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

PTEN (phosphatase and tensin homolog deleted on chromosome ten) also referred to as MMAC (mutated in multiple advanced cancers) was discovered as a tumor suppressor gene and later found to be a phospholipid phosphatase. PTEN negatively regulates Akt activation by preventing its phosphorylation. PTEN therefore inhibits the PI 3-kinase/Akt signaling pathway which is important for cell growth and survival. Overexpression or enhanced activation of PTEN can potentially impair injury healing by at least 4 mechanisms. PTEN can: 1) inhibit entry into the cell cycle by inhibiting G1 to S phase progression and arrest cell proliferation required for tissue reconstruction during injury healing; 2) increase apoptosis by blocking Akt activation leading to increased Bad and Caspase-9 activities; 3) inhibit hypoxia-induced angiogenesis required for injury healing by blocking Akt-mediated VEGF gene transcription; 4) inhibit Akt-mediated cell migration, i.e. re-epithelialization, which is also required for injury healing. The same mechanisms can also suppress cancer growth and metastases. Therefore, elucidating the role of the PTEN/PI 3-kinase/Akt pathway will likely advance our knowledge of the mechanisms controlling the processes of injury healing and cancer growth.
 ...
PMID:Biological role of phosphatase PTEN in cancer and tissue injury healing. 1199 59

It has been well established that hepatocellular carcinomas (HCCs) accumulate [18F]fluorodeoxyglucose (FDG) to varying degrees; this is thought to be due to differing amounts of FDG-6-phosphatase activity. The purpose of this study was to evaluate the impact of FDG imaging on the management of patients diagnosed with hepatocellular carcinoma. We conducted a retrospective review of the clinical data of 91 consecutive patients diagnosed with HCC who underwent FDG-positron emission tomography (PET) imaging between August 1993 and March 2001. The patients were divided into two groups. In Group one 67 of 91 (74%) patients were evaluated for proven but untreated hepatic lesions using PET. In Group two the remaining 24 patients (26%) were referred for evaluation of HCC recurrence but did not have prior PET. The FDG images were acquired with two dedicated PET tomographs [Siemens ECAT 933, CTI (Knoxville, TN) and GE Advance, General Electric Medical Systems (Milwaukee, WI)] one hour after the intravenous administration of 10 mCi of FDG. Tumor biopsy or resection specimens were available for review from 34 patients and were evaluated for histologic grade, presence of cirrhosis, tumor necrosis, and intratumoral fibrosis. In group one 43 of 67 (64%) of the HCCs accumulated FDG. Sixteen of the 43 patients in whom FDG was accumulated had multiple subsequent FDG-PET scans either for monitoring therapy or for detection of recurrence. FDG-PET imaging had an impact on the management of 20 of these patients: by guiding the biopsy at the metabolically active site of a large necrotic tumor (one), by identifying distant metastases (five), by monitoring the response to treatment with hepatic chemoembolization and guiding additional regional therapy (12), and by detecting recurrence (two). In group two recurrence and/or metastases were demonstrated with FDG-PET imaging in six of 24 (25%) patients, three of whom had multiple subsequent FDG-PET scans to monitor their treatment. Higher histopathologic grade and intratumoral fibrosis but not necrosis or cirrhosis correlated with PET positivity. In this study only 64 per cent of HCCs accumulated FDG. Despite this limitation FDG-PET imaging remains a useful tool in the diagnosis and treatment of HCC. FDG-PET imaging had a clinically significant impact in 26 of 91 (28%) patients with HCC. This includes detection of unsuspected metastatic disease in high-risk patients-including liver transplant candidates-and monitoring response to hepatic-directed therapy. FDG-PET should be considered as part of the workup and management of selected patients with HCC.
 ...
PMID:The role of [18F]fluorodeoxyglucose positron emission tomography imaging in the evaluation of hepatocellular carcinoma. 1264 51

