Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RHAMM is an oncogene that regulates signaling through ras and controls mitogen-activated protein kinase [extracellular signal-regulated protein kinase (ERK)] expression in embryonic murine fibroblasts. ERK is a dual-specificity kinase that controls expression of proteins relevant to tumorigenesis, proliferation, and motility. To assess whether RHAMM and ERK are involved in human breast tumor progression, we examined RHAMM, ras, and ERK expression in two cohorts of breast cancer patients using reverse transcription-PCR and immunocytochemistry. We show that overexpression of RHAMM in primary tumors of two patient cohorts was significantly prognostic of poor outcome in breast cancer progression. Furthermore, RHAMM overexpression occurred within subsets of tumor cells in the primary tumor, and this staining pattern was associated with lymph node metastases. The metastases exhibited a significantly higher level of staining for RHAMM than did the primary tumor. RHAMM expression strongly correlated with overexpression of both ras and ERK, although overexpression of either of these two signaling molecules was not by itself a prognostic indicator. These results identify a new parameter that is involved in lymph node metastasis of primary breast cancers and suggest that quantification of RHAMM overexpression may be a useful prognostic indicator for breast carcinoma progression.
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PMID:The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. 953 23

CD44s (standard isoform), which binds hyaluronan (HA), has been analyzed for its significance during fibrosarcoma progression and metastasis in an athymic nude mouse model using Balb/c 3T3 cells transformed with ras or sis oncogenes. While ras (but not sis) transformation leads to upregulated expression of mouse CD44s and HA binding, transfection/overexpression of human CD44s gene (hCD44s) elicited remarkable plasticity of expression during progression and metastasis. In 3T3, hCD44s induced tumorigenesis, HA binding, and micrometastatic competence to lungs and other organs. In tumorigenic (but nonmetastatic) sis transformants or ras-deleted revertants, it also induced micrometastatic competence. Conversely, large primary tumors and overt metastases lost hCD44s expression and HA binding via hypermethylation of hCD44s gene. Tail vein injections revealed that hCD44s greatly increased the efficiency of colonization of the lung microvasculature at the earliest stages. These studies indicate that hCD44s overexpression and possibly its HA binding are critical for conveying metastatic competence but are antagonistic or selected against during aggressive primary tumor or overt metastasis outgrowth. This remarkable plasticity of expression and its consequences offer an ideal system for dissecting the molecular mechanisms operating during fibrosarcoma progression and metastasis.
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PMID:Plasticity of CD44s expression during progression and metastasis of fibrosarcoma in an animal model system. 963 40

It is widely recognized that various oncogenes and tumor suppressor genes contribute to tumorigenesis and progression of osteosarcomas. However, whether genetic alternations enable us to predict the prognosis of patients with osteosarcomas is unclear. Southern blotting and polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) analyses were performed to search for MDM2, ras family and p53 gene alterations in 17 patients with high-grade osteosarcomas. Amplification of the MDM2 gene was found in three tumors, two of which were obtained from a regional lymph node metastasis and the other from a locally advanced lesion. Point mutations of the p53 gene were found in exons 4 and 5 in two tumors each. One of the four tumors with p53 mutations was obtained from a lymph node metastasis, one from a recurrent tumor and another from the primary tumor of a patient who developed lung metastases. Coexistence of MDM2 amplification with point mutation of the p53 gene was observed in two tumors. A point mutation of the K-ras oncogene was detected at codon 13 in two tumors. MDM2 amplification and p53 mutation may reflect tumor progression, although no correlation between alteration and response to chemotherapy or patient survival was demonstrated.
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PMID:Clinicopathologic implications of MDM2, p53 and K-ras gene alterations in osteosarcomas: MDM2 amplification and p53 mutations found in progressive tumors. 979 60

As clinical oncologists, our ultimate goal in treating patients with cancer is to be able to cure their disease with a combination of treatment modalities directed at the primary tumor (surgery or radiation), and potential metastases (chemotherapy). The validity of this multimodality approach to treating cancer was initially demonstrated with the successful treatment and cure of highly chemosensitive childhood cancers, such as Wilms' tumor, and these cures were only realized when adjuvant chemotherapy was included with local control measures. We attribute our treatment successes in childhood cancers to the use of cytotoxic chemotherapy, and we attribute our inability to cure many adults with more common forms of solid tumors to the ineffectiveness of chemotherapy in these diseases. Curing disease is not the goal of most pharmacological interventions in nonmalignant diseases. With the exception of antimicrobial and anticancer chemotherapy, most of the common classes of drugs are administered with the intent of controlling the disease or the symptoms caused by disease. We administer antihypertensive agents to control blood pressure, but the underlying cause of the hypertension is not cured by this therapy. If the hypertension recurs after antihypertensive therapy is stopped, we would conclude that the therapy was successful at controlling the disease. However, if a patient's tumor relapses after completing anticancer chemotherapy, the anticancer therapy would be considered to be unsuccessful. By setting lofty goals for our therapy, we increase the probability that the treatment will not meet our own and our patient's expectations. Schipper et al. [J Clin Oncol 1995;13:801-805] proposed that we abandon the "killing paradigm," which dictates that the treatment of cancer is directed toward eradication of all cancer cells, and that we adopt a "regulatory model" of cancer. This model views cancer as a maladaptive, constantly evolving process in which cancer cells differ only slightly from normal cells as a result of a few critical genetic changes that lead to dysregulation of growth. The treatment approach under this new paradigm is debulking of tumor burden with standard multimodality therapy followed by control of residual disease by "reregulation" of the remaining cancer cells. Controlling growth and spread of this residual disease would be accomplished with non-cytotoxic agents which target pathways that are responsible for the dysregulation in cancer cells. We are now on the verge of having the capacity to test this new paradigm of cancer. Advances in our understanding of the pathogenesis of many common forms of cancer at a molecular level have led to a revolution in anticancer drug development. A number of new agents that target a variety of critical molecular targets, such as the farnesyl transferase inhibitors that block ras oncogene activation, the matrix metalloproteinase inhibitors that block the enzymes involved in tissue invasion and metastasis [Editor's note: please see "New Drugs on the Horizon, page 271], and the angiogenesis inhibitors that block new vessel formation in growing tumors, are now being clinically tested. These new classes of anticancer drugs are aimed at regulating or controlling cancers rather than killing them. The potential utility of targeting the critical molecular lesion in tumor cells is illustrated by the efficacy of all-trans-retinoic acid in acute promyelocytic leukemia (APL). Although the capacity of all-trans-retinoic acid to induce complete remissions by inducing terminal differentiation of leukemic blasts was discovered empirically, the subsequent demonstration that the pathognomonic 15:17 translocation that is present in up to 90% of cases of APL results in the production of a dysfunctional retinoid receptor appears to explain the specificity and high level of activity of retinoid therapy in this disease. This is the first example of a cancer that can be treated by specifically targeting therapy to a pathogenetic molecular lesion. Retinoids are now being used in combination with standard chemotherapy for the treatment of APL, an example of the successful application of combining a molecularly targeted agent with conventional cytotoxic chemotherapy. The development and use of molecularly targeted agents for the treatment of cancer may require us to view cancer in a new light and to adjust our goals and expectations of its treatment as well as the endpoints of our clinical trials. However, pharmacologically controlling cancer may result in an equally acceptable outcome for our patients if it leads to what Schipper et al. termed a "functional cure."
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PMID:The Goal of Cancer Treatment. 1038 18

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been identified, the Raf protein kinases which are upstream regulators of the mitogen-activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic effectors. Constitutive upregulation of this pathway by oncogenic ras is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2 were not detectable under conditions of exponential growth or serum-starvation. Depending upon the cell line, the block in Erk signaling was observed to occur at either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack of Erk activation observed in both cell lines and primary tumor tissue suggests that constitutive Erk activation may not be required for tumor maintenance or progression in K-ras transformed pancreatic cells. We hypothesize that other Ras-dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have important implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.
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PMID:Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. 1040 37

