aldehyde dehydrogenase inhibitor To our knowledge immunohist
To our knowledge, immunohistochemical analysis for proGRP was done in 5 cases , , , . Takagi-Takahashi et al. reported that the tumor aldehyde dehydrogenase inhibitor were positive for proGRP in one case . Yamaguchi et al. also showed that tumor cells in two patients of ES/PNET with elevated serum proGRP were positive for proGRP . On the other hand, in one of the two cases of pulmonary PNET without elevation of serum proGRP level reported by Imamura et al. , tumor cells were immunohistochemically negative for proGRP. And also Mikami et al. reported a case of pulmonary PNET which was negative for proGRP in both serum and tumor cells . In our case, IHC for proGRP was not performed.
Since our case was young, high level of serum/plasma proGRP unlikely meant that the chest tumor was SCLC. In older patients, on the other hand, elevated serum/plasma proGRP strongly suggests that the chest tumor could be SCLC. However, there is a possibility that middle-aged or even rather old people are affected by ES/PNETs. Since the tumor cells of ES/PNET are somewhat reminiscent of those of SCLC, ES/PNET cases arising from the thorax in older patients with elevated serum/plasma proGRP level might be erroneously diagnosed as SCLCs and treated as SCLCs like a case of Takagi-Takahashi et al. . Careful pathological examination including appropriate IHC and genetic analyses is recommended in such situation.
The number of ES/PNET cases in which serum/plasma proGRP level was examined is unclear and the frequency of blood proGRP elevation in all ES/PNET patients also remains to be clarified. Therefore, the significance and the regulatory mechanism of proGRP production remain to be elucidated in ES/PNETs. Considering that both CEA and proGRP are expressed by primitive cells during embryonal and developmental stages , , expression of such markers with high serum/plasma level might indicate the primitive nature of ES/PNETs.
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Introduction Ewing\'s sarcoma (ES) is the second most frequent pediatric bone cancer after osteosarcoma. It is a rare, aggressive, poorly differentiated tumor of bone and soft tissue which occurs primarily in children, adolescents and young adults , , . ES is characterized by a rapid proliferation of tumor cells with small round nuclei that causes extensive and rapidly progressive bone destruction . ES is a classic example of a malignancy driven by a fusion oncogene, 85% of ES tumor specimens harboring the t(11;22)(q24;q12) chromosomal rearrangement . The resultant fusion transcript EWS–FLI1 is formed by the N-terminal part of the EWS protein linking to the DNA-binding domain (ETS domain) of the FLI1 transcription factor . FLI1 possesses carcinogenic properties of cell cycle induction, aberrant transcription and promotion of cell survival when associated with EWS . Alternative rarer translocations are known such as, EWS/ERG occurs in approximately 10% of cases, EWS/ETV, EWS/EIAF and EWS/FEV each in <1% of cases. Although the cell origin of ES remains unknown, there is a growing body of evidence that suggests ES is derived from human mesenchymal stem cells (hMSC). Indeed, strong arguments indicate that the fusion gene EWS-FLI1 may induce the transformation of hMSC into ES cells . Connexins, the structural proteins of gap junctions, are a family of transmembrane proteins that oligomerize into hemichannels containing six connexin subunits . Upon reaching the cell surface, two hemichannels pair to complete an intercellular gap junction channel, which directly links the cytoplasm of neighboring cells and mediate the exchange of low-molecular-mass molecules (<1000Da), including cAMP, inositol trisphosphate, and Ca . The permeability of gap junctions is finely regulated at the transcriptional ,  and posttranslational level via cycles of connexin phosphorylation , intracellular Ca or H+ concentrations ,  (for reviews, see Refs. , , ). A critical role in the progression of a variety of tumors has been attributed to gap junction intercellular communication (GJIC) , . Reduced or loss of gap junctional activity through different mechanisms including reduced expression has been implicated in various human cancers . The crucial role of altered GJIC in tumor progression was further demonstrated by the exogenous expression of connexins in gap junction-deficient cell lines, which was shown to restore functional communication and to delay tumor growth , . The number of possible mechanisms responsible for connexin-mediated tumor suppression has grown with insights into the possible functional roles of hemichannels , cross-talk between gap junctions and other adhesion-based junctional complexes  and the discovery of novel connexin-binding proteins . Thus, increasing evidence suggests that GJ-independent mechanisms are also involved in connexin-mediated tumor suppression , .