ABSTRACT
BACKGROUND: Polysialic acids (abbr. polySia) are found on numerous tumors, including neuroendocrine lung tumors. They have previously been shown to impact metastatic potential, as they can influence the signaling and adhesion properties of neuronal cell adhesion molecules (abbr. NCAM) and other cell adhesion molecules. Therefore, the aim of this small pilot study was to analyze whether there was a correlation between polySia-NCAM expression and specific clinical or histopathologic characteristics, and if polySia-NCAM expression had an impact on treatment response, disease progression and prognosis of lung neuroendocrine neoplasms. METHODS: This work was based on an analysis of 28 digitized patient records and corresponding patient samples. The response to therapy was radiologically determined at the time of diagnosis and at certain intervals during therapy following the current RECIST1.1 and volumetric sphere calculation. To analyze whether polySia-NCAM expression had prognostic relevance, polySia-NCAM-positive and -negative cases were compared in a Kaplan-Meier survival analysis. FINDINGS: A majority of 78.6% lung neuroendocrine neoplasms showed a strong staining signal for polySia-NCAM. There was a significant correlation between expression and histopathological grade (p = 0.0140), since carcinoids were less likely polySia-NCAM-positive compared to small cell lung carcinoma (abbr. SCLC) and large cell neuroendocrine carcinomas of the lung (abbr. LCNEC). There was no significant association between polySia-NCAM expression and clinical characteristics (age: p = 0.3405; gender: p = 0.6730; smoking history: p = 0.1145; ECOG: p = 0.1756, UICC8 stage: p = 0.1182) or radiologically determined disease progression, regardless of the criteria used to categorize response (RECIST 1.1: p = 0.0759; sphere: p = 0.0580). Furthermore, polySia-NCAM expression did not affect progression-free survival (p = 0.4198) or overall survival (p = 0.6918). INTERPRETATION: PolySia-NCAM expression was more common in high-grade compared to low-grade neuroendocrine neoplasms of the lung; however, this small pilot study failed to show an association between polySia-NCAM expression and response to therapy.
ABSTRACT
Polysialyltransferases synthesize polysialic acid on cell surface-expressed glycoconjugates, which is crucial for developing processes and signaling pathways in eukaryotes. Recent advances in cancer research have rendered polysialyltransferases important drug targets because polysialic acid contributes to cancer cell progression, metastasis, and treatment of resistant tumors. To aid the development of high-throughput screening assays for polysialyltransferase inhibitors, we demonstrate that a previously developed class of fluorescent CMP-sialic acid mimetics for sialyltransferases has nanomolar affinities for oligo- and polysialyltransferases and can be used for the rapid screening of new polysialyltransferase inhibitors. We demonstrate that these CMP-Neu5Ac mimetics inhibit polysialylation in vitro and perform cell culture experiments, where we observe reduced polysialylation of NCAM. Furthermore, we describe the structural basis of CMP-Neu5Ac mimetics binding to the human oligosialyltransferase ST8SiaIII and extrapolate why their affinity is high for human polysialyltransferases. Our results show that this novel class of compounds is a promising tool for the development of potent and selective drugs against polysialyltransferase activity.
