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Interstitial cells of Cajal (ICC) is a peculiar cell network composed of cells having processes described by the eminent Spanish neuroanatomist of the 19th century, S. Ramon y Cajal. ICC became a fascinating subject to many investigators and it is estimated that there are over 100 publications yearly on the subject related to ICC, in the last three years. Now it is widely accepted that ICC are pace maker cells of the gut and probable progenitor cells of gastrointestinal stromal tumors (GIST). Lately, interstitial Cajal-like cells (ICLC) are being found in various organs and their physiological role is still to be defined. We have reviewed the literature trying to evaluate the validity of the current concept and found that there are a few salient points to be considered. 1) There has been some important departure in defining the identity of ICC from the original criteria of Cajal. In particular, ICC with myoid feafures in intestinal smooth muscle layers (ICC-DPM) do not seem to fit to the original description of interstitial cell network by Cajal. We have also pointed out that the current reports assigning a pace maker role to ICC vastly depend on the scientific data on "ICC with myoid features", not on "fibroblast-like ICC", which are more abundant and easier to identify. 2) There seem to be an overwhelming amount of data proving the relationship between ICC and GIST. Both are known to express c-Kit and the ultrastructural characteristics seen in GIST roughly parallel those of ICC including minimal myoid differentiation seen in the majority of GIST, supporting the current concept that GIST are ICC tumors. 3) According to the original description of Cajal, ICC was not limited to the gut, suggesting an existence of ICC in other organs. The list of organs reported to contain ICC (currently identified by immunohistochemistry and electron microscopy) is ever growing and further studies are needed to define their identity and pathophysiologic role. 4). Recent data concerning gut development suggest that both c-Kit expressing ICC (fibroblasts-like as well as muscle-like) and gut muscle cells derive from the common progenitor cells of the embryonic gut unifying the histogenetic concept of all GIST with heterogeneous cytomorphologic features. In this review we attempted to incorporate recent information on interstitial Cajal-like cells (ICLC) found in other organs to broaden our understanding of ICC in general in terms of their ultrastructure, physiology, and neoplasia.
J Cell Mol Med
PMID:Interstitial cells of Cajal (ICC) and gastrointestinal stromal tumor (GIST): facts, speculations, and myths. 1712 1

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors driven by KIT or PDGFRA mutations. A majority of these mutations affect KIT exon 11 and represent deletions or point mutations, but insertions and duplications have also been reported. The latter have been found exclusively in the 3' part of KIT exon 11. Reported frequency of duplications varies, and a higher frequency has been reported in studies based on frozen tissue. Recently, we have hypothesized that in some cases, the duplications might remain undetected in formalin-fixed, paraffin-embedded GISTs because of the preferential polymerase chain reaction (PCR) amplification of wild-type KIT over the mutant allele. In this study, 16 GISTs initially diagnosed as a wild-type KIT were evaluated using PCR assay amplifying only the 3' part of KIT exon 11, the region commonly affected by duplications. Denaturing high-pressure liquid chromatography and direct sequencing analyses revealed duplications in 4 (25%) of 16 analyzed cases. Use of the PCR assay amplifying the specific region affected by duplications and yielding 129 bp in wild-type KIT can substantially improve the detection of these mutations in formalin-fixed, paraffin-embedded GISTs.
J Mol Diagn 2007 Feb
PMID:Improved detection of KIT exon 11 duplications in formalin-fixed, paraffin-embedded gastrointestinal stromal tumors. 1725 40

