sphingosine-1-phosphate and Colorectal-Neoplasms

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, with a prevalence exceeding 400 per 100 000 in North America. Individuals with UC have a lower life expectancy and are at increased risk for colectomy and colorectal cancer.. UC impairs quality of life secondary to inflammation of the colon causing chronic diarrhea and rectal bleeding. Extraintestinal manifestations, such as primary sclerosing cholangitis, occur in approximately 27% of patients with UC. People with UC require monitoring of symptoms and biomarkers of inflammation (eg, fecal calprotectin), and require colonoscopy at 8 years from diagnosis for surveillance of dysplasia. Risk stratification by disease location (eg, Montreal Classification) and disease activity (eg, Mayo Score) can guide management of UC. First-line therapy for induction and maintenance of remission of mild to moderate UC is 5-aminosalicylic acid. Moderate to severe UC may require oral corticosteroids for induction of remission as a bridge to medications that sustain remission (biologic monoclonal antibodies against tumor necrosis factor [eg, infliximab], α4β7 integrins [vedolizumab], and interleukin [IL] 12 and IL-23 [ustekinumab]) and oral small molecules that inhibit janus kinase (eg, tofacitinib) or modulate sphingosine-1-phosphate (ozanimod). Despite advances in medical therapies, the highest response to these treatments ranges from 30% to 60% in clinical trials. Within 5 years of diagnosis, approximately 20% of patients with UC are hospitalized and approximately 7% undergo colectomy. The risk of colorectal cancer after 20 years of disease duration is 4.5%, and people with UC have a 1.7-fold higher risk for colorectal cancer compared with the general population. Life expectancy in people with UC is approximately 80.5 years for females and 76.7 years for males, which is approximately 5 years shorter than people without UC.. UC affects approximately 400 of every 100 000 people in North America. An effective treatment for mild to moderate UC is 5-aminosalicylic acid, whereas moderate to severe UC can be treated with advanced therapies that target specific inflammation pathways, including monoclonal antibodies to tumor necrosis factor, α4β7 integrins, and IL-12 and IL-23 cytokines, as well as oral small molecule therapies targeting janus kinase or sphingosine-1-phosphate.

Topics: Adult; Antibodies, Monoclonal; Colitis, Ulcerative; Colorectal Neoplasms; Female; Humans; Inflammation; Male; Mesalamine; Quality of Life; Tumor Necrosis Factor-alpha

Sphingosine-1-Phosphate (S1P) plays an important role in normal physiology, inflammation, initiation and progression of cancer. Deregulation of S1P signaling causes aberrant proliferation, affects survival, leads to angiogenesis and metastasis. Sphingolipid rheostat is crucial for cellular homeostasis. Discrepancy in sphingolipid metabolism is linked to cancer and drug insensitivity. Owing to these diverse functions and being a potent mediator of tumor growth, S1P signaling might be a suitable candidate for anti-tumor therapy or combination therapy. In this review, with a focus on colorectal cancer we have summarized the interacting partners of S1P signaling pathway, its therapeutic approaches along with the contribution of S1P signaling to various cancer hallmarks.

Topics: Colorectal Neoplasms; Humans; Lysophospholipids; Signal Transduction; Sphingosine

Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.

Topics: Animals; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine

Accumulated evidences have demonstrated that signal transducer and activator of transcription 3 (STAT3) is a critical link between inflammation and cancer. Multiple studies have indicated that persistent activation of STAT3 in epithelial/tumor cells in inflammation-associated colorectal cancer (CRC) is associated with sphingosine-1-phosphate (S1P) receptor signaling. In inflammatory response whereby interleukin (IL)-6 production is abundant, STAT3-mediated pathways were found to promote the activation of sphingosine kinases (SphK1 and SphK2) leading to the production of S1P. Reciprocally, S1P encourages the activation of STAT3 through a positive autocrine-loop signaling. The crosstalk between IL-6, STAT3 and sphingolipid regulated pathways may play an essential role in tumorigenesis and tumor progression in inflamed intestines. Therapeutics targeting both STAT3 and sphingolipid are therefore likely to contribute novel and more effective therapeutic strategies against inflammation-associated CRC.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Autocrine Communication; Colorectal Neoplasms; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Lysophospholipids; Molecular Targeted Therapy; Signal Transduction; Sphingosine; STAT3 Transcription Factor

Topics: Apoptosis; Caspase 3; Cathepsins; Ceramides; Colonic Neoplasms; Colorectal Neoplasms; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingolipids; Sphingosine

Topics: Aged; Ceramides; Cholesterol; Colorectal Neoplasms; Early Detection of Cancer; Female; Humans; Lipidomics; Lipoproteins, HDL; Lipoproteins, LDL; Lysophosphatidylcholines; Lysophospholipids; Male; Middle Aged; Plasmalogens; Sphingosine; Triglycerides

Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that is generated by sphingosine kinase 1 (SphK1) and is known to play an important role in inflammation and cancer progression. Moreover, SphK1 and S1P act as upstream mediators of proinflammatory cytokine interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT3). We hypothesized that the expression levels of phosphorylated SphK1 (pSphK1), phosphorylated STAT3 (pSTAT3), and IL-6 are universally higher in CAC patients than in sporadic colorectal cancer (CRC) patients because all of these factors are associated with inflammation. In this study, we determined the expression levels of pSphK1 in patients with sporadic CRC and CAC and clarified the importance of S1P in CAC patients.. We randomly selected 10 sporadic CRC patients and 10 CAC patients who underwent curative resection, and we examined their surgical specimens by immunohistochemistry. We determined the expression levels of pSphK1, pSTAT3, and IL-6 in these samples.. We found pSphK1 expression to be more prevalent in CAC patients (P = 0.019) and to have a higher immunohistochemistry score (P = 0.005) than in sporadic CRC patients. However, the expression of pSTAT3 and IL-6 did not differ between the patient groups.. To our knowledge, this is the first report comparing pSphK1 expression levels in CAC with those in sporadic CRC. The high levels of pSphK1 expression in CAC suggest an important role of S1P in the disease process of CAC.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Colitis, Ulcerative; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Interleukin-6; Lysophospholipids; Male; Middle Aged; Retrospective Studies; Sphingosine; STAT3 Transcription Factor; Up-Regulation

Incidence of colorectal cancer (CRC) is growing worldwide. Pathogenetic mechanisms responsible for its onset and progression need further clarification. Colorectal adenomatous polyps are precancerous lesions with malignant potential dependent on histological architecture and grade of nuclear dysplasia. One of the factors conditioning CRC development are abnormalities in sphingolipid metabolism. The aim of this study was to assess the levels of sphingolipids in human colorectal adenomas. The control group (C, n = 12) consisted of patients with no colonic polyps. The examined group consisted of patients with prior diagnosed colonic polyps, qualified to endoscopic polypectomy. This group was further divided due to histological architecture into tubular adenomas group (TA, n = 10), tubulovillous adenomas with low-grade dysplasia (LGD-TVA, n = 10), and tubulovillous adenomas group with high-grade dysplasia (HGD-TVA, n = 11). In tissue samples, sphingolipd metabolite contents were measured using high performance liquid chromatography (HPLC). In cases of polypoid lesions with low malignancy potential (tubular adenomas), concentration of ceramide, which is characterized by proapