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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retroviral oncogenes are genetic elements, the expression of which is responsible for the transformed phenotype of cells. These genes are derived from normal cellular DNA sequences called cellular protooncogenes, which are present in all human cells and seem to have potential transforming ability in tumors of nonviral origin, since it is possible that they undergo structural alterations and/or changes in their expression. Human skin tumors were analyzed in this study with respect to the expression of the c-src protooncogene, the cellular homologue of the Rous sarcoma virus transforming gene, by measuring the enzymatic activity of its gene product, the pp60c-src kinase activity. Tyrosine-specific kinase activity was detected in all skin tumors tested. The expression pattern of the c-src gene product in the melanomas tested was differential and varying kinase levels in different metastases from the same patient were detected. The elevation of kinase activity as compared to normal skin ranged from about 4- to 20-fold.
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PMID:Expression of the c-src protooncogene in human skin tumors. 243 64

Transgenic mice expressing the polyomavirus (PyV) middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metastasize with high frequency. The potent transforming activity of PyV middle T antigen can, in part, be attributed to its ability to associate with and to activate a number of c-Src family tyrosine kinases (c-Src, c-Yes, and Fyn). As a first step toward assessing the role of individual c-Src family tyrosine kinases in PyV middle T antigen-induced mammary tumorigenesis, we have crossed transgenic mice carrying the mouse mammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice bearing a disrupted c-src proto-oncogene. In contrast to the rapid tumor progression seen in the original MMTV/PyV middle T antigen strains, mice expressing the transgene in the absence of functional c-Src rarely developed mammary tumors. After long latency, these mice did eventually develop abnormal hyperplastic mammary tissue. This growth disturbance was correlated with elevated expression of the PyV middle T antigen and the activation of the PyV middle T antigen-associated c-Yes tyrosine kinase. However, transgenic mice expressing the PyV middle T antigen in the mammary epithelium of wild-type or Yes-deficient mice developed multifocal mammary tumors with comparable kinetics. Taken together, these findings suggest that c-Src tyrosine kinase activity is required for PyV middle T antigen-induced mammary tumorigenesis and also illustrate an in vivo genetic approach to the dissection of mitogenic signal transduction pathways.
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PMID:Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice. 750 74

The c-src proto-oncogene has been implicated in the progression of primary human colorectal carcinoma to hepatic metastasis. To determine if increased pp60c-src tyrosine kinase activity is a colon-specific phenomenon present in colorectal metastases to all sites, the pp60c-src-specific kinase activity of noncolon tumor metastases to the liver was compared to that of colorectal liver metastases. Activity of extrahepatic colon carcinoma metastases was compared to that of colorectal liver metastases as well as that of normal colonic mucosa. The specific activity of pp60c-src in multiple synchronous metastases from colon carcinoma was also examined. Tyrosine kinase activity was determined by immune complex kinase assay; protein levels were determined by immunoblotting. Specific activity was calculated for each group by dividing the total activity by protein level. Colon carcinoma metastases to the liver had significantly (P < 0.04) increased pp60c-src activity with an average 2.2-fold increase over normal mucosa. In contrast, noncolon tumor metastases to the liver showed minimal pp60c-src kinase activity. Extrahepatic colorectal metastases demonstrated significantly increased (P < 0.005) pp60c-src activity with an average 12.7-fold increase over normal mucosa. When compared to colon liver metastases, extrahepatic colorectal tumor metastases show a significant difference in activity (P < 0.05) with an average 5.7-fold increase. Examination of multiple synchronous colon carcinoma metastases confirmed these results. In summary, we conclude that (1) the activation of pp60c-src between primary tumors and metastases is specific to colon metastases, and (2) although pp60c-src activity is significantly increased in colorectal metastases, site-specific differences in the magnitude of activity are evident.
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PMID:Site-specific differences in pp60c-src activity in human colorectal metastases. 768 14

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

Adhesion of metastatic cancer cells at secondary sites is known to be regulated by several families of adhesion proteins, including selectins and integrins. Colon carcinoma cells have been shown to tether to and roll on both stimulated endothelial cells and purified E-selectin. We have demonstrated that HT-29 human colon carcinoma cells adhere specifically to an E-selectin-IgG chimera. Upon adhesion to E-selectin, the amount of tyrosine phosphorylation of several proteins in HT-29 cell lysates increases compared with cells in bovine serum albumin-coated wells on phosphotyrosine Western blots; this increase is statistically significant. This effect is specific for adhesion to E-selectin, since addition of an E-selectin blocking monoclonal antibody (MAb), E3, to the wells causes a statistically significant decrease in tyrosine phosphorylation relative to E-selectin alone on phosphotyrosine Western blots. One protein that is affected this way has been identified as c-src. Kinase assays show a dose-dependent and statistically significant decrease in c-src activity upon adhesion to E-selectin, which correlates with an increase in phosphorylation of Tyr 527, the negative regulatory tyrosine. CnBr digestion of 32P-labeled c-src shows an increase in phosphorylation of tyrosine 527 after adhesion to E-selectin. Our results may identify a signaling pathway involving the E-selectin ligand on HT-29 cells and c-src.
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PMID:Adhesion of HT-29 colon carcinoma cells to E-selectin results in increased tyrosine phosphorylation and decreased activity of c-src. 917 21

