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)

In our previous study, we found no genetic alteration in exons 1 and 2 of Ha- and Ki-ras oncogenes nor in exons 5 to 9 of the p53 suppressor gene in seven Japanese malignant mesothelioma patients exposed to asbestos. To examine further whether malignant mesothelioma due to asbestos has genetic alterations in the p53 suppressor gene and in Ha- and Ki-ras oncogenes, we analyzed point mutations of these genes in paraffin embedded operative open biopsied samples of the primary tumor of malignant mesothelioma in twelve American patients. The genetic analysis was conducted by the PCR-SSCP (polymerase chain reaction single-strand conformation polymorphism) method in all patients and by sequencing analysis of DNA bases in the two patients with suspected gene mutation. The analysis of the p53 suppressor gene showed an amino acid converting mutation of exon 7 in one patient and a polymorphism of exon 6 in another patient; the former patient was a heavy smoker with a biphasic cell type. No genetic alteration was found in exons 1 and 2 of Ha- and Ki-ras oncogenes in any of the patients. The results suggest that the effects of asbestos on the p53 suppressor gene and Ha- and Ki-ras oncogenes in malignant mesothelioma are negligible. Further studies are needed to examine whether the observed mutation of the p53 suppressor gene is due to the combined effects of asbestos and smoking or to other unknown factors.
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PMID:Assessment of the mutations of p53 suppressor gene and Ha- and Ki-ras oncogenes in malignant mesothelioma in relation to asbestos exposure: a study of 12 American patients. 1206 59

It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.
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PMID:Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. 1208 6

Stage II colorectal carcinoma is characterized by negative lymph node pathology as determined by conventional microscopic examination. These patients generally do not receive adjuvant therapy although 20%-30% will die from metastatic disease. To determine whether K-ras mutations at codon 12 could be used as a sensitive indicator of occult lymph node metastasis in stage II colon carcinoma, a retrospective study was performed using restriction endonuclease-mediated selective polymerase chain reaction (REMS-PCR) amplification. Of 106 colonic tumors analyzed, 46 were identified as positive for a K12-ras mutation in the primary tumor. Multiple lymph node samples from 38 of these 46 patients were examined by a sensitive nested PCR protocol for the presence of a K12-ras mutation. Of these 38 patients, 14 had 1 or more positive lymph nodes by PCR (37%) and 24 were negative for the mutation (63%). Of the 14 patients with a K12-ras mutation detected in lymph nodes, 8 died of the disease within 5 years (57%) compared to only 4 of the 24 patients with ras-negative lymph nodes (17%). The difference in time to death from disease, stratified using K12-ras status of lymph nodes, was statistically significant (P = 0.036; log-rank test). These results suggest K-ras mutation status of lymph nodes in patients with stage II colon cancer might identify a subgroup of patients who are more likely to develop recurrent and/or metastatic disease and benefit from adjuvant therapy. Larger studies are indicated to determine whether detection of K-ras mutation positivity in histologically negative lymph nodes portends a poor prognosis and to determine whether more aggressive use of adjuvant therapy is warranted.
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PMID:Detection of mutated K12-ras in histologically negative lymph nodes as an indicator of poor prognosis in stage II colorectal cancer. 1244 69

In human carcinomas, stromelysin-3/matrix metalloproteinase 11 (ST3, MMP11) expression by nonmalignant fibroblastic cells located in the immediate vicinity of cancer cells is a bad prognostic factor. Using mouse models of primary tumors, it has been demonstrated that ST3 is a key player during local invasion, favoring cancer cell survival in connective tissue through an antiapoptotic function. To investigate the ST3 impact on additional phases of cancer cell invasion, we developed mammary gland cancer prone MMTV-ras transgenic mice in wild-type (ras+/+;ST3+/+) or ST3-deficient (ras+/+;ST3-/-) genotype and studied their whole natural cancer history. The tumor-free survival and delay between the first ras oncogenic hit and primary tumor appearance increased in ras+/+;ST3-/- mice (P < 0.000001 and <0.0000007, respectively). A systematic search for occult primary tumors and metastases revealed, in addition to a lower total number and size of primary tumors (P < 0.02), an unexpected higher number of metastases (P < 0.01) in ras+/+;ST3-/- mice. Moreover, for a similar number and size of primary invasive tumors, ras+/+;ST3-/- mice developed more metastases, indicating that the cancer cells evolving in ST3-deficient stroma have an increased potential to hematogenous dissemination. We conclude that the ST3 microenvironment is a consistently active partner of invading cancer cells but that its function differs throughout cancer progression, being tumor enhancer or repressor in processes leading to local or distal invasion. Such a dual effect for an MMP might shed light, at least partially, for the absence of survival benefit for patients included in anti-MMP clinical trials.
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PMID:Dual stromelysin-3 function during natural mouse mammary tumor virus-ras tumor progression. 1452 8

Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of beta-carotene, alpha-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor beta (RAR-beta), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
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PMID:Molecularly targeted approaches to the chemoprevention of lung cancer. 1521 68

Analysis of the genetic status of Ki-ras and p53 in primary colorectal carcinomas and matched colorectal liver metastasis from 30 patients reveals an overall heterogeneity both within and between the two tumoral tissues. Both genes were found mutated with a similar frequency in both tissues; however, identical mutations in primary tumor and matched metastasis were found less frequently in the case of the Ki-ras than the p53 gene. Only in three cases the same p53 and Ki-ras mutations found in the primary tumor were found also in the metastasis. In several metastatic specimens the DNA bearing a mutation detected also in the primary tumor appears significantly less abundant than the wild-type DNA. These data are discussed in the light of current models of primary tumor/metastasis relationships.
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PMID:Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations. 1554 58

The virtual lack of well-characterized metastatic pancreatic cancer tissues for study has limited systematic studies of the metastatic process of this deadly disease. To address this important issue, we have instituted a rapid autopsy protocol for the collection of high quality tissues from patients with metastatic pancreatic cancer, called the Gastrointestinal Cancer Rapid Medical Donation Program (GICRMDP). At the time of preparation of this manuscript, 20 patients with metastatic pancreatic cancer and one patient with metastatic colon cancer have undergone a rapid autopsy in association with the GICRMDP. The average time interval achieved for these 21 patients was 8.0 hours, with more than 500 individual samples of matched high quality primary and metastatic pancreatic cancer tissues, peritoneal/pleural fluid and blood obtained so far. For the first four patients in which the autopsy was performed in <6 hours, we have successfully xenografted the primary tumor and/or two to four independent matched metastases from a variety of target organ sites, with a take rate of almost 60% for the first 26 xenografted tumors attempted. In an initial survey of KRAS2, TP53 and DPC4 genetic status in lethal metastatic pancreatic cancers, activating KRAS2 mutations were detected in 82% of cases and inactivating TP53 mutations in 55% of cases, consistent with rates of genetic alteration of these genes in early stage pancreatic cancers. However, DPC4 inactivation was found in 75% of patients analyzed, suggesting that genetic inactivation of the DPC4 tumor suppressor gene continues to be selected for with growth at the primary site and metastatic spread to other organs. The invaluable tissue resources generated by the success of the GICRMDP will provide an unparalleled resource for study of metastatic pancreatic cancer and of the metastatic process in general.
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PMID:Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy. 1584 69

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy.
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PMID:Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. 1592 28

Osteopontin (OPN) is a predominantly secreted extracellular matrix glycophosphoprotein which binds to alpha v-containing integrins and has an important role in malignant cell attachment and invasion. High OPN expression in the primary tumor is associated with early metastasis and poor outcome in human breast and other cancers. Forced OPN overexpression in benign cells may induce neoplastic-like cell behaviour including increased attachment and invasion in vitro as well as the ability to metastasize in vivo. Conversely, OPN inhibition by antisense cDNA impedes cell growth and tumor forming capacity. OPN is not mutationally activated in cancer but its expression is regulated by Wnt/Tcf signaling, steroid receptors, growth factors, ras, Ets and AP-1 transcription factors. Presumably these factors are implicated in induction of OPN overexpression in cancer. Greater understanding of the role of OPN in neoplastic change and its transcriptional regulation may enable development of novel cancer treatment strategies.
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PMID:The regulation and role of osteopontin in malignant transformation and cancer. 1711 38

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, was approved in 2004 for use in combination with intravenous 5-fluorouracil-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is the first approved agent that targets tumor angiogenesis. The pivotal phase III trial showed significantly greater overall and progression-free survival with the addition of bevacizumab to irinotecan, 5-fluorouracil, and leucovorin. These outcomes were observed irrespective of patients' pretreatment characteristics (age >/=65 years, >/=1 site of metastasis, or location of primary tumor). Furthermore, there was a significant survival benefit regardless of pretreatment biomarkers, including plasma vascular endothelial growth factor level, tumor thrombospondin and p53 expression, and mutational status in k-ras, b-raf, and p53. Analysis of data in responders and nonresponders showed a response-independent survival benefit, indicating that even those in whom there was not an objective tumor response by standard criteria benefited from the addition of bevacizumab. Preliminary data on the addition of bevacizumab to oxaliplatin- and capecitabine-based regimens for the first-line treatment of metastatic colorectal cancer show that these regimens are well tolerated, with consistent increases in objective response rates, time to progression, and overall survival. The survival advantages in patients with metastatic colorectal cancer with the addition of bevacizumab to chemotherapy support the use of this agent in first-line treatment.
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PMID:Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. 1714 25


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