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PubMed2003

[Target-based therapy against gastrointestinal stromal tumors--from molecular diagnosis to molecular target therapy].

Gastrointestinal stromal tumors (GIST) are composed of KIT-positive mesenchymal-origin spindle- or polygonal-shaped tumor cells in the gastrointestinal tract without immunoreactivity for desmin and S-100. The gain-of-function mutations in the c-kit gene (90%) or platelet-derived growth factor receptor alpha (PDGF-R alpha) gene (5%) are now considered to be causative for GIST. STI571 (Glivec), a molecule designed to selectively inhibit Bcr-Abl, KIT, and PDGF-R activity, shows high response rate and efficacy for non-resectable and/or relapsed GIST (PR 60%). Its serious adverse effects (more than Grade 3) were infrequent, thus, tolerability and safety are good. Glivec is the first successful case of molecular target therapy for solid tumors. However, new resistance against this new generation of drug is going to appear and becomes an urgent problem.

Antineoplastic Agents↗
PubMed1992

Identification of residues in GTPase-activating protein Src homology 2 domains that control binding to tyrosine phosphorylated growth factor receptors and p62.

Ras GTPase-activating protein (GAP) contains two Src homology 2 (SH2) domains which are implicated in binding to tyrosine-phosphorylated sites in specific activated growth factor receptors and to a cytoplasmic tyrosine-phosphorylated protein, p62. We have used site-directed mutagenesis of the two GAP SH2 domains (SH2-N and SH2-C) to identify residues involved in receptor and p62 binding. A bacterial fusion protein containing the precise SH2-N domain, as defined by sequence homology, associated with both the activated beta platelet-derived growth factor receptor and epidermal growth factor receptor, and p62 in vitro. However, short deletions at either the N or C termini of the SH2-N domain abolished binding, suggesting that the entire SH2 sequence is required for formation of an active domain. Conservative substitutions of 2 highly conserved basic residues in the SH2-N domain, an arginine and a histidine, resulted in complete loss of receptor and p62 binding, whereas other basic residues, and residues at variable SH2 sites, were more tolerant of substitution. The conserved arginine and histidine therefore appear critical for association with phosphotyrosine-containing proteins, possibly through an interaction with phosphotyrosine. The GAP SH2-C domain, unlike SH2-N, does not bind efficiently to activated receptors or p62 in vitro. The SH2-C domain lacks 3 residues which are otherwise well conserved, and contribute to high affinity SH2-N binding. Replacement of 1 of these residues, a cysteine, with the consensus glycine, conferred SH2-C binding activity toward tyrosine-phosphorylated p62 and epidermal growth factor receptor. Loss-of-function and gain-of-function mutations in the GAP SH2 domains can therefore be used to identify residues that are critical for receptor and p62 binding.

Amino Acid Sequence↗
PubMed2003

An evolutionary model of carcinogenesis.

A quantitative model of carcinogenesis based on methods from population biology and game theory demonstrates normal cells in vivo occupy a ridge-shaped maximum in a well-defined tissue fitness landscape, a novel configuration that allows cooperative coexistence of multiple cellular populations. This state, although necessary for development of functioning multicellular organisms, is subject to invasion by fitter, mutant phenotypes permitting somatic evolution of cancer. The model demonstrates carcinogenesis is an emergent phenomenon requiring a sequence of evolutionary steps as cellular proliferation follows successful adaptation to varying environmental constraints. In the initial development of preneoplastic lesions, cellular proliferation is controlled exclusively by interactions with other cells, the extracellular matrix, and soluble or insoluble growth factors so that gain of function mutations in oncogenes, loss of function mutations in tumor suppressor genes, and disruption of normal senescence pathways will permit clonal expansion. This provides explicit selection mechanisms for the mutations depicted in the classical Fearon-Vogelstein model of colorectal carcinogenesis. The model demonstrates neoplastic cellular proliferation can also be promoted by alterations in the somatic landscape that reduce inhibitory signals produced by the normal cells and extracellular matrix. This is consistent with experimental evidence for a strong microenvironmental influence in tumorigenesis independent of genomic changes in the neoplastic populations. However, we find that these changes alone produce only self-limited neoplastic growth because cellular crowding alters system dynamics so that proliferation is dependent on substrate availability. Consequent cellular competition for critical nutrients results in Darwinian selection pressures favoring phenotypes that increase substrate delivery (e.g., angiogenesis) or uptake (e.g., amplify membrane transporters). These previously unknown substrate dynamics in the later stages of carcinogenesis provide a mechanism for evolution of cellular properties typically found in invasive cancers including the angiogenic and glycolytic phenotypes.

Animals↗
PubMed2003

[New oncological treatment principle with imatinib].

One of the undoubted major breakthroughs in the recent treatment of cancer is imatinib, a tyrosine-kinase inhibitor of the bcr-abl fusion protein, the stem-cell factor receptor c-kit (KIT) and the platelet-derived growth-factor receptor. The successes obtained with imatinib in the treatment of chronic myeloid leukaemia (CML), gastrointestinal stroma-cell tumours (GIST), and dermatofibrosarcoma protuberans, demonstrate that targeted therapy with a rationally designed, small, synthetic molecule can be highly successful. However, experience so far with imatinib in KIT-positive tumours indicates that imatinib seems only to be effective in those tumours with a gain-of-function mutation in c-kit. There are arguments in favour of investigating a combined therapy of imatinib and classical chemotherapy.

Antineoplastic Agents↗
PubMed2003

Imatinib mesylate: a molecularly targeted therapy for gastrointestinal stromal tumors.

Although their overall incidence is uncommon, gastrointestinal stromal tumors (GIST) are the most frequently encountered mesenchymal tumors of the GI tract. Their pathology has been recently defined by the presence of KIT (transmembrane receptor tyrosine kinase). The majority of GISTs have c-kit gain-of-function mutations mainly in exon 11 (highly conserved juxtamembrane region) that eventuates in constitutive activation of KIT, promoting proliferation and antiapoptotic signaling. Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase activation, and in phase II clinical trials has proven to be remarkably efficacious in heavily pretreated GIST patients with advanced disease. The molecular and genomic determinants of response/resistance patterns are the subject of ongoing studies, and adjuvant studies are also under way. The initial evaluations of imatinib provide proof of concept for the hypothesis-driven design of selective molecularly targeted therapies for solid tumor malignancies.

Antineoplastic Agents↗
PubMed2004

[Gastrointestinal stromal tumor].

Gastrointestinal stromal tumors (GISTs), the most common submucosal tumor in the gut, express the KIT protein. Gain-of-function mutations in the KIT or PDGF-R alpha gene is involved in oncogenesis and growth of GISTs. Although the first-line therapy of resectable GISTs is surgery, imatinib mesylate, a target-based molecule against KIT and PDGF-R alpha proteins, showed remarkable clinical effects and good tolerability for non-resectable GISTs. Now, imatinib is in the first-line for non-resectable GISTs. Resistance against imatinib, however, is proved after long-standing use of the drug.

Antineoplastic Agents↗
PubMed2004

Gastrointestinal stromal tumor presenting as a large abdominal mass.

OBJECTIVE: We report on a male patient operated on for a mesenchymal tumor of the digestive tract presenting a mega cyst-like abdominal mass. MATERIAL AND METHODS: The size of the lesion was magnum, the mass presented as unilocular, the wall thickness was not uniform (0.1 to 1 cm) with hemorragic areas, the lesions were multiple measuring 3x2 cm and less, the mitotic index was borderline. The diagnosis was histologically defined as GIST borderline (low mitotic count and tumor size < 5 cm). The ultrasonography and TAC were unable to diagnostic information. CONCLUSION: The GIST presents no specific signs and the most frequent symptoms are abdominal pain and abdominal mass, the CT scan and ultrasonography are sensitive in the evaluation of location, size, invasion of adjacent organs but not for diagnosis. Prognostic predictions are on the basis of mitotic index and tumor size (1). The precise cellular origin of GIST (2) has recently been proposed to be the interstitial cell of Cajal, an intestinal pacemaker cell. The gain-of function mutation of c-kit (receptor tyrosine kinase--KIT positive tumor) proto-oncogene has been detected in GIST and its role in molecular pathogenesis has been established. The treatment of unresectable and metastatic lesion is Imatinib mesylate, inhibitor of tyrosine-kinase activity (Gleevec, Novartis).

Gastrointestinal Stromal Tumors↗
PubMed2005

Genetic factors in pancreatitis.

The understanding of pathogenesis of acute and chronic pancreatitis has benefited from the progress made in genetic investigations. The discoveries of the gain of function mutations of cationic trypsinogen gene (PRSS1) and the loss of function mutations of pancreatic secretory trypsin inhibitor (SPINK 1) or other potential defects in genes that regulate pancreatic secretory function or modulate inflammatory response to pancreatic injury has changed our current concepts on the pathogenesis of pancreatitis. Genetic factors play an important role in the susceptibility to pancreatic injury, severity and evolution of inflammatory process, leading in some cases to chronic inflammation and/or fibrosis. Acute pancreatitis is viewed as an event and chronic pancreatitis as a process, sequentially linked, reflecting a complex interaction between genetic and environmental factors.

Carrier Proteins↗
PubMed2005

[Histopathologic diagnosis of gastrointestinal stromal tumor (GIST)].

Gastrointestinal stromal tumor (GIST) as an ideal model for targeted therapy in recent years has been placed in the lime-light of oncology. Once thought to be a tumor of smooth muscle origin and formerly practically therapy resistant lesion is now justified to differentiate toward interstitial cells of Cajal; and crucial step of the development of this tumor is the gain-of-function mutation of c-kit gene localized to chromosome 4q11-21. Due to phenotypic variability of GISTs for reliable diagnosis, it is essential to perform c-kit (CD117) immunohistochemical reaction. The positive reaction not only supports the diagnosis, but also predicts efficiency of imatinib therapy. Differential diagnosis of GISTs includes, among others, the possibility of gastrointestinal leiomyomas, leiomyosarcomas, schwannomas, inflammatory fibroid polyps or GIST mimicking secondary tumors. When an abdominal lesion is suspicious for GIST, application of wider range of antibodies including c-kit (CD117), CD34, desmin, S100, alpha smooth-muscle actin is justified. The aim of this synopsis is to overview development of our knowledge about GIST and to discuss differential diagnostic problems. Basic molecular mechanisms responsible for development of GIST are also reviewed.

Antigens, CD34↗
PubMed2005

[Referral of patients with parathyroid dysfunction to specialists--which patients should be referred to parathyroidologists?].

Although a diagnosis of primary hyperparathyroidism and hypothyroidism becomes very easy at the present time due to development of highly sensitive assay for parathyroid hormone, the diagnosis of hyper- and hypothyroidism should be made by excluding the loss and gain of function mutation of calcium sensing receptor, respectively. When a diagnosis of primary hyperparathyroidism is made but the localization of adenoma(s) is not identified, the patient should be referred to specialists for parathyroid surgery. Although patients with primary hypoparathyroidism can be followed by a general physician, they should be referred to specialists when they become pregnant, since active vitamin D is increased and decreased in the late pregnancy and in the postpartum period, respectively.

Female↗
PubMed1993

Roles of Hox genes: what we have learnt from gain of function and loss of function mutations in the mouse.

Transgenic mice expressing ectopically a gene from one of the Hox complexes, and mice carrying a null mutation in a Hox gene, provide useful tools for studying the roles of this gene family during development. Here, we discuss the phenotypes of two kinds of Hox mutant mice which show that vertebrate Hox genes are functional homologues of Drosophila genes of the HOM-C complex.

Alleles↗
PubMed1997

Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes.

Growth of prostatic epithelial cells is androgen-dependent; however, the mechanism of androgen action on cell growth is not well defined. We investigated whether androgen-dependent prostatic epithelial cell growth is mediated by androgen regulation of expression of genes controlling cell cycle progression. For this purpose, we used an androgen-dependent prostatic cancer cell line, LNCaP-FGC, as an in vitro model. We found that expression of CDK2 and CDK4 genes were up-regulated within hours of androgen treatment as detected in Northern and Western blot analyses. Kinase assay also confirmed that there was increased CDK2 kinase activity upon androgen stimulation. Moreover, androgen down-regulated expression of the cyclin-dependent kinase inhibitor p16 (MTS1, CDKN2) gene. The overall effects of these androgen actions result in an increased cyclin-dependent kinase activity and stimulation of the cell to enter S phase of the cell cycle, thereby enhancing cell proliferation. In contrast, an androgen-independent PC-3 cell line lost its response to androgen stimulation, and higher basal levels of CDK2, CDK4, and p16 genes were constitutively expressed in PC-3 cells. Collectively, these data suggest a possible signaling pathway of androgen in stimulating cell growth. These results also imply that in androgen-dependent prostate cancer, increased androgen receptor (AR) activity, resulting from AR gain-of-function mutations, AR gene amplification, or AR gene overexpression, malignantly stimulates proliferation of prostatic epithelial cells and constitutes one possible mechanism of androgen-dependent tumorigenesis.

Adenocarcinoma↗
PubMed1998

Embryonic overexpression of the c-Fos protooncogene. A murine stem cell chimera applicable to the study of fibrodysplasia ossificans progressiva in humans.

Murine embryonic overexpression of the c-fos protooncogene leads to early postnatal heterotopic chondrogenesis and osteogenesis with phenotypic features similar to those seen in children who have the disabling heritable disease fibrodysplasia ossificans progressiva. The overexpression of Fos in embryonic stem cell chimeras leads to heterotopic endochondral osteogenesis at least in part through a bone morphogenetic protein 4 mediated signal transduction pathway. In contrast, early fibrodysplasia ossificans progressiva lesions express abundant bone morphogenetic protein 4, without abundant expression of c-Fos, suggesting that the primary molecular defect in fibrodysplasia ossificans progressiva may be independent of the sustained Fos effects on chondrogenesis and osteogenesis. Comparisons of the clinical, molecular, and pathogenetic features of the c-Fos embryonic stem cell chimeras with those of fibrodysplasia ossificans progressiva provide insight into the earliest events in the molecular pathogenesis of genetically induced heterotopic chondrogenesis and osteogenesis. The relevance of the c-Fos embryonic stem cell chimera to the study of the currently untreatable human disease fibrodysplasia ossificans progressiva demonstrates the power of using embryonic stem cell technology for generating gain of function mutations in the study of human bone disease.

Animals↗
PubMed1999

[F-18-FDG PET in autonomous goiter].

AIM: Gain-of-function mutations of the thyrotropin receptor (TSHR) gene have been invoked as one of the major causes of toxic thyroid adenomas. This study evaluates F-18-FDG-PET in these patients. METHODS: Twenty patients with focal autonomous nodules and ten with disseminated autonomy were investigated the day before radioiodine therapy. Twenty patients with cancer of the head or neck and normal thyroid function served as controls. RESULTS: F-18-FDG-Uptake was higher in patients than in controls. Focal autonomous nodules were associated with focally enhanced glucose metabolism. Disseminated autonomous goiters showed various patterns of focal or global hypermetabolism. CONCLUSION: Autonomous thyroid tissue caused by constitutive mutations of the TSH receptor is characterised by simultaneous increases in glucose and iodine metabolism which are correlated.

Adenoma↗
PubMed2002

Using cancer genetics to guide the selection of anticancer drug targets.

The genetic alterations that cause cancer are coming into view. Genes that are recurrently mutated in a particular form of human cancer flag the proteins (or molecular pathways) that are critical for the evolution of that malignancy. The first generation of anticancer agents prospectively guided by these principles, for which imatinib mesylate is a prototype, inhibit the biochemical activities that result from gain-of-function oncogenic mutations. Advances in somatic cell genetics and chemical biology should facilitate the development of a second generation of agents that will inhibit proteins that are selectively required for survival in the context of specific cancer-causing mutations, whether loss-of-function or gain-of-function.

Animals↗
PubMed2003

Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53.

Mutations of p53 are common in hormone-refractory prostate cancer (CaP), suggesting the possibility that these mutations may be involved in the progression of CaP to androgen-independent (AI) growth. However, at present no direct evidence has been presented linking p53 mutations with AI growth of CaP. We established five stably transfected LNCaP cell lines: four containing gain-of-function (GOF) mutant p53 alleles (G245S, R248W, R273H, and R273C) and one containing a non-GOF p53 mutant allele (P151S). The four GOF p53 sublines were able to grow under androgen-depleted conditions, whereas the LNCaP parental line, vector-only line, and the non-GOF line were unable to grow. To investigate the mechanism of the AI growth displayed by the GOF p53 mutants, Western blotting or ELISA were used to examine the expression of the androgen receptor (AR), the AR-regulated prostate-specific antigen (PSA), as well as Akt and Bcl-2 under androgen-depleted conditions. On androgen ablation, the levels of AR decreased in the four GOF p53 sublines compared with the control lines. This decreased AR expression was accompanied by attenuated receptor activity, because a decrease in prostate-specific antigen levels compared with parental LNCaP cells was also observed. Levels of phosphorylated Akt increased in both the GOF p53 sublines and the control lines. Bcl-2 remains unchanged or showed reduced expression in all of the cell lines in the absence of androgen compared to the presence of androgen. These observations suggest that GOF p53 mutants mediate the AI growth of LNCaP cells in an AR-independent fashion, and that both Akt and Bcl-2 are not involved in this process.

Alleles↗
PubMed2006

A novel mutation in the tyrosine kinase domain of ERBB2 in hepatocellular carcinoma.

BACKGROUND: Several studies showed that gain-of-function somatic mutations affecting the catalytic domain of EGFR in non-small cell lung carcinomas were associated with response to gefitinib and erlotinib, both EGFR-tyrosine kinase inhibitors. In addition, 4% of non-small cell lung carcinomas were shown to have ERBB2 mutations in the kinase domain. In our study, we sought to determine if similar respective gain-of-function EGFR and ERBB2 mutations were present in hepatoma and/or biliary cancers. METHODS: We extracted genomic DNA from 40 hepatoma (18) and biliary cancers (22) samples, and 44 adenocarcinomas of the lung, this latter as a positive control for mutation detection. We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing targeting exons 18-21 of EGFR and ERBB2. All samples were tested against matched normal DNA. RESULTS: We found 11% of hepatoma, but no biliary cancers, harbored a novel ERBB2 H878Y mutation in the activating domain. CONCLUSION: These newly described mutations may play a role in predicting response to EGFR-targeted therapy in hepatoma and their role should be explored in prospective studies.

Carcinoma, Hepatocellular↗
PubMed2005

The role of the periplasmic loop residue glutamine 65 for MscL mechanosensitivity.

The periplasmic loop of MscL, the mechanosensitive channel of large conductance, acts as a spring resisting the opening of the channel. Recently, a high-throughput functional screening of a range of MscL structural mutants indicated that the substitution of residue glutamine (Q) 65 with arginine (R) or leucine (L) leads to a wild-type (WT)-like and a loss-of-function (LOF) phenotype, respectively. We used electron paramagnetic resonance (EPR) spectroscopy, single-channel recording and in vivo experiments to investigate further the effect of R and L mutation of Q65 on the gating mechanism of MscL. Structural analysis of Q65R and Q65L was carried out by coupling the site-directed spin labeling (SDSL) with EPR spectroscopy. A SDSL cysteine mutant of the isoleucine 24 residue (I24C-SL) in the first transmembrane domain, TM1, of MscL served as a reporter residue in EPR experiments. This was due to its strong spin-spin interaction with the neighboring I24C-SL residues in the MscL channel pentamer. The effects of bilayer incorporation of lysophosphatidylcholine on the MscL mutants were also investigated. Functional analysis was carried out using patch-clamp recordings from these mutants and WT MscL reconstituted into artificial liposomes. Although our data are largely in agreement with the high-throughput mutational analysis of Maurer and Dougherty, this study shows that Q65R and Q65L form functional channels and that these mutations lead to partial gain-of-function (GOF) and LOF mutation, respectively. Overall, our study confirms and advances the notion that the periplasmic loop plays a role in setting the channel mechanosensitivity.

Arginine↗