Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular genetic alterations in colorectal carcinoma are among the best understood of any common human cancer. Identified abnormalities include both dominant-acting oncogenes (ras, myc, src) and suppressor genes which undergo inactivation or deletion (deleted in colorectal carcinoma gene [DCC], p53, adenomatous polyposis coli gene [APC], and probably loci on chromosomes 1p and 22q). Accumulation of multiple abnormalities is evident in the adenoma-carcinoma sequence with a preferential order, and alteration of DNA methylation is an especially early event. Identification of molecular genetic markers useful for classification and staging of colorectal carcinoma is in its infancy. Deletion of the p53 gene on chromosome 17p, deletion of the DCC gene on 18q, and high fractional allelic loss (fraction of evaluable nonacrocentric autosomal arms with deletion) have been associated with distant metastases and with poorer prognosis in patients without initial evidence of disseminated disease. Additional studies are needed to determine the possible role of these alterations in clinical management.
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PMID:Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma. 154 Sep

p97 is a human tumor-associated Ag present on most melanoma cells that represents a possible target for immunologic attack. To evaluate the capacity of T cells reactive with this protein to promote elimination of melanoma cells expressing p97, a murine model was developed by transfecting a C3H/HeN melanoma with the p97 cDNA, generating p97-specific CD4+ T cells by in vivo immunization of C3H/HeN mice with a vaccinia/p97 recombinant virus followed by in vitro cloning with soluble p97 protein, and determining whether these CD4+ T cells could mediate rejection of pulmonary metastases. Characterization of the T cell clones demonstrated the presence of both I-Ak and I-Ek-restricted clones, although the majority of clones recognized p97 in the context of I-Ek. Analysis of clonal specificity using truncated p97 proteins revealed that at least three epitopes were immunogenic, and further studies with overlapping 15-amino acid peptides from a region of the p97 molecule defined by these truncated proteins identified an immunodominant epitope responsible for the majority of the I-Ek response. The T cell clones were not capable of directly recognizing the p97-expressing melanoma cells but responded to the tumor if syngeneic APC were present to process the tumor-derived p97 Ag. The therapeutic efficacy of these CD4+ T cell clones was evaluated in an adoptive therapy model in which mice bearing metastatic pulmonary lesions were treated by i.v. administration of the p97-specific cells. Despite the inability of the CD4+ clones to directly respond to or lyse the tumor cells, the clones were effective in promoting tumor eradication. In vitro studies demonstrated that this may have reflected secretion of lymphokines that activated macrophages to lyse the tumor. The results suggest that noncytolytic p97-specific CD4+ T cell clones can be effective in therapy of pulmonary melanoma metastases. Moreover, if human T cells reactive with the p97 protein could be generated, the expression of this tumor-associated Ag in melanoma cells might be adequate for such T cells to mediate a therapeutic antitumor response.
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PMID:CD4+ T cell clones specific for the human p97 melanoma-associated antigen can eradicate pulmonary metastases from a murine tumor expressing the p97 antigen. 170 34

Immunotherapy with Interleukin-2 (IL-2) and LAK cells has shown antitumoral activity in metastatic cancer patients. So far, thrombocytopenia is the major side effect reported in hemostasis. We have studied coagulation parameters in 6 patients treated with r-Met Hu IL-2 [ala-125]. In each case, we have observed a significant fall in prothrombin time, fibrinogen, protein C, anti-thrombin III, plasminogen, alpha 2-antiplasmin and all of the clotting factors except factor VIII. There was a significant increase in the activated thromboplastin time. No significant modifications of the D-Dimer test, fibrin-fibrinogen degradation products (FDP) and thrombin time were observed. Our data suggest that r-Met Hu IL-2 [ala-125] could interfere with the hepatic synthesis of the clotting factors and their inhibitors.
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PMID:Blood coagulation abnormalities during adoptive immunotherapy with interleukin-2 (r-Met Hu IL-2 [ala 125]). 200 36