Although squamous cell carcinoma of the head and neck region very rarely metastasize to the skeleton, epithelial cells have been found in bone marrow aspirates of these patients. This observation reflects the general spread of the disease, indicating a poor clinical prognosis with a much higher risk of developing local or distant recurrences. In a first attempt to characterize the phenotypic properties, the expression of the major histo-compatibility complex (MHC) class I antigens on bone marrow micrometastases was assessed. It has been shown that the down-regulation of these molecules is a potential mechanism to escape from HLA class I restricted lysis by cytotoxic T-cells. The significance of reduced MHC class I expression might be relevant for the survival of residual metastatic cells in the bone marrow of patients with squamous cell carcinoma of the head and neck region. Bone marrow aspirates were screened for individual disseminated epithelial cells using the immunoalkaline phosphatase technique with monoclonal antibodies to the epithelial differentiation marker cytokeratin 19 (CK19), as described previously. Specimens containing CK19-positive cells were colabelled with the monoclonal antibody W6/32. The loss of MHC expression is not related to the tumor stage but clearly to the degree of differentiation: 6 out of 7 patients with low-grade SCCHN, but only 3 out of 13 patients with medium-grade SCCHN showed a complete loss of MHC class I molecules. This finding could indicate the reduced prognosis of undifferentiated SCCHN. The lack of MHC class I expression could encourage the survival of residual tumor cells in the bone marrow of patients with SCCHN that evade immunosurveillance.
 ...
PMID:MHC-class I antigen expression on micrometastases in bone marrow of patients with head and neck squamous cell cancer. 1282 Apr 11

Women with ErbB2-positive breast cancer have a poor prognosis, and frequently, chemotherapy treatment is ineffective. The ErbB2-targeted antibody trastuzumab improves survival when given with chemotherapy to patients with ErbB2-overexpressing metastatic disease, but treatment is not curative, and primary resistance is common. Postulated mechanisms of action for trastuzumab include immune-mediated cytotoxicity and receptor downmodulation. A study in this issue of Cancer Cell suggests that trastuzumab causes rapid activation of the PTEN lipid phosphatase, which in turn downregulates the phosphatidylinositol 3'-kinase (PI3K) pathway. Resistance to trastuzumab occurs when PTEN function is lost, suggesting that PTEN activation is a critical component of the therapeutic effect.
 ...
PMID:Successful targeting of ErbB2 receptors-is PTEN the key? 1532 95

PRL-3, a protein tyrosine phosphatase, has attracted much attention as its transcript is consistently upregulated in the process of colorectal cancer metastases to secondary organs. We studied mice injected via the tail vein with CHO cells stably expressing EGFP-tagged PRL-3 or catalytically inactive mutant PRL-3 (C104S). Our data showed that the EGFP-PRL-3-expressing cells rapidly induce metastatic tumor formation in lung, while EGFP-PRL-3 (C104S)-expressing cells lose this metastastic activity. Furthermore, detailed microscopic examinations revealed that some EGF-PRL-3-, but not EGFP-PRL-3 (C104S)-, expressing cells form micro- and macro-metastatic solid tumors that sprout into blood vessels. Our studies provide clear evidence for a causative role of PRL-3 phosphatase activity in cancer metastasis and tumor-related angiogenesis events. The catalytic domain of PRL-3 could serve as an ideal therapeutic target for drug development to block the spread of colorectal cancer.
 ...
PMID:Catalytic domain of PRL-3 plays an essential role in tumor metastasis: formation of PRL-3 tumors inside the blood vessels. 1546 31

PTEN is a dual-specificity phosphatase with both protein phosphatase and lipid phosphatase activity. PTEN is the first phosphatase identified as a tumor suppressor. Not since the discovery of p53 has a tumor suppressor generated such interest. Initial studies performed on cancer cell lines suggested that PTEN may be responsible for almost all types of cancer, both solid tumors and hematological malignancies. Biallelic deletion of PTEN has been associated with advanced stage tumors or metastatic disease. PTEN has been shown to play a pivotal role in apoptosis, cell cycle arrest, and possibly cell migration. Emerging data suggest that this may be an oversimplification of PTEN's role, and that PTEN may be haploinsufficient for tumor progression and may play important roles in other cellular functions such as angiogenesis and MAP kinase signaling.
 ...
PMID:PTEN regulatory functions in tumor suppression and cell biology. 1544 14

Identification of specific genes or signaling pathways involved in development of melanoma could lead to new therapies that target and correct these defects. Recent studies have revealed deregulation of the Akt signaling pathway occurring in 43-67% of melanomas. Akt kinase family members, Akt1/PKBalpha, Akt2/PKBbeta and Akt3/PKBgamma, share extensive structural similarity and perform common as well as unique functions within cells. The Akt signaling cascade initiates at the cell surface when growth factors or other extracellular stimuli activate phosphoinositide 3-kinase (PI3K). Activated PI3K generates a lipid second messenger, phosphatidylinositol-3,4,5-trisphosphate (PIP3), causing translocation of Akt to the plasma membrane where it becomes phosphorylated and activated. The balance of cellular PIP3 is regulated primarily by a phosphatase called PTEN that reduces PIP3 levels thereby lowering Akt activity. In melanomas, decreased PTEN activity elevates PIP3 levels resulting in Akt activation. Active Akt then phosphorylates downstream cellular proteins that promote melanoma cell proliferation and survival. Recently, Akt3 was discovered to be the predominant isoform activated in sporadic melanomas. Levels of activity increased during melanoma progression with metastatic melanomas having the highest activity. Although mechanisms of Akt3 activation remain to be fully characterized, overexpression of Akt3 and decreased PTEN activity play important roles in this process. Targeted reduction of Akt3 activity decreased survival of melanoma tumor cells leading to inhibition of tumor development, which may be therapeutically effective for shrinking tumors in melanoma patients. This review surveys recent developments in Akt deregulation in melanoma and its potential as a selective therapeutic target in patients in the advanced stages of this disease.
Cancer Metastasis Rev 2005 Jun
PMID:Functional and therapeutic significance of Akt deregulation in malignant melanoma. 1598 37