Certain mutations within c-KIT cause constitutive activation of the receptor and have been associated with several human malignancies. These include gastrointestinal stromal tumors (GIST), mastocytosis, acute myelogenous leukemia, and germ cell tumors. The kinase inhibitor imatinib potently inhibits c-KIT and is approved for treatment of GIST. However, secondary point mutations can develop within the kinase domain to confer resistance to imatinib and cause drug-resistant relapse. A common mutation, which results in a V654A substitution, has been documented in imatinib-resistant GIST patients. We expressed c-KIT cDNA constructs encoding the V654A substitution alone and in combination with a typical activating exon 11 mutation characteristic of GIST, V560G, in factor-dependent FDC-P1 cells. The V654A substitution alone resulted in enhanced proliferation in c-KIT ligand (stem cell factor) but not factor independence. Cells expressing the double mutant were, like those expressing single V560G mutant c-KIT, factor independent. Analysis of cellular proliferation in the presence of imatinib showed that the V654A substitution alone conferred resistance. The difference in sensitivity was especially pronounced for cells expressing single mutant V560G c-KIT compared with double mutant V560G/V654A c-KIT. The findings were supported by studies of c-KIT phosphorylation. Analysis of the crystal structure of imatinib in complex with the kinase domain of c-KIT predicts that the V654A substitution directly affects the binding of imatinib to the receptor. Alternative c-KIT inhibitors, nilotinib (AMN107) and PKC412, were also less active on V560G/V654A c-KIT than on the V560G single mutant; however, nilotinib, like imatinib, potently inhibited the V560G mutant. PKC412 strongly inhibited imatinib-resistant D816V c-KIT.
Mol Cancer Ther 2007 Mar
PMID:Resistance to c-KIT kinase inhibitors conferred by V654A mutation. 1736 9

Gastrointestinal stromal tumors (GISTs) frequently harbor mutations in the KIT and PDGFRA genes, the presence and type of which correlate with the response to the kinase inhibitor imatinib mesylate. Because most GIST mutations are deletions/insertions, we used a microfluidic apparatus to detect these size variations in polymerase chain reaction-amplified DNA. This approach, termed microfluidic deletion/insertion analysis (MIDIA), identified mutations in 30 of 50 DNA samples from paraffin-embedded CD117-positive GISTs (60%), comprising 25 deletions and five insertions. Sequencing of 14 MIDIA-positive samples confirmed the deletions/insertions, including two 3-bp alterations. Sequencing of all 20 MIDIA-negative samples also showed highly consistent results with MIDIA because 10 cases were wild type and eight displayed a single base substitution in which detection by MIDIA was not expected. Sequencing also revealed a 3-bp deletion undetected by MIDIA, thus establishing the resolution limit of MIDIA at deletions/insertions >or=3 bp. Denaturing high-pressure liquid chromatography analysis confirmed all mutations detected by MIDIA and sequencing. We pro-pose MIDIA as the first step in mutational screening of GIST because it allowed the detection of 75% of mutated cases (94% of deletions/insertions) in less than 30 minutes after polymerase chain reaction amplification and at a lower cost compared with denaturing high-pressure liquid chromatography and sequencing, which might then be used only for MIDIA-negative cases.
J Mol Diagn 2007 Apr
PMID:Microfluidic deletion/insertion analysis for rapid screening of KIT and PDGFRA mutations in CD117-positive gastrointestinal stromal tumors: diagnostic applications and report of a new KIT mutation. 1738 6

In this issue, Molecular Cancer Therapeutics inaugurates a new feature-The Cutting Edge: Spotlight on Clinical Response-whose objective is the rapid publication of breaking discoveries regarding target- or mechanism-based clinical responses in cancer. Targeted molecules are poised to alter the landscape of clinical cancer treatment. For example, because they can distinguish cancer cells from their normal counterparts, agents such as imatinib mesylate, a Bcr-Abl and Kit kinase inhibitor, can result in remarkable responses with minimal host toxicity in patients suffering from diseases characterized by abnormalities in the targeted kinases. Indeed, studies of imatinib mesylate in early-stage chronic myelogenous leukemia, whose hallmark is the aberrant Bcr-Abl, show response rates of more than 90%. Furthermore, gastrointestinal stromal tumors (GIST), a notoriously chemotherapy-refractory sarcoma, characterized by activating Kit kinase mutations, can show dramatic metabolic responses within days after initiation of treatment. With the wealth of new knowledge in this field, and numerous novel targeted molecules entering clinical trials, the above examples are likely to represent the tip of the iceberg. Indeed, in this issue, a paper by Senzer et al. documents, for the first time, successful use of adenoviral p53 therapy to treat a tumor in a patient with Li Fraumeni Syndrome, a hereditary cancer syndrome caused by the mutation of the p53 tumor suppressor gene. Some of the features of this response, such as the early disappearance of metabolic activity on fluorodeoxyglucose-positron emission tomography scans, are reminiscent of those of GIST responses to imatinib. These findings have important implications for patients with this syndrome, who are prone to develop numerous tumors and often succumb at a young age. In addition, because mutations in p53 are one of the more common aberrations in cancer in general, identification of these mutations and exploration of this approach is warranted in patients with sporadic cancers. In summary, the era of "molecular cancer therapeutics" has begun. Even so, results in the laboratory and in animals often do not translate into salutary effects in patients. However, when they do, it is important that the information be made quickly available to the investigative community. Molecular Cancer Therapeutics believes that providing a forum for the rapid dissemination of cutting-edge findings of successful, albeit early, clinical research should stimulate further study and will ultimately benefit patients with cancer.
Mol Cancer Ther 2007 May
PMID:Studies in target-based treatment. 1748 34