Hemostatic abnormalities are present in a majority of patients with metastatic cancer. These abnormalities can be categorized as 1) increased platelet aggregation and activation, 2) abnormal activation of coagulation cascade, 3) release of plasminogen activator, and 4) decreased hepatic synthesis of anticoagulant proteins like Protein C and antithrombin III. The abnormal activation of coagulation cascade is mediated through release of Tissue Factor, Factor X activators, and other miscellaneous procoagulants from the plasma membrane vesicles of tumor cells. Macrophages of a tumor-bearing host also produce increased amounts of Tissue Factor. Production of Factor X activators and macrophage Tissue Factor is decreased by warfarin. The ability of the tumor cells to produce platelet-aggregating activity and plasminogen activator parallels their metastatic potential in animal and experimental systems. These studies also show that antiplatelet agents and antibodies against plasminogen activator can suppress the metastatic process. One or more laboratory abnormalities of hemostasis can be shown in up to 95% of patients with metastatic cancer. These abnormalities, however, are unable to predict subsequent development of thromboembolic or hemorrhagic complications. Clinical complications occur in 9-15% of the patients in the form of thrombotic or hemorrhagic disorders. The therapy of tumor-related coagulopathy should be guided by its clinical expression. Subclinical DIC should not be treated. Coumadin is generally ineffective for therapy of thrombosis in cancer patients. There is no consensus regarding the use of heparin in acute promyelocytic leukemia (APL). The defibrination in APL may be from disseminated intravascular coagulation as well as systemic fibrinolysis, as shown by decreased alpha 2 antiplasmin levels. In such cases, epsilon aminocaproic acid plus heparin therapy may be of benefit.
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PMID:Hemostasis in malignancy. 174 46

Recent reports have documented an increase of thrombotic complications in patients with carcinoma of the breast receiving chemotherapy regimens containing cyclophosphamide, methotrexate, and 5-fluorouracil. The authors studied blood from nine such patients screening for abnormalities that might predispose to thrombosis or indicate that the coagulation cascade had been activated. Six of the patients were in the adjuvant setting, and three had metastatic disease. Samples were collected from each patient before, during, and after completion of the chemotherapy in question. In each patient a statistically significant decline in functional protein C activity (P = 0.001) was demonstrated at midtherapy. In seven of nine patients functional protein C level normalized after the cessation of therapy. No other positive results were found. The authors conclude that the combination of cyclophosphamide, methotrexate, and 5-fluorouracil, when administered to patients with a diagnosis of carcinoma of the breast, causes a reversible decline in the activity of protein C.
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PMID:Acquired protein C deficiency in patients with breast cancer receiving cyclophosphamide, methotrexate, and 5-fluorouracil. 292 Mar 59

To investigate genetic features of esophageal cancer, we have examined 93 squamous cell carcinomas of the esophagus for loss of heterozygosity (LOH), using 41 restriction fragment length polymorphism (RFLP) markers representing all autosomal chromosomes. Allelic losses at frequencies of at least 30% were observed at loci on chromosomal arms 3p (35%), 3q (30%), 5q (36%), 9p (57%), 9q (60%), 10p (33%), 13q (43%), 17p (62%), 17q (46%), 18q (38%), 19q (32%), and 21q (37%). These results suggest that several putative tumor suppressor genes, in addition to the cyclin D and TP53 genes that are sometimes mutated in esophageal carcinomas, may be associated with development and/or progression of esophageal cancer. By a comparison of LOH on each chromosomal arm with clinicopathological parameters, we have found a significant correlation between LOH on 19q and regional lymph node metastases. Interestingly, the frequency of LOH on 17q was significantly higher in tumors in female patients (12 of 14 cases) than in those in male patients (20 of 56 cases) (P = 0.0009 by Fisher's exact test). Furthermore, we examined for mutations of the APC gene on chromosome arm 5q. Screening of nearly one third of the APC coding region, including the MCR (mutation cluster region), revealed no alterations. Therefore, although allelic loss at the APC locus is frequent in squamous cell carcinomas of the esophagus, it is likely that a gene on 5q other than APC is involved in esophageal tumorigenesis.
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PMID:Allelotype study of esophageal carcinoma. 752 40