A truncating mutation (C to T transition) at codon 531 of the human protooncogene c-src, possibly accounting for the activation of c-src tyrosine kinase, has been recently identified in a subset of advanced colorectal cancer from North-American patients. However, two subsequent studies have failed to confirm the occurrence of SRC 531 mutation in colorectal cancers from North-European and Asiatic patients, raising the hypothesis that the genetic activation of src in colon cancer might be restricted to patients belonging to specific ethnic groups. We investigated a large series of colorectal cancers from Italian patients (155 cases) with a high prevalence of liver metastasis (43%). Using a PCR-RFLP assay, the occurrence of a SRC 531 mutation was ruled out in all the investigated specimens of primary tumours and/or metastases. Our results demonstrate that SRC Gln531AMB plays no role in the development or in the progression of colorectal cancer among Italian patients.
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PMID:Lack of mutation at codon 531 of SRC in advanced colorectal cancers from Italian patients. 1116 76

AIM:To investigate the activation, expression of c-src gene and its role in the carcinogenetic process of human cardia adenocarcinoma (CA).METHODS:Fifty six cases of CA, 34 cases of normal, 36 cases of protiferative epithelia adjacent to carcinoma, and 20 cases of lymph node metastases of CA were studied for PP60(c-src),the expression product of c-src gene immunohistochemically by using the specific monoclonal antibody,Mab327.RESULTS: The positive rates of PP60(c-src) in the normal epithelia,protiferative epithelia, CA and lymph node metastases were 29.4% (10/34), 94.4% (34/36), 71.4% (40/56) and 60.0%(12/20), respectively, among them, the differences of the positive rates were statistically significant (P < 0.01). The expression levels of PP60(c-src) in CA and proli ferative epithelia were significantly higher than that in the normal epithelia(P< 0.01).The PP60(c-src) positive rates in the papillary, tubular, poorly different-tiated and mucous adenocarcinoma were 75.0% (6/8), 81.8% (18/22), 50.0% (10/20) and 100.0% (6/6), respectively, whereas those of tubular and mucous adenocarcinomas were significantly higher than those of papillary and poorly differentiated adenocar-cinomas (P < 0.05), and the PP60(c-src) expression levels of tubular and mucous adenocarcinomas were also significantly higher than those of papillary and poorly differentiated adenocarcinomas (P< 0.01).CONCLUSION:The activation and expression of c-src gene are associated with the initiation and development of human CA; the protein amount of PP60(c-src)increased during the process of carcinogenesis; and PP60(c-src) expression is also related to lymph node metastases.
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PMID:The expression of c-src gene in the carcinogenesis process of human cardia adenocarcinoma. 1181 97

In this study, we generated transgenic mice that overexpressed either a constitutively active human c-src mutant (src(530)) or a wild-type human c-src (src(wt)) in epidermal basal cells driven by human keratin 14 (HK14) or bovine keratin 5 (BK5) promoters, respectively. HK14.src(530) transgenic mice developed severe epidermal hyperplasia and hyperkeratosis, and did not survive beyond 3 weeks of age. Four transgenic founders were obtained after injection of a BK5.src(wt) construct with variable phenotypes, and three lines (lines A-C) were established. BK5.src(wt) founder D exhibited a severe skin phenotype similar to HK14.src(530) transgenic mice and died 5 days after birth. Line C transgenic mice also exhibited significant epidermal hyperplasia and hyperkeratosis, and developed spontaneous squamous cell carcinomas (SCCs) of the skin beginning at approximately 3 months of age (70% incidence at 1 year). Mice from lines A and B did not show a marked phenotype; however, elevated human src(wt) protein in the epidermis of line B mice was clearly evident. Additional analyses of line B transgenic mice showed an enhanced responsiveness to 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and cell proliferation. Analysis of the susceptibility of line B mice to two-stage skin carcinogenesis revealed that papillomas and SCCs arose earlier and in greater numbers compared with nontransgenic littermates. In addition, malignant conversion occurred more rapidly, and the SCCs that developed in line B transgenic mice had a greater propensity to metastasize to peripheral lymph nodes and other organs. These observations support the hypothesis that c-src plays an important role in skin tumor promotion. In addition, the data show that elevated c-src activity enhances malignant progression and metastasis in this model system.
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PMID:Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis. 1294 1

The proto-oncogene, c-src, has been implicated in the tumorigenesis in breast cancer. However, the relationship of c-src with distant metastasis is unclear. Moreover, the role of c-src in organ-preferential metastasis of breast cancer is unknown. Because breast cancer has a strong predilection for metastasizing to bone, we examined the role of c-src in bone metastases using an animal model in which inoculation of the MDA-231 human breast cancer cells into the left cardiac ventricle preferentially developed osteolytic bone metastases in female nude mice. A clone of the MDA-231 with the increased capacity of bone metastasis exhibited elevated c-src tyrosine kinase (TK) activity compared with parental cells. MDAsrc527 cells caused significantly increased size of the osteolytic bone metastases with increased number of osteoclasts and mitotic cancer cells compared with MDA-231EV or MDAsrcWT. In contrast, MDAsrc295 cells caused impaired metastases to bone. Of note, mice inoculated with MDAsrc295 cells via tail vein developed reduced lung metastases and prolonged survival compared with mice with MDA-231EV cells, suggesting that c-src TK is unlikely to play a specific role in bone metastases. The growth in vitro and in vivo and production of parathyroid hormone-related protein, a key cytokine in the pathogenesis of osteolytic bone metastases in breast cancer, were promoted in MDAsrc527 and diminished in MDAsrc295. These results suggest that c-src TK is associated with the capacity of breast cancer to metastasize to bone through regulating cell growth and parathyroid hormone-related protein production. Our results together with the fact that c-src is an essential molecule for bone resorption by osteoclasts, which are central players in osteolytic bone metastases, support the notion that c-src TK is a potential target molecule for designing novel therapeutic interventions, especially for bone metastases in breast cancer.
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PMID:C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. 1294 30

The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (DeltaSH2 or DeltaSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The DeltaSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The DeltaSH2 retrovirus injected embryos survived longer than v-src or DeltaSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.
Clin Exp Metastasis 2005
PMID:Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation. 1608 37


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