亜森 マハムット

BACKGROUND: Small cell carcinoma (SmCC) of the bladder is a rare and aggressive malignancy. Characterizing transcription factor (TF)-defined subtypes may provide insights into its biology and inform targeted therapies. This study investigates lineage-specific TF expression in bladder SmCC, its association with clinicopathological features, and comparisons with prostate SmCC. METHODS: A retrospective analysis was conducted on 9 cases of bladder SmCC and 6 cases of prostate SmCC diagnosed at a single cancer hospital in Japan. Immunohistochemistry was performed for lineage-specific TFs (ASCL1, NEUROD1, POU2F3, and YAP1) and neuroendocrine and other markers. Statistical comparisons were made using Fisher's exact test and independent samples t-tests. RESULTS: Combined SmCC morphology, including urothelial carcinoma (UC) (5 cases) and adenocarcinoma (2 cases), was more frequent in bladder SmCC than in prostate SmCC (78% [7 of 9 cases] vs. 17% [1 of 6 cases], p = 0.041). NEUROD1 was more frequently expressed in bladder SmCC than in prostate SmCC (67% [6 of 9 cases] vs. 0% [0 of 6 cases]; p = 0.028). NEUROD1 expression was more frequent in combined SmCC and UC bladder tumors than in other bladder SmCC tumors (100% [5 of 5 cases] vs. 25% [1 of 4 cases], p = 0.048). Conversely, HNF4A expression was absent in all combined SmCC and UC bladder tumors (0 of 5) but present in 75% (3 of 4) of other bladder SmCC tumors (p = 0.048). In 2 cases of bladder SmCC, NEUROD1 and POU2F3 were expressed in a mutually exclusive manner, with neuroendocrine markers expressed only in the NEUROD1-expressing component. CONCLUSIONS: NEUROD1 is characteristically expressed in bladder SmCC, especially in SmCC combined with UC, suggesting a distinct phenotype from prostate SmCC. These findings highlight the potential for TF-based classification to improve diagnostic accuracy and inform therapeutic strategies.

BACKGROUND: The intratumor heterogeneity (ITH) of cancer cells plays an important role in breast cancer resistance and recurrence. To develop better therapeutic strategies, it is necessary to understand the molecular mechanisms underlying ITH and their functional significance. Patient-derived organoids (PDOs) have recently been utilized in cancer research. They can also be used to study ITH as cancer cell diversity is thought to be maintained within the organoid line. However, no reports investigated intratumor transcriptomic heterogeneity in organoids derived from patients with breast cancer. This study aimed to investigate transcriptomic ITH in breast cancer PDOs. METHODS: We established PDO lines from ten patients with breast cancer and performed single-cell transcriptomic analysis. First, we clustered cancer cells for each PDO using the Seurat package. Then, we defined and compared the cluster-specific gene signature (ClustGS) corresponding to each cell cluster in each PDO. RESULTS: Cancer cells were clustered into 3-6 cell populations with distinct cellular states in each PDO line. We identified 38 clusters with ClustGS in 10 PDO lines and used Jaccard similarity index to compare the similarity of these signatures. We found that 29 signatures could be categorized into 7 shared meta-ClustGSs, such as those related to the cell cycle or epithelial-mesenchymal transition, and 9 signatures were unique to single PDO lines. These unique cell populations appeared to represent the characteristics of the original tumors derived from patients. CONCLUSIONS: We confirmed the existence of transcriptomic ITH in breast cancer PDOs. Some cellular states were commonly observed in multiple PDOs, whereas others were specific to single PDO lines. The combination of these shared and unique cellular states formed the ITH of each PDO.

PURPOSE: Recent genetic studies have suggested that tumor suppressor genes are often silenced during carcinogenesis via epigenetic modification caused by methylation of promoter CpG islands. Here, we characterized genes inactivated by DNA methylation in human hepatocellular carcinoma (HCC) to identify the genes and pathways involved in DNA methylation in hepatocellular carcinoma. METHODS: Eight HCC-derived cell lines were treated with a DNA demethylating agent, 5-aza-2'-deoxycytidine. Additionally, 100 pairs of primary HCC and adjacent non-cancerous tissues as well as 15 normal liver tissues were analyzed by comprehensive gene expression analysis using microarrays. Moreover, gene set enrichment analysis identified the major molecular pathways associated with DNA methylation. Validation of gene expression and DNA methylation status was performed by real-time PCR after bisulfite modification. RESULTS: We showed that CXCL2, an immune-related chemokine, expression was significantly downregulated in tumor tissues and also significantly upregulated by DAC treatment in cell lines. Furthermore, we observed a statistically significant difference in methylation status between normal liver tissues and tumor tissues (P < 0.05). In addition, tumors with higher CXCL2 expression included significantly more numbers of multiple tumors than the lower expression group. CONCLUSIONS: We identified CXCL2, an immune-related chemokine, decreased in hepatocellular carcinoma and the regulation mechanism may be controlled by methylation. Further studies should be warranted to examine if and to what extent the gene is actually suppressed by methylation and if there is a possibility that the CXCL2 axis plays a role for diagnosis and treatment of hepatocellular carcinoma.