Serum Anti-p53 Antibody Can Serve as a Predictive Marker for Histological Grade of Intraductal Papillary Mucinous Neoplasms of the Pancreas.
血清 Anti-p53 抗体可作为胰腺导管内乳头状黏液性肿瘤组织学分级的预测指标。
- 作者列表："Hata T","Mizuma M","Motoi F","Iseki M","Omori Y","Hayashi H","Nakagawa K","Morikawa T","Kamei T","Naitoh T","Furukawa T","Unno M
OBJECTIVE:The aim of the study was to clarify the diagnostic impact of measuring serum anti-p53 antibody (S-p53Ab) in predicting the histological grades of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS:We compared the measured values and positive prevalence of S-p53Ab across the different histological grades of 111 resected IPMN cases. We also evaluated the TP53 alterations using immunohistochemistry and next-generation sequencing. RESULTS:Serum anti-p53 antibody were detected in 6 of 111 cases, all of their histological grades were high-grade dysplasia (HGD) and invasive carcinoma (INV). Positive prevalence of S-p53Ab was higher in cases with INV (4/35 cases, 11.4%) than those with HGD (2/38 cases, 5.3%), whereas S-p53Abs were undetectable in cases with low-grade dysplasia. Measured S-p53Ab values were not correlated with either carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9). In 4 of 6 S-p53Ab-positive cases, the TP53 alterations-somatic pathogenic mutations or aberrant immunoreactivity-were identified in their IPMN lesions. A combination assay of S-p53Ab, CEA, and CA 19-9 revealed a 38.4% sensitivity and 81.6% specificity for predicting HGD/INV. CONCLUSIONS:Serum anti-p53 antibody can serve as a surrogate marker for TP53 alterations and help predict the presence of HGD/INV in cases with IPMN, in combination with CEA and CA 19-9.
目的: 探讨血清 anti-p53 抗体 (S-p53Ab) 对胰腺导管内乳头状黏液性肿瘤 (IPMNs) 的诊断价值。 方法: 对 111 例手术切除的 IPMN 病例的不同组织学分级的 S-p53Ab 实测值及阳性率进行比较。我们还使用免疫组化和新一代测序评估了 TP53 改变。 结果: 111 例中 6 例检测到血清 anti-p53 抗体，组织学分级均为高度异型增生 (HGD) 和浸润癌 (INV)。INV 组 S-p53Ab 阳性率 (4/35 例，11.4%) 高于 HGD 组 (2/38 例，5.3%)，而低度异型增生组 S-p53Abs 检测不到。测定的 S-p53Ab 值与癌胚抗原 (CEA) 或糖类抗原 19-9 (CA 19-9) 均不相关。在 6 例 S-p53Ab-positive 中，有 4 例在其 IPMN 病变中发现了 TP53 改变-体细胞致病突变或异常免疫反应性。联合检测 S-p53Ab 、 CEA 和 CA 19-9 预测 HGD/INV 的敏感性为 38.4%，特异性为 81.6%。 结论: 血清 anti-p53 抗体可作为 TP53 改变的替代指标，并有助于预测 IPMN 合并 CEA 和 ca19-9 患者是否存在 HGD/INV。
METHODS::Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.
METHODS::Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly-expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.
METHODS:PURPOSE:Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. METHODS:We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. RESULTS:Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P 50% was determined at 1.40 × 10-3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. CONCLUSIONS:Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.