High levels of sphingolipids in human breast cancer Nagahashi, Masayuki, MD, PhD; Tsuchida, Junko, MD; Moro, Kazuki, MD ...
The Journal of surgical research,
08/2016, Letnik:
204, Številka:
2
Journal Article
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Abstract Background Sphingolipids, including sphingosine-1-phosphate (S1P) and ceramide, have emerged as key regulatory molecules that control various aspects of cell growth and proliferation in ...cancer. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients have yet to be determined. The aim of this study is to determine the levels of sphingolipids including S1P, ceramides, and other sphingolipids, in breast cancer and normal breast tissue and to compare the difference in levels of each sphingolipid between the two tissues. Materials and Methods Tumor and non-cancerous breast tissue were obtained from 12 patients with breast cancer. Sphingolipids including S1P, ceramides, and their metabolites of sphingosine, sphingomyelin, and monohexosylceramide were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results The levels of S1P, ceramides, and other sphingolipids in the tumor were significantly higher than those in normal breast tissue. There was a relatively strong correlation in the levels of S1P between the tumor and that of normal breast tissue from the same person. On the other hand, there was no correlation in the levels of most of the ceramide species between the tumor and that of normal breast tissue from the same person. Conclusions To our knowledge this is the first study to reveal that levels of sphingolipids in cancer tissue are generally higher than normal breast tissue in patients with breast cancer. The correlation of S1P levels in these tissues implicates the role of S1P in interaction between cancer and the tumor microenvironment.
Development of innovative strategies for cancer treatment is a pressing public health issue. Despite recent advances, the mechanisms of cancer progression and the resistance to cancer treatment have ...not been fully elucidated. Sphingolipids, including ceramide and sphingoshin-1-phosphate, are bioactive mediators that regulate cancer cell death and survival through the dynamic balance of what has been termed the ‘sphingolipid rheostat’. Specifically, ceramide, which acts as the central hub of sphingolipid metabolism, is generated via three major pathways by many stressors, including anti-cancer treatments, environmental stresses, and cytokines. We have previously shown in breast cancer patients that elevated ceramide correlated with less aggressive cancer phenotypes, leading to a prognostic impact. Recent studies showed that ceramide have the possibility of becoming the reinforcing agent of cancer treatment as well as other roles such as nanoparticles and diagnostic biomarker. We review ceramide as one of the key molecules to investigate in overcoming resistance to current drug therapies and in becoming one of the newest cancer treatments.
Inflammation is a central process in several disorders and contributes to cancer progression. Inflammation involves a complex cascade of pro-inflammatory and anti-inflammatory signaling events with ...protein and lipid mediators. Recent advances in lipid detection have revealed the importance of lipid mediators in inflammation. Omega three polyunsaturated fatty acids (ω-3 PUFA) are found naturally in fish oil and have been extensively studied in multiple inflammatory diseases with improved outcomes. Resolvins are thought to be the active metabolites of ω-3 PUFA, and are responsible for facilitating the resolving phase of acute inflammation. Clinically, resolvins have been associated with resolution of acute kidney injury and acute lung injury, micro and macro vascular response to injury, and inhibition of microglia-activated inflammation in neurodegenerative disorders. In addition to inflammatory diseases, ω-3 PUFA and resolvins appear to modulate cancer progression. ω-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and favorable phenotype in breast cancer. Resolvins offer promising therapeutic potential as they may modulate inflammation with minimal side-effects, in contrast to currently available anti-inflammatory medications. This review describes the roles of ω-3 PUFA and resolvins in the inflammatory cascade, various inflammatory diseases, and specific cancers. Additionally, it will discuss the clinical therapeutic potential of resolvins as targets in inflammatory diseases and cancers.
Background Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and ...fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. Methods ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. Results ERBB2 AMP (greater than or equal to 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen's kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. Conclusions A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC. Keywords: Gastric cancer, HER2, ERBB2, Targeted tumour sequencing test, Trastuzumab
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to ...the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (
= 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (
= 0.012), lymph node metastasis (
= 0.014), and advanced cancer stage (
= 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.
The cystic duct has been included in the staging classification scheme for gallbladder cancer since the 2010 publication of the AJCC Cancer Staging Manual (7th edition). To our knowledge, only seven ...other cases of adenocarcinoma arising in the remnant cystic duct following cholecystectomy have been reported in the English-language literature, and none has been reported as primary early-stage T1b remnant cystic duct cancer (CDC). We report, herein, a case of primary adenocarcinoma arising in the remnant cystic duct in a patient with history of laparoscopic cholecystectomy for gallstone disease.
