Kazuki Moro

High levels of sphingolipids in human breast cancer

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 aims of this study were 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 noncancerous 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. 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 those 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 those 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 those of 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.

Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer.

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.

Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis

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 clinicopathologic 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 those patients without. S1P levels were lower in patients with human epidermal growth factor receptor 2 overexpression and/or amplification than those patients without. Furthermore, 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 the 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.

DNA damage response and sphingolipid signaling in liver diseases

Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness

Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.

Predictive Factors for Non-Sentinel Lymph Node Metastasis in the Case of Positive Sentinel Lymph Node Metastasis in Two or Fewer Nodes in Breast Cancer

Background In breast cancer, recent clinical trials have shown that sentinel lymph node biopsy (SLNB) alone without axillary lymph node dissection results in excellent prognosis if there is sentinel lymph node (SLN) metastasis in two or fewer nodes. The aim of the present study was to investigate the association between non-SLN metastasis and clinicopathological factors in case of SLN metastasis in two or fewer nodes in breast cancer. Methods Patients who underwent SLNB for invasive breast cancer and were found to have positive SLN in two or fewer nodes were evaluated. The associations between non-SLN metastasis and clinicopahological factors were examined. Statistical analyses were performed using the Mann-Whitney and Chi-square tests, with statistical significance set at P < 0.05. Results A total of 358 patients were enrolled during the study period and all of these patients were female and 54 patients had SLN metastasis (15%). Positive SLN in two or fewer nodes was identified in 44 patients (81.5%). Among these patients, 17 (38.6%) were found to have non-SLN metastasis. Non-SLN metastasis was associated with invasive tumor size (P = 0.015) and lymphatic involvement (P = 0.035). Multivariate analysis showed that tumor size (P = 0.011) and lymphatic involvement (P = 0.019) remained significant independent predictors of non-SLN metastasis, and that an invasive tumor size cut-off point of 28 mm was useful for dividing patients with positive SLN in two or fewer nodes into non-SLN-positive and non-SLN-negative groups. Conclusions Non-SLN metastasis was found in more than 30% of patients with SLN metastasis present in two or fewer nodes. Large tumor size and the presence of lymphatic involvement were significantly associated with non-SLN metastasis.