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 colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.
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PMID:Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. 1107 15

Overexpression of the membrane mucin MUC4/Sialomucin complex (SMC) has been observed during malignant progression of mammary tumors in both humans and rats, suggesting that deregulation of MUC4/SMC expression might facilitate development of these malignancies. As previously reported, overexpression of SMC results in suppression of both cell adhesion and immune killing of tumor cells. SMC also acts as a ligand for ErbB2/Neu, modulating phosphorylation of the receptor tyrosine kinase in the presence and absence of heregulin. The present studies investigated the effect of Muc4/SMC up-regulation on primary tumor growth using a tetracycline-inducible SMC expression system in a xenotransplanted tumor model. SMC up-regulation provoked rapid growth of transfected A375 melanoma in nude mice. Up-regulation of SMC, however, did not significantly increase proliferation of A375 cells in vitro. Instead, a strong suppression of apoptosis was observed in situ in SMC-overexpressing tumors. These data suggest that Muc4/SMC expression promotes tumor growth in vivo at least in part via suppression of tumor cell apoptosis. Importantly, reduction of apoptosis was also observed in vitro, indicating that anti-apoptotic effect of SMC is independent of tumor-host interactions. These findings strongly suggest that SMC up-regulation alters intracellular signaling to favor cell survival, providing for the first time evidence for the regulation of programmed cell death by a gene of the MUC family.
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PMID:Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor. 1131 77

Two readily synthesized anthranilamide, VEGF receptor tyrosine kinase inhibitors have been prepared and evaluated as angiogenesis inhibitors. 2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide (5) and N-3-isoquinolinyl-2-[(4-pyridinylmethyl)amino]benzamide (7) potently and selectively inhibit recombinant VEGFR-2 and VEGFR-3 kinases. As a consequence of their physicochemical properties, these anthranilamides readily penetrate cells and are absorbed following once daily oral administration to mice. Both 5 and 7 potently inhibit VEGF-induced angiogenesis in an implant model, with ED(50) values of 7 mg/kg. In a mouse orthotopic model of melanoma, 5 and 7 potently inhibited both the growth of the primary tumor as well as the formation of spontaneous peripheral metastases. The anthranilamides 5 and 7 represent a new structural class of VEGFR kinase inhibitors, which possess potent antiangiogenic and antitumor properties.
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PMID:Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. 1247 52

Aberrant receptor tyrosine kinase signaling plays an important role in the molecular pathogenesis of brain tumors. We have been studying a previously identified human glioblastoma-derived PDGFR-alpha mutant that has an in-frame deletion in the extracellular domain, causing loss of exons 8 and 9 (PDGFR-alpha(delta8,9)). In the primary tumor, this deletion mutant receptor was shown to be amplified and overexpressed. The purpose of this study was to determine the expression, activity, localization, and transformation properties of this deletion mutant. In the absence of serum, or PDGF-AA, PDGFR-alpha(delta8,9) was phosphorylated on tyrosine residues, indicating ligand-independent autoactivation. Localization by staining and cell surface biotinylation studies revealed expression of the deletion mutant predominantly in the cytoplasm, with very little present on the cell surface. To determine if PDGFR-alpha(delta8,9) was oncogenic, we transfected wild-type and mutant receptors into Rat1 cells and performed analyses of cell growth, in vitro transformation, and subcutaneous growth in the nude mouse. PDGFR-alpha(delta8,9)-expressing cells displayed enhanced cell growth and survival in low serum, and formed foci in monolayer cultures. PDGFR-alpha(delta8,9)-expressing Rat1 cells were also tumorigenic when injected subcutaneously into nude mice. Expression of PDGFR-alpha(delta8,9) was also associated with increased c-Jun phosphorylation in the absence of PDGF ligand, demonstrating also that the mutant receptor is associated with altered intracellular signaling. These data demonstrate that PDGFR-alpha(delta8,9) is transforming, and it is the first demonstration of a naturally occurring tumor-derived mutant PDGFR-alpha with oncogenic properties.
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PMID:A human brain tumor-derived PDGFR-alpha deletion mutant is transforming. 1256 64

EphB4 is a receptor tyrosine kinase that is expressed on epithelial cells during fetal life. It is also expressed on some venous endothelial cells. We conducted a study of six men with primary squamous cell carcinoma of the head and neck (HNSCC) that had metastasized to the cervical lymph nodes. Our goal was to determine if EphB4 is aberrantly expressed in cases of HNSCC and to determine if there is a qualitative difference between the expression of EphB4 on primary and metastatic tumors and its expression on normal mucosa adjacent to primary tumors. From each patient, we obtained specimens of the primary tumor, the nodal metastasis, and the adjacent normal mucosa, and we performed immunocytochemistry on each. We observed EphB4 expression in all primary and metastatic tumors and no expression in the normal tissue. In each of the six patients, expression was greater in the metastatic tumor than in the primary tumor. We conclude that EphB4 is a novel target in the treatment of HNSCC.
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PMID:Expression of EphB4 in head and neck squamous cell carcinoma. 1466 37

Metastatic tumor cells originating from cancers of a variety of tissues such as breast, skin, and prostate may remain dormant for long periods of time. In the case of uveal melanoma, the principal malignancy of the eye, complete removal of the primary tumor by enucleation can nonetheless be followed by metastatic tumor growth in distant organs months, years, or even decades later. This suggests that tumor cells have already spread to secondary sites at the time of treatment and remain dormant as micrometastases. Identifying factors that govern long-lived survival of metastatic tumor cells is therefore key to decreasing mortality associated with this and other diseases. While investigating factors differentially expressed in melanoma cells and normal melanocytes, we identified the receptor tyrosine kinase Axl and found up-regulation of Axl in uveal melanomas and melanoma cell lines by RNase protection, Western analysis, and immunohistochemistry. Axl has been shown to mediate cell growth and survival through its ligand Gas6 in non-transformed cells. To test whether stimulation of Axl can enhance survival of uveal melanoma cells, we assessed the degree of mitogenesis and cell survival by bromodeoxyuridine incorporation and trypan blue exclusion, respectively, upon stimulation of Mel 290 uveal melanoma cells with Gas6 in vitro. We show that Gas6 mediates mitogenesis and cell survival in Mel 290 cells. We further demonstrate that these effects occur specifically through the Axl receptor by modulating the expression of Axl with an antisense construct. cDNA microarray analysis of 12,687 genes then revealed that Gas6 stimulation of Axl in Mel 290 cells results primarily in the down-regulation of Cyr61, a member of the CCN protein family involved in tumor progression. These data show that the Axl pathway mediates increased survival of uveal melanoma cells, potentially advantageous during cancer dormancy, and that Axl may function in part through regulation of Cyr61.
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PMID:Expression of the receptor tyrosine kinase Axl promotes ocular melanoma cell survival. 1472 16

The introduction of imatinib, an orally administered inhibitor of the KIT receptor tyrosine kinase, is prompting revision of the management algorithms that have traditionally guided the treatment of gastrointestinal stromal tumor (GIST). Historically, patients with GISTs have had substantial rates of relapse as well as limited long-term survival even after complete surgical resection of a primary tumor. Imatinib has been shown to induce durable tumor responses in more than half of the patients with malignant metastatic or unresectable GISTs and to halt disease progression in an additional third. These encouraging results have led to the initiation of clinical trials of imatinib as an adjuvant or neoadjuvant therapy with surgery. Until relevant data are reported to provide definitive direction for the management of operable or potentially operable GISTs, treatment decisions must be made on the basis of the available evidence and clinical experience with imatinib. This paper presents selected case studies describing approaches to the combined use of surgery and systemic therapy that have been applied in the treatment of individual GIST patients. The management of GIST in these cases required a coordinated, multidisciplinary approach involving medical oncologists, diagnostic radiologists, gastroenterologists, surgeons, and pathologists.
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PMID:Management of gastrointestinal stromal tumors in the imatinib era: selected case studies. 1640 9