Inhibin is a secreted tumor suppressor and an activin antagonist. Inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance and die of a cachexia-like syndrome due to increased activin signaling. Because Sma and Mad-related protein (SMAD)2 and SMAD3 transduce activin signals in vitro, we attempted to define the role of SMAD3 in gonadal tumorigenesis and the wasting syndrome by generating inhibin alpha and Smad3 double mutant mice. Inhibin alpha and Smad3 double homozygous males were protected from early tumorigenesis and the usual weight loss and death. Approximately 90% of these males survived to 26 wk in contrast to 95% of inhibin-deficient males, which develop bilateral testicular tumors and die of the wasting syndrome by 12 wk. Testicular tumors were either absent or unilaterally slow growing and less hemorrhagic in the majority of double-knockout males. In contrast, development of the ovarian tumors and wasting syndrome was delayed, but still occurred, in the majority of the double-knockout females by 26 wk. In double mutant females, tumor development was accompanied by typical activin-induced pathological changes. In summary, we identify an important function of SMAD3 in gonadal tumorigenesis in both sexes. However, this effect is significantly more pronounced in the male, indicating that SMAD3 is the primary transducer of male gonadal tumorigenesis, whereas SMAD3 potentially overlaps with SMAD2 function in the ovary. Moreover, the activin-induced cachexia syndrome is potentially mediated through both SMAD2 and SMAD3 or only through SMAD2 in the liver and stomach. These studies identify sexually dimorphic functions of SMAD3 in gonadal tumorigenesis.
Mol Endocrinol 2007 Oct
PMID:SMAD3 regulates gonadal tumorigenesis. 1759 16

Inhibin is a secreted tumor suppressor, and inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance at an early age. Inhibin-deficient mice die of a severe wasting syndrome due to increased activin signaling through activin receptor type II. The current study was designed to assess the in vivo effects of an activin antagonist, a chimeric activin receptor type II fused to the Fc region of a murine IgG2a (ActRII-mFc), administered transiently to the inhibin-deficient mice. Results showed that the severe weight loss was prevented in the ActRII-mFc-treated mice, FSH levels were reduced, and an extended life span was observed for these mice compared with phosphate-buffered saline-treated controls. Although ActRII-mFc treatment did not seem to prevent the formation of gonadal tumors, tumors were smaller in the majority of experimentally treated mice and were characterized by the presence of variable numbers and sizes of cysts in contrast to the solid hemorrhagic tumors that typically developed in the controls. Moreover, the ActRII-mFc-treated mice were less anemic, and their livers and stomachs were histologically normal. In summary, this study demonstrated that in vivo administration of the activin antagonist, ActRII-mFc, not only prevents the cachexia-like symptoms in the inhibin-deficient mouse model, but also reduces tumor progression. These results support an essential role of activins in the cachexia-like syndrome development and implicate activins as growth-promoting factors in gonadal tumor progression. The current findings have potential implications in the design of new drugs or strategies for the treatment of ovarian and testicular tumors and other conditions where ligands signal through ActRII.
Mol Hum Reprod 2007 Sep
PMID:Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein. 1770 37

