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BMC Medicine Feb 2013Fascin-1 is an actin-bundling protein expressed in many human carcinomas, although absent from most normal epithelia. Fascin-1 promotes filopodia formation, migration... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fascin-1 is an actin-bundling protein expressed in many human carcinomas, although absent from most normal epithelia. Fascin-1 promotes filopodia formation, migration and invasion in carcinoma cells; in mouse xenograft tumor models it contributes to metastasis. Fascin-1 is an interesting candidate biomarker for aggressive, metastatic carcinomas but data from individual studies of human tumors have not yet been pooled systematically.
METHODS
This systematic review was conducted in accordance with PRISMA guidelines, using fixed and random effects models, as appropriate, to undertake meta-analysis.
RESULTS
A total of 26 immunohistochemical studies of 5 prevalent human carcinomas were identified for meta-analysis. Fascin-1 was associated with increased risk of mortality for breast (pooled hazard ratio, (HR) = 2.58; 95% confidence interval (CI) 1.48 to 4.52; P = 0.001), colorectal (HR = 1.60 (1.37 to 1.86; P <0.001) and esophageal carcinomas (HR = 1.35; CI 1.13 to 1.60; P = 0.001). There was no evidence of association of fascin-1 with mortality in gastric and lung carcinomas. Fascin-1 was associated with increased risk of disease progression in breast (HR = 2.48; CI 1.38 to 4.46; P = 0.002) and colorectal carcinomas (HR = 2.12; CI 1.00 to 4.47; P = 0.05), but not with progression of lung carcinomas (HR = 0.95; CI 0.49 to 1.85; P = 0.9). Fascin-1 was associated with increased risk of lymph node metastasis in colorectal (pooled risk ratio (RR) = 1.47; CI 1.26 to 1.71; P <0.001) and gastric carcinomas (RR = 1.43; CI 1.21 to 1.70; P <0.001). There was no evidence of association of fascin-1 with lymph node metastasis in lung or esophageal carcinomas. Fascin-1 was associated with increased risk of distant metastasis in colorectal (RR = 1.70; CI 1.18 to 2.45; P = 0.004) and gastric carcinomas (RR = 1.93; CI 1.21 to 3.33; P = 0.02). No association with distant metastasis in esophageal carcinomas was observed. Pooling across all the carcinomas provided strong evidence for association of fascin-1 with increased risk of mortality (HR = 1.44; CI 1.24 to 1.68; P <0.001; n = 3,645), lymph node metastasis (RR = 1.36; CI 1.18 to 1.55; P <0.001; n = 2,906) and distant metastasis (1.76; 1.34 to 2.32; P <0.001; n = 1,514).
CONCLUSIONS
Fascin-1 is associated consistently with increased risk of mortality in breast, colorectal and esophageal carcinomas and with metastasis in colorectal and gastric carcinomas. The results were stable to various sensitivity analyses and did not vary by predefined subgroups. These data will assist rational decision making for focusing investigations of fascin-1 as a biomarker or therapeutic target onto the most relevant carcinomas.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma; Carrier Proteins; Disease Progression; Female; Humans; Immunohistochemistry; Male; Microfilament Proteins; Middle Aged; Neoplasm Metastasis; Young Adult
PubMed: 23442983
DOI: 10.1186/1741-7015-11-52 -
Chinese Journal of Cancer Jul 2012The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently,... (Review)
Review
The phosphatidylinositol-3 kinase(PI3K) pathway regulates a number of cellular processes, including cell survival, cell growth, and cell cycle progression. Consequently, this pathway is commonly deregulated in cancer. In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice. These data underscore the role of this pathway during oncogenesis. Thus, an ongoing, large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway. However, conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome, compared with the wild-type PIK3CA gene. In the current study, we performed a systematic review of breast cancer clinical studies. Upon evaluation of 2587 breast cancer cases from 12 independent studies, we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene. Importantly, this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer. We propose three potential explanations for this paradoxical observation. First, PIK3CA mutations may interfere with the metastasis process or may induce senescence, which results in a better outcome for patients with mutated tumors. Secondly, we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells. Lastly, we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy, giving a therapeutic advantage to these patients. Ultimately, an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors. This effort will be important to prevent or explain therapeutic failures and select patients who are most likely to respond to new therapies that inhibit the PI3K pathway.
Topics: Antineoplastic Agents, Hormonal; Apoptosis; Breast Neoplasms; Cellular Senescence; Class I Phosphatidylinositol 3-Kinases; Disease-Free Survival; Early Detection of Cancer; Female; Humans; Mutation; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Survival Rate
PubMed: 22640628
DOI: 10.5732/cjc.012.10032 -
Human Reproduction Update 2010Uterine contractile activity plays an important role in many and varied reproductive functions including sperm and embryo transport, implantation, menstruation,... (Review)
Review
BACKGROUND
Uterine contractile activity plays an important role in many and varied reproductive functions including sperm and embryo transport, implantation, menstruation, gestation and parturition. Abnormal contractility might underlie common and important disorders such as infertility, implantation failure, dysmenorrhea, endometriosis, spontaneous miscarriage or preterm birth.
METHODS
A systematic review of the US National Library of Medicine was performed linking 'uterus' or 'uterine myocyte' with 'calcium ion' (Ca(2+)), 'myosin light chain kinase' and 'myosin light chain phosphatase'. This led to many cross-references involving non-uterine myocytes and, where relevant, these data have been incorporated into the following synthesis.
RESULTS
We have grouped the data according to three main components that determine uterine contractility: the contractile apparatus; electrophysiology of the myocyte including excitation-contraction coupling; and regulation of the sensitivity of the contractile apparatus to Ca(2+). We also have included information regarding potential therapeutic methods for regulating uterine contractility.
CONCLUSIONS
More research is necessary to understand the mechanisms that generate the frequency, amplitude, duration and direction of propagation of uterine contractile activity. On the basis of current knowledge of the molecular control of uterine myocyte function, there are opportunities for systematic testing of the efficacy of a variety of available potential pharmacological agents and for the development of new agents. Taking advantage of these opportunities could result in an overall improvement in reproductive health.
Topics: Actin Cytoskeleton; Calcium Signaling; Electrophysiology; Female; Humans; Models, Biological; Myocytes, Smooth Muscle; Myometrium; Myosin-Light-Chain Kinase; Myosin-Light-Chain Phosphatase; Uterine Contraction; rho-Associated Kinases; rhoA GTP-Binding Protein
PubMed: 20551073
DOI: 10.1093/humupd/dmq016