Most cancer lethality is caused by metastasis. To gain insight into the molecular basis of tumor progression to metastasis, we used the 21T series of human mammary epithelial cells obtained by successive biopsies from one breast cancer patient. The c-erbB2 gene is amplified and overexpressed in each of three 21T tumor lines. The erbB receptor tyrosine kinase-activated phosphatidylinositol 3-kinase/Akt signaling cascade is crucial for the development and maintenance of epithelial cells, and dysregulation of this pathway is frequently associated with cellular transformation and cancer. For Akt to be fully activated, Ser(473) on its COOH terminus needs to be phosphorylated. We detected more Ser(473) Akt phosphorylation in MT cells, derived from a pleural effusion, compared with cells from the primary tumor. This phosphorylation has recently been shown to be catalyzed by mammalian target of rapamycin (mTOR)/rictor kinase. By using genetic and pharmacologic activators and inhibitors, we showed that Ser(473) Akt phosphorylation is more sensitive to mTOR/rictor inhibition in metastatic tumor cells than normal mammary epithelial and primary tumor cells. The mTOR/rictor kinase activity was indispensable for both Ser(473) Akt phosphorylation and migration of metastatic MT2 cells. In addition, a large decrease of protein phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) was found, which could be responsible for the overexpression of Ser(473) Akt in MT cells. Our data indicate that these breast cancer cells acquire new vulnerabilities, rictor and PHLPP, which might provide an Achilles' heel for therapeutic intervention of breast cancer metastasis.
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PMID:Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation. 1754 9

Angiogenesis and its role in the growth and development of metastases has become a topic of increasing importance. In non-small cell lung cancer (NSCLC), vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, growth of the primary tumor, and development of metastases. In addition, elevated expression in tissue samples is a negative prognostic feature. For these reasons, VEGF is a worthy target for novel therapies. Recent clinical trials have shown that the anti-VEGF monoclonal antibody bevacizumab adds to the effect of chemotherapy in the metastatic setting. Hypertension and proteinuria are, as expected, commonly seen in this patient population, but the unexpected toxicity of life-threatening hemoptysis has also been observed. This makes careful patient selection especially important for this class of drugs. Our understanding of the VEGF pathway is increasing, as are the number of available targeted agents. In addition to the monoclonal antibody, bevacizumab, VEGF receptor tyrosine kinase inhibitors, multitargeted kinase inhibitors, and combination VEGF and epidermal growth factor receptor (EGFR) inhibition, are all being evaluated in NSCLC. Small phase I and II trials have suggested modest benefit when used alone; however, we now know that the anti-angiogenic therapies work best in combination with chemotherapy. The results of ongoing trials using these agents in combination with standard therapy will provide more insight into their potential benefit. As it is known that small tumors require angiogenesis to grow and metastasize, the use of anti-angiogenic therapies in the adjuvant setting may provide even greater benefit, and increase the potential cure rate in this population of patients. The results of well-designed phase III trials will be required to truly understand how to best use this class of targeted therapies in resectable and metastatic NSCLC.
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PMID:Inhibition of angiogenesis in the treatment of non-small cell lung cancer. 1789 8

Signal transduction exerted by the microenvironment around the primary tumor locus may trigger tumor metastasis especially at the migration stage. Sustained mitogen activated protein kinase (MAPK) signaling involved in uncontrolled tumor cell migration rely on the cross talks between integrin, receptor tyrosine kinase (RTK) and protein kinase C (PKC). The molecular mechanisms for cross talking between these migration-related signal cascades leading to sustained cell migration are reviewed, focusing on the focal adhesion scaffold protein paxillin as the platform for signal integration. We proposed reactive oxygen species (ROS) as the critical signal messenger sustaining these signal cascades. For the cross talk of integrin with RTK, ROS may suppress paxillin-associated protein tyrosine phosphatase (PTP-PEST) relieving its negative regulatory effects. For the cross talk of integrin with PKC, PKC itself may phosphorylate integrin or paxillin-associated focal adhesion proteins to induce generation of ROS which may reactivate PKC. In the future, ROS will be validated as the promising therapeutic targets for prevention of tumor metastasis.
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PMID:Signal cross talks for sustained MAPK activation and cell migration: the potential role of reactive oxygen species. 1829 6


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