Several key areas are targeted by novel therapies. Growth factors and their receptors are overexpressed in a high percentage of pancreatic tumors. These factors are critical to tumor cell growth and development. They also promote tumor growth by stimulating angiogenesis. Mutations in other molecules that regulate cell growth, such as the ras protein and the tumor suppressor p53, contribute to a state of continuously stimulated cell proliferation. Other types of molecules such as mucins are also altered or overexpressed in tumors. Mucins are immunosuppressive and are important in tumor cell metastasis. A number of promising new therapeutic strategies are now being tested. Ribozymes or antisense nucleic acids can prevent synthesis of growth factor receptors or ras protein. Monoclonal antibodies block interaction between receptor and its ligand. Newly developed drugs prevent tyrosine phosphorylation of growth factor receptors or farnesylation of ras protein. Gene therapy is another approach that is under investigation. Transduction or transfection of genes for wild-type tumor suppressors could correct defects in growth regulation. Vaccines developed against tumor antigens provide hope for the control of not only the primary tumor, but also of the metastatic lesions as well.
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PMID:Biliopancreatic malignancy: future prospects for progress. 1043 45

Human solid tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. We sought to determine whether there are specific sequences of occurrence of these progressive evolutionary changes in human breast cancers by performing correlated cell-by-cell measurements of cell DNA content, p53 protein, Her-2/neu protein, and ras protein by multiparameter flow cytometry in 56 primary tumor samples obtained at surgery. In addition, p53 allelic loss and Her-2/neu gene amplification were determined by fluorescence in situ hybridization in cells from the same samples. We reasoned that if there is a specific order in which genetic changes occur, the same early changes would be found consistently in the cells with the fewest abnormalities. We reasoned further that late-developing abnormalities would not occur alone in individual cells but would almost always be found together with the early changes inherited by the same cells. By these criteria, abnormalities involving p53 generally occurred early in the course of development of invasive breast cancers, whereas ras protein overexpression was found to be a late-occurring phenomenon. Within individual tumors, cellular p53 overexpression was often observed alone in individual cells, whereas ras protein overexpression was rarely observed in the absence of p53 overexpression and/or Her-2/neu overexpression in the same cells. Furthermore, the intracellular level of each abnormally expressed protein was found to increase progressively as new abnormalities were acquired. Infiltrating ductal carcinomas exhibited characteristic phenotypic patterns in which p53 allelic loss and/or p53 protein overexpression, Her-2/neu amplification and/or overexpression, aneuploidy, and ras overexpression accumulated within individual cells. However, this pattern was not a prominent feature of lobular breast cancers. All six lobular breast cancers studied were diploid. p53 allelic loss and/or early p53 overexpression, and late ras cooverexpression in the same cells were less common in lobular breast cancers than in infiltrating ductal carcinomas. Although Her-21neu overexpression was a common finding in lobular breast cancers, Her-2/neu amplification was not observed in these tumors.
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PMID:Correlations among p53, Her-2/neu, and ras overexpression and aneuploidy by multiparameter flow cytometry in human breast cancer: evidence for a common phenotypic evolutionary pattern in infiltrating ductal carcinomas. 1065 39

Transgenic mice expressing c-myc and v-Ha-ras specifically in the mammary gland under the control of the mammary specific promoter MMTV develop unifocal mammary tumors with a half time of about 46 days, and these tumors express high levels of osteopontin mRNA and protein. In order to evaluate the requirement for osteopontin expression by these tumors, we have crossed transgenic mice expressing these two oncogenes with mice with a targeted disruption of the osteopontin gene. Littermates expressing both myc and ras, and with either wild-type or disrupted OPN alleles were evaluated for tumor incidence and growth rate. Both of these parameters were found to be unaffected by a lack of osteopontin in the whole animal. Ras and myc expression level, measured at the level of mRNA, was not different in tumors of the two genotypes. Macrophage accumulation, while extremely variable among different tumors, did not correlate with the OPN status of the animals. Expression of the related gene BSP was not detected in any of the tumors, and was similar in bones of wildtype and OPN -/- mice. Similarly, the vitronectin gene was expressed at very low levels in tumors of either genotype. These results indicate that despite its high level of expression, OPN is either not required for mammary primary tumor formation and growth in this system, or can be replaced by molecules other than BSP and vitronectin in mice that totally lack osteopontin.
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PMID:Mammary tumor development in MMTV-c-myc/MMTV-v-Ha-ras transgenic mice is unaffected by osteopontin deficiency. 1107 61

The type and number of genetic aberrations required for a fully malignant tumor are still unclear. This study describes the genetic analysis of a series of skin squamous cell carcinomas, representing the primary tumor, two recurrences, and a metastatic lesion from a single patient and cell lines established therefrom (MET-1 to MET-4). Comparative genomic hybridization demonstrated that: (i) most of the gains and losses were common for tumors and cell lines and affected chromosomes 3 (3p loss, 3q gain), 5 (5p gain, 5q loss), 7 (7p gain), 8 (8p loss, 8q gain), 11 (11q gain), and 17 (17p loss), and (ii) only one aberration was present in a tumor but not in the cell line (10 loss in tumor 4); and only few aberrations were cell line specific. From these, 10p loss and 17q gain were shared by all lines and tumor 4, suggesting that they were already present in all tumors, although in only a subpopulation of cells, whereas 20q gain (shared by all lines), 4q loss (MET-2), and 18p gain/18q loss (MET-3) seem to be culture derived. In agreement, multiplex fluorescence in situ hybridization demonstrated a set of common translocations for all lines thereby further confirming their common origin. In addition, each cell line, exhibited one or more individual translocation chromosomes, which suggested that MET-1 was a precursor of MET-4, whereas MET-2 and MET-3 developed in parallel. Whereas MET-1 to MET-3 were hypodiploid or hyperdiploid, MET-4 was characterized by polyploidization, a set of specific aberrations (t(3;7), t(X;2), i(10q)), and increased heterogeneity (varying translocations in individual metaphases). Using sequencing and expression studies, cells from all lines were wild type for p53, did not exhibit mutations in any of the ras genes (Harvey, Kirsten, or N-ras), and expressed wild-type fragile histidine triad gene (FHIT; mapped to 3p14.2, a locus underrepresented in all cells) transcripts. Thus, with the MET cell lines we present an in vivo skin carcinoma progression model that was genetically well defined, and which, despite originating from a sun-exposed site, is wild type for p53.
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PMID:Genetic characterization of a human skin carcinoma progression model: from primary tumor to metastasis. 1112 Nov 47

The presence of DNA fragments circulating in cancer patients was described a number of years ago. The mere presence of DNA in the circulation is not indicative of cancer. However, there are reports that apoptosis and necrosis of the cancer cells can increase the levels of circulating DNA. The study of plasma DNA with the detection of genetic abnormalities associated with specific cancers has produced some promising results. Primary cancer often harbors ras or p53 mutations and the detection of these mutations in free circulating DNA could indicate the presence of cancer. Other approaches have included detection of specific losses of heterozygosity (LOH), microsatellite instability (MI) and promoter hyper-methylation. For breast cancer, studies published to date have focused on detecting LOH, MI and methylation of the p16INK4A promoter. Good concordance between alterations in the primary tumor and detection of the same alterations in the circulation has been observed. Also, it is encouraging to note that DNA alterations have been detected in patients with small or even in situ lesions, indicating that circulating tumor DNA is shed early in the disease process. If 'universal' breast-specific DNA alterations can be identified, this approach may hold significant promise for early detection of breast cancer.
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PMID:Tumor-specific DNA in plasma of breast cancer patients. 1198 80


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