunohistochemical study. 1087 65

Pancreatic cancer is a highly aggressive, treatment refractory cancer and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas overexpress altered forms of a tumor-specific Ag, mucin 1 (MUC1; an epithelial mucin glycoprotein), which is a potential target for immunotherapy. We have established a clinically relevant animal model for pancreatic cancer by developing a double transgenic mouse model (called MET) that expresses human MUC1 as self molecule and develops spontaneous tumors of the pancreas. These mice exhibit acinar cell dysplasia at birth, which progresses to microadenomas and acinar cell carcinomas. The tumors express large amounts of underglycosylated MUC1 similar to humans. Tumor-bearing MET mice develop low affinity MUC1-specific CTLs that have no effect on the spontaneously occurring pancreatic tumors in vivo. However, adoptive transfer of these CTLs was able to completely eradicate MUC1-expressing injectable tumors in MUC1 transgenic mice, and these mice developed long-term immunity. These CTLs were MHC class I restricted and recognized peptide epitopes in the immunodominant tandem repeat region of MUC1. The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.
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PMID:Mice with spontaneous pancreatic cancer naturally develop MUC-1-specific CTLs that eradicate tumors when adoptively transferred. 1097 66

Control of cell growth and differentiation occurs via extracellular signals known as growth factors. Growth factors are high affinity ligands for transmembrane receptors belonging to the family of receptor tyrosine kinases (RTKs). A number of genetic evidences have implicated RTKs in human diseases including developmental disorders and cancer. For instance, germline missense mutations involving the Ret receptor are found in patients affected by multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) or familial medullary thyroid carcinomas. Somatic mutations in the Kit receptor are found in mastocytomas and in gastrointestinal tumors. Germline and sporadic mutations of the Met receptor have been described in kidney and hepatocellular carcinomas. Overexpression of the HER-2/neu receptor in breast cancer has been associated with tumor progression. The enzymatic activity of RTKs is strictly regulated and is usually inhibited under basal conditions. Receptor activation triggers a biochemical signalling cascade inside the cytoplasm, named signal transduction, which is subverted during the malignant transformation of cells. Signal transduction by RTKs is a multistep process which includes: (i) Ligand binding and receptor dimerization, (ii) receptor phosphorylation on tyrosine residues; (iii) recruitment to the receptor and activation of cytoplasmic signaling molecules that transmit signals to the nucleus. Each of the steps involved in this process can potentially be targeted to block the aberrant properties of tyrosine kinase receptors. By using the MET oncogene as a model this review focuses on the strategies that can be applied to therapeutically target RTKs.
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PMID:Receptor tyrosine kinases as therapeutic targets: the model of the MET oncogene. 1146 38

Tumor progression may be viewed as an evolutionary process at the cellular level. Because blood supply to solid tumors is inadequate, the cancer cells face a hostile microenvironment characterized by hypoxia or anoxia, acidic extracellular pH and nutrient deficiencies. It has been proposed that these factors result in increased levels of spontaneous mutagenesis and thereby contribute to tumor progression. We have examined spontaneous mutagenesis in vitro and in vivo, using previously characterized cell lines (mammary epithelial cells [ME] and mammary fibroblast cells [MFib]) from the mammary gland of the BigBluetrade mark rat, carrying a transgene construct suitable for the detection of mutations. Cells were exposed in vitro to control conditions, low pH, or to glucose deprivation, under normoxic or hypoxic culture conditions, and were also grown as xenografted tumors in immune-deficient mice. We examined cell survival and mutant frequency/spectrum at the cII locus. Significant increases in mutant frequency were observed in ME cells exposed to hypoxia alone or in combination with no glucose; the latter condition also resulted in reduced clonogenic survival. Cells grown as xenografts and then recovered and expanded in culture also had elevated frequencies of spontaneous mutations. We observed a shift in the spontaneous mutation spectrum between the ME cells and the MET cells (cultured in vitro or isolated from mouse xenograft tumors). These results support the concept that the tumor microenvironment contributes to tumor progression by enhancing spontaneous mutagenesis, that different cell types from the same organ can respond differently to these stresses and that differences in microenvironment may influence the types of mutations that arise.
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PMID:Microenvironmental influences on mutagenesis in mammary epithelial cells. 1584 43

In a screen for gene copy number alterations in mouse mammary tumors initiated by loss of the Brca1 and Trp53 genes, we observed that the majority (11 of 15; 73%) had high-level amplification of wild-type Met, encoding a growth factor receptor implicated in tumor progression. Met amplification was localized to unstable double minute chromosomes and was uniquely found in mouse breast tumors driven by loss of Brca1 and Trp53. Whereas analogous MET amplification was not found in human breast cancers, the identification of a dominant somatic genetic lesion in the Brca1/Trp53 mouse model suggests that recurrent secondary hits may also exist in BRCA1-initiated human breast cancer.
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PMID:Frequent met oncogene amplification in a Brca1/Trp53 mouse model of mammary tumorigenesis. 1658 67


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