A limited number of whole-cell assays allow monitoring of receptor tyrosine kinase (RTK) activity in a signaling pathway-specific manner. We present the general use of the bioluminescence resonance energy transfer (BRET) technology to quantitatively study the pharmacology and signaling properties of the receptor tyrosine kinase (RTK) superfamily. RTK BRET-2 assays monitor, in living cells, the specific interaction between RTKs and their effector proteins, which control the activation of specific downstream signaling pathways. A total of 22 BRET assays have been established for nine RTKs derived from four subfamilies [erythroblastic leukemia viral (v-erb-b) oncogene homolog (ErbB), platelet-derived growth factor (PDGF), neurotrophic tyrosine kinase receptor (TRK), vascular endothelial growth factor (VEGF)] monitoring the interactions with five effectors (Grb2, p85, Stat5a, Shc46, PLCgamma1). These interactions are dependent on the RTK kinase activity and autophosphorylation of specific tyrosine residues in the carboxyl terminus. RTK BRET assays are highly sensitive for quantifying ligand-independent (constitutive), agonist-induced, or antagonist-inhibited RTK activity levels. We studied the signaling properties of the PDGF receptor, alpha polypeptide (PDGFRA) isoforms (V561D; D842V and delta842-845) carrying activating mutations identified in gastrointestinal stromal tumors (GIST). All three PDGFRA isoforms are fully constitutively activated, insensitive to the growth factor PDGF-BB, but show differential sensitivity of their constitutive activity to be inhibited by the inhibitor imatinib (Gleevec). Epidermal growth factor receptor (EGFR) BRET structure-function studies identify the tyrosine residues 1068, 1114, and 1148 as the main residues mediating the interaction of EGFR with the adapter protein Grb2. The BRET technology provides an assay platform to study signaling pathway-specific RTK structure-function and will facilitate drug discovery efforts for the identification of novel RTK modulators.
Mol Pharmacol 2007 Dec
PMID:Monitoring interactions between receptor tyrosine kinases and their downstream effector proteins in living cells using bioluminescence resonance energy transfer. 1771 95

SU11248 sunitinib malate sutent is a selective inhibitor of certain protein tyrosine kinases including VEGF-R types 1-3 PDGF-R-a and -b, c-kit, and RET. Its antitumor activity may result from both inhibition of angiogenesis and direct antiproliferative effects on certain tumor types. In several phase I/II/III studies, sutent was found to be effective as second and first line treatment in metastatic renal cell carcinoma (RCC). In fact, with a 37% response rate and an additional 48% stable disease sutent became the drug of choice for first line treatment in RCC. Sutent was also effective as second line treatment in patients with gastrointestinal stromal tumors (GIST) with 8% response rate, 70% stable disease and a 20-month median survival. Prolonged stable disease was also documented in neuroendocrine tumors. In addition, a phase II study in multitreated women with breast cancer, sutent demonstrated a moderate activity with 16% clinical benefit. Finally, in non-small cell lung cancer (NSCLC) in patients' progressing on chemotherapy sutent was able to achieve a 10% response rate, a level of activity similar to those documented by other agents approved for lung cancer. The agent is being tested in other tumors with a modified schedule of dosage.
J Steroid Biochem Mol Biol 2008 Feb
PMID:Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma and various other solid tumors. 1794 82

Versican is a large chondroitin sulfate proteoglycan that is an integral component of the extracellular matrix protein. It regulates cell proliferation, adhesion, and migration, and is expressed in a variety of normal tissues and tumors. We studied the pattern of versican expression in various epithelial, mesenchymal, neural, and hematopoietic tumors using immunohistochemistry on tissue microarrays. The primary antibody used was mouse monoclonal antibody to versican (clone 8S270, 1:4000, US Biological). Sections from 3 healing wounds were also included to demonstrate versican expression in reactive tissues. The extracellular matrix in all tissues including all tumors (epithelial and nonepithelial) was positive for versican. However, intracellular cytoplasmic expression of versican was seen only in spindle cells, for example, fibroblasts in healing wounds, 11 of 16 (69%) gastrointestinal stromal tumors and 12 of 42 (28%) smooth muscle tumors. Intracellular versican was not seen in any other tumor [0/344 carcinomas (64 breast, 63 prostate, 61 colorectal, 59 lung, 68 ovarian, and 29 thyroid), 0/22 glioblastoma multiforme, 0/46 lymphomas, and 0/21 melanomas]. As versican plays a role in cell proliferation, differentiation, adhesion, and migration, its differential expression in spindle cell tumors may be associated with the differentiation, progression, and spread of these tumors, which is different from epithelial tumors.
Appl Immunohistochem Mol Morphol 2008 May
PMID:Intracellular versican expression in mesenchymal spindle cell tumors contrasts with extracellular expression in epithelial and other tumors--a tissue microarray-based study. 1830 Dec 43


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