• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • aldehyde dehydrogenase inhibitor To our knowledge immunohist


    To our knowledge, immunohistochemical analysis for proGRP was done in 5 cases [9], [10], [17], [18]. Takagi-Takahashi et al. reported that the tumor aldehyde dehydrogenase inhibitor were positive for proGRP in one case [9]. Yamaguchi et al. also showed that tumor cells in two patients of ES/PNET with elevated serum proGRP were positive for proGRP [10]. On the other hand, in one of the two cases of pulmonary PNET without elevation of serum proGRP level reported by Imamura et al. [17], 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 [18]. 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. [9]. 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 [19], [20], expression of such markers with high serum/plasma level might indicate the primitive nature of ES/PNETs.
    Conflict of interest
    Source of funding
    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 [1], [2], [3]. ES is characterized by a rapid proliferation of tumor cells with small round nuclei that causes extensive and rapidly progressive bone destruction [4]. 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 [5]. 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 [6]. FLI1 possesses carcinogenic properties of cell cycle induction, aberrant transcription and promotion of cell survival when associated with EWS [7]. 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 [8]. Connexins, the structural proteins of gap junctions, are a family of transmembrane proteins that oligomerize into hemichannels containing six connexin subunits [9]. 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 [10]. The permeability of gap junctions is finely regulated at the transcriptional [11], [12] and posttranslational level via cycles of connexin phosphorylation [13], intracellular Ca or H+ concentrations [14], [15] (for reviews, see Refs. [16], [17], [18]). A critical role in the progression of a variety of tumors has been attributed to gap junction intercellular communication (GJIC) [19], [20]. Reduced or loss of gap junctional activity through different mechanisms including reduced expression has been implicated in various human cancers [21]. 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 [22], [23]. The number of possible mechanisms responsible for connexin-mediated tumor suppression has grown with insights into the possible functional roles of hemichannels [24], cross-talk between gap junctions and other adhesion-based junctional complexes [25] and the discovery of novel connexin-binding proteins [26]. Thus, increasing evidence suggests that GJ-independent mechanisms are also involved in connexin-mediated tumor suppression [20], [21].