Our purpose was to analyze, by immunohisto-chemistry, the expression of activated serine-threonine protein kinase B (p-Akt) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in benign nevi and primary and metastatic melanomas and to correlate the expression level with clinical variables. We observed cytoplasmic and/or nuclear expression of p-Akt in 22 (54%) of 41 benign nevi, 112 (71.3%) of 157 primary tumors, and 50 (71%) of 70 metastases. Cytoplasmic PTEN staining was observed in 0 (0%), 152 (87.7%), and 64 (90%) of 41 nevi, 162 primary tumors, and 71 metastases, respectively. A significant positive correlation was seen between PTEN and p-Akt cytoplasmic expression (P < .001) in primary melanomas. Cytoplasmic p-Akt expression showed a positive association with cyclin A in superficial spreading (P = .038) but not in nodular (P = .22) melanomas. Cytoplasmic p-Akt and PTEN expression did not have an impact on disease-free and overall survival, but complete lack of nuclear p-Akt expression was a predictor of shorter disease-free survival (P = .025) for patients with superficial spreading melanoma.
 ...
PMID:Expression of activated Akt and PTEN in malignant melanomas: relationship with clinical outcome. 1614 7

The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL-1, PRL-2, and PRL-3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Individual PRLs are overexpressed in a variety of cancer cell lines and tissues when compared with their normal counterparts. More importantly, several recent studies have shown that PRL-3 is expressed at higher levels and at a greater frequency in colorectal cancer metastases compared with primary colorectal tumors and normal colon tissue. Ectopic expression of PRLs in nontumorigenic cells can influence proliferation and the migratory and invasive properties of cells, while knockdown of endogenous PRL-3 or PRL-1 in cancerous cells using small interfering RNA can abrogate cell motility and ability to metastasize in a mouse model. However, the exact biological function and cellular substrates of the PRLs remain unclear. This review will discuss what is known about the PRLs, what makes the PRLs possible attractive targets for therapeutic intervention, and the possible future directions in PRL biology and inhibitor identification.
 ...
PMID:PRL phosphatases as potential molecular targets in cancer. 1627 86

Phosphatase found in regenerating liver (PRL)-1, PRL-2, and PRL-3 [also known as PTP4A1, PTP4A2, and PTP4A3, respectively] constitute a unique family of putative protein tyrosine phosphatases (PTPs) modified by farnesylation. PRL-3 is amplified and its message is up-regulated in colorectal carcinoma metastases. Its ectopic expression promotes invasive and metastatic properties, supporting a causal link between PRL-3 and late-stage cancer development. However, neither PRL phosphatase substrates nor their signaling pathways have been defined. To address possible mechanisms for the biological activity of PRL-3, we sought to identify its downstream targets, reasoning that regulators of motility and invasion, such as the Rho family of small GTPases, might be logical candidates. We found that levels of active RhoA and RhoC were increased 4- to 7-fold in SW480 colorectal carcinoma cells expressing exogenous PRL-1 and PRL-3, and that PRL-mediated motility and Matrigel invasion were blocked by pharmacologic inhibition of Rho kinase (ROCK), a key Rho effector. In contrast, the activity of Rac was reduced by PRL PTPs, whereas Cdc42 activity was unaffected. PRL-3 stimulated transcription driven by the serum response element in a Rho-dependent manner. We also confirmed that the ability of PRL PTPs to induce invasion and motility is dependent on farnesylation. Catalytic PRL-3 mutants (C104A or D72A) were impaired in PRL-3-induced invasion and Rho activation, indicating that these properties require phosphatase activity. We conclude that PRL PTPs stimulate Rho signaling pathways to promote motility and invasion. Characterization of PRL activity and regulatory pathways should enhance efforts to understand and interfere with PRL-mediated events in invasion and metastasis.
 ...
PMID:PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. 1654 Jun 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>