Colorectal carcinomas demonstrate extensive molecular genetic alterations throughout the genome. The genetic changes in cancer of the colon and rectum are among the best understood of any common human cancer. The genetic abnormalities include both dominant-acting oncogenes (Ki-ras, c-src) and tumor-suppressor genes which undergo inactivation or loss (APC, DCC, p53). The evolution of the cancer is a complicated and multistep process. At the various steps of this phenomenon we can recognize specific molecular genetic alterations. These particular genetic changes may be useful as improved markers to predict those patients who have an aggressive cancer of the colon, with occult metastases or increased metastatic capability and this selection of patients could lead to improved surgical and medical management.
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PMID:The genetic basis of colorectal cancer--clinical implications. 785 69

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and mutations in the dominant oncogene K-ras, with loss of wild type alleles. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which were either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or unaffected by TGF beta 1, indicating that a switch in response to TGF beta 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. The current study shows that while the poorly differentiated, TGF beta 1-stimulated sublines are most tumorigenic, all the sublines have the same spectrum of mutations: truncating mutations in both APC (adenomatous polyposis coli) alleles, no activated ras genes, mutated and thus overexpressed p53, and very low expression of DCC compared to normal colon cells. Genes other than the four already implicated in colon carcinoma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.
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PMID:The capacity for growth stimulation by TGF beta 1 seen only in advanced colon cancers cannot be ascribed to mutations in APC, DCC, p53 or ras. 797 Jul 29

Genetic and environmental aspects play an important role in the development of colorectal cancer. However, the common molecular alteration in both hereditary and sporadic colon cancer is localized in the APC gene. the APC gene maps in the long arm of chromosome 5 and was discovered in patients with familial adenomatous polyposis (FAP). The search for the APC gene led to the identification of restriction fragment length polymorphisms (RFLPs) in FAP patients. Using these RFLPs in relatives of FAP patients it is possible to make the presymptomatic and prenatal diagnosis. The FAP syndrome is an interesting model of carcinogenesis in vivo. Thus the different stages involved in the FAP syndrome which include hyperproliferative epithelium, adenoma, adenocarcinoma and metastases, have allowed the analysis of molecular alterations in oncogenes and tumor suppressor genes. The APC gene alteration if not inherited, occurs as the earliest molecular alteration in the development of colorectal cancer whereas structural alterations of the genes myc, ras, p53, MCC and DCC are considered to be late events. All these investigations have lead to 1) a better understanding of the ethiology of cancer and 2) early diagnosis of colorectal cancer in both the hereditary and sporadic forms of the disease.
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PMID:[Molecular genetics of colorectal cancer and carcinogenesis]. 813 31

Murine liver contains alpha beta T cells with intermediate TCR (TCRint) as well as alpha beta T cells with bright TCR. Liver TCRint cells express NK1.1 Ag (NK1+ TCRint) and IL-2 receptor beta chain, both of which are NK cell markers and are not expressed on conventional T cells. Liver NK1+ TCRint cells consist of CD4-8- double negative T cells and CD4+ T cells and have V beta 8+ T cell preponderance. They are dependent on class Ib or CD1 molecules of APC for their development. They can also develop thymus independent manner, because athymic nude mice have this population. These NK1+ TCRint cells in the livers of both euthymic and athymic mice were found to be activated by systemic administration of IL-12 and increased NK1 expression (NK1high TCRint) and cytotoxicity against various NK-sensitive and resistant tumors. Cytotoxicity assays after treatment of IL-12 stimulated hepatic MNC with respective Abs and C revealed that CD4+ NK1high TCRint cells are responsible for IL-12 induced cytotoxicity. Although NK1+ TCRint cells were normally few in the lungs, a significant proportion of NK1high TCRint cells with strong cytotoxicity was also induced in the lung by IL-12. Interestingly, adoptive transfer of IL-12 stimulated hepatic MNC into other mice, which were pre-injected with tumors, inhibits hepatic metastases of EL4 cells and pulmonary metastases of 3LL cells as similarly as IL-12 administration. Transfer experiments after treatment of IL-12 stimulated hepatic MNC with respective Ab and C revealed that depletion of either NK1+ cells, CD3+ cells or CD4+ cells but not CD8+ cells greatly impaired antimetastatic effect in both organs. Thus, CD4+ NK1high TCRint cells are a major antimetastatic population, especially, against hematogenous metastases.
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PMID:[The function and role of extrathymic T cells]. 853 54


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