An 81-year-old female presented with abdominal pain. Her medical history included a laparoscopic cholecystectomy for cholecystolithiasis two years prior. Jaundice was observed; imaging studies suggested that this was caused by choledocholithiasis. Blood chemistry findings showed severe liver dysfunction. Endoscopic retrograde cholangiography revealed haemobilia from the common bile duct with no evidence of choledocholithiasis. A bile sample showed Papanicolaou class IV cytology. As the extent of tumour spread was undetermined by abdominal ultrasonography and endoscopic ultrasonography, peroral cholangioscopy (POCS) was performed, which revealed tiny papillary lesions within the confluence of cystic duct, and fine granular lesions in the centre of bile ducts, signifying early-stage remnant CDC. Extrahepatic bile duct resection with regional lymphadenectomy was done. Histopathological findings revealed a 42-mm tubular adenocarcinoma originating from the remnant cystic duct with the considerable shallow spread across the extrahepatic bile ducts. It invaded the fibromuscular layer, with no lymphovascular or perineural invasion, no lymph node metastasis (13 nodes examined), and uninvolved surgical resection margin (R0 resection), and was staged as pT1bN0M0, Stage I.
Primary early-stage T1b remnant CDC is an uncommon condition for which early diagnosis is challenging; if intraoperatively recognized, it can complicate surgery. Our experience of this case and an overview of the English literature suggest that POCS is an efficient tool to diagnosis this tumour and assess its spread along the extrahepatic bile ducts.
Abstract Background Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, has been implicated as a key regulatory molecule in cancer through its ability to promote cell ...proliferation, migration, angiogenesis and lymphangiogenesis. Previous studies suggested that S1P produced by sphingosine kinase 1 (SphK1) in breast cancer plays important roles in progression of disease and metastasis. However, the associations between S1P and clinical parameters in human breast cancer have not been well investigated to date. Materials and Methods We determined levels of S1P and other sphingolipids in breast cancer tissue by electrospray ionization-tandem mass spectrometry. Associations between S1P levels and clinicopathological features of the tumors were analyzed. Expression of phospho-SphK1 (pSphK1) in breast cancer tissues was determined by immunohistochemical scoring. Results Levels of S1P in breast cancer tissues were significantly higher in patients with high white blood cell count in the blood than patients without. S1P levels were lower in patients with HER2 overexpression/amplification than patients without. Further, cancer tissues with high pSphK1 expression showed significantly higher levels of S1P than cancer tissues without. Finally, patients with lymph node metastasis showed significantly higher levels of S1P in tumor tissues than patients with negative nodes. Conclusions To our knowledge, this is the first study to demonstrate that high expression of pSphK1 is associated with higher levels of S1P, which in turn is associated with lymphatic metastasis in breast cancer.
Background
Bochdalek hernias are one of the most common types of diaphragmatic hernia, with most cases diagnosed during the neonatal period. In contrast, diagnosis of a Bochdalek hernia in an adult ...is rare and is typically observed on the left side of the diaphragm. Even more rare is the diagnosis of a right-sided Bochdalek hernia in an adult, where there is concurrent visceral malformation in most cases.
Case presentation
We describe a case of an 89-year-old female who presented with abdominal pain. An abdominal computed tomography (CT) scan showed decreased intravenous contrast uptake and thickening of the wall of herniated small intestine through the right side of the diaphragm, which led to the diagnosis of a strangulated diaphragmatic hernia. The patient underwent emergent laparotomy and required a partial resection of the necrotic ileum and a hernia repair with direct closure. Interestingly, in this case, organ malformation was not observed. The patient was discharged approximately 2 weeks after surgery without complication.
Conclusions
Adult right-sided Bochdalek hernia with strangulation in the absence of hepatic atrophy is a rare entity. Considering the severity of this condition, accurate diagnosis and proper treatment are needed. A tailored operative approach is required on an individual case basis.
Background
Neurofibromatosis type 1 (NF1) is an autosomal dominant disease of the skin and soft tissue. Aneurysms associated with NF1 can occur, but a secondary aneurysm rupture is very rare, with ...very few cases reported in literature.
Case presentation
We describe the case of a 67-year-old female with NF1 who underwent endovascular aneurysm repair (EVAR) for an abdominal aortic aneurysm (AAA) rupture. She developed a type Ib endoleak requiring a redo-EVAR. Eighteen days after her primary operation, she was found to have two new left colic artery aneurysms. She required emergency surgery consisting of a left hemicolectomy and transverse colon colostomy. Pathology showed neurofibromatous changes to the peri-vasculature tissue, consistent with her underlying disease.
Conclusions
Although rare, secondary aneurysms can occur following AAA repair. Patients with soft tissue connective tissue disorders, like NF1, may be at an increased risk for development of these secondary aneurysms. Endovascular repair appears to be a safe approach for NF1 patients with AAA, but endovascular management can be challenging in the setting of NF1. Surgeons should be ready to convert to open surgery if the patient displays persistent signs of bleeding or structural changes related to connective tissue disorders like NF1.
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