Carcinosarcoma of the pancreas: comprehensive clinicopathological and molecular characterization.
- 作者列表："Li J","Wei T","Zhang J","Wei S","Chen Q","Chen BW","Zhou Y","Wen L","Qin H","Bai X","Liang T
BACKGROUND:Carcinosarcoma of pancreas is a rare subtype of pancreatic cancer. The aim of this study was to comprehensively elaborate the clinicopathological and molecular features of this rare malignancy. METHODS:Patients who were diagnosed with carcinosarcoma of the pancreas were retrospectively identified from pathology database of a single institution between 2012 and 2018. RESULTS:A total of nine patients were identified. Pathological examination of tumor tissues from included patients showed coexisting carcinomatous and sarcomatous components. These two components were distinguished by mutually exclusive expression of cytokeratin and vimentin. The sarcomatous tissue exhibited more extensive proliferation, as revealed by Ki67 staining, and necrosis compared with the carcinomatous counterpart. Genomic analysis of tumor tissues for two patients demonstrated hotspot mutation at KRAS and TP53. Carcinomatous and sarcomatous components were separately obtained via laser captured microdissection in one patient, and mutations of driving genes were highly concordant between them. Besides, immunostaining of frequently-altered tumor suppressor genes for these two components suggested consistent expression patterns. The median overall survival for six patients with adequate follow-up was 14 months. CONCLUSION:Carcinosarcoma of the pancreas represent a rare malignancy with distinct histological characteristics. Genomic and molecular analysis suggested monoclonal origin of carcinomatous and sarcomatous components.
背景: 胰腺癌肉瘤是一种罕见的胰腺癌亚型。本研究的目的是全面阐述这种罕见恶性肿瘤的临床病理和分子特征。 方法: 从 2018 和 2012年单个机构的病理学数据库中回顾性地鉴定诊断为胰腺癌肉瘤的患者。 结果: 共确定 9 例患者。对纳入患者的肿瘤组织进行病理检查，发现癌和肉瘤成分并存。这两种成分通过细胞角蛋白和波形蛋白的互斥表达来区分。与癌对体相比，肉瘤组织表现出更广泛的增殖和坏死，如 Ki67 染色所示。2 例患者肿瘤组织的基因组分析显示 KRAS 和 tp53 存在热点突变。1 例患者通过激光捕获显微切割分别获得癌瘤和肉瘤成分，驱动基因突变高度一致。此外，这两个组分频繁改变的肿瘤抑制基因的免疫染色提示一致的表达模式。经过充分随访的 6 例患者的中位总生存期为 14 个月。 结论: 胰腺癌肉瘤是一种罕见的恶性肿瘤，具有独特的组织学特征。基因组和分子分析提示癌性和肉瘤成分的单克隆起源。
METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.
METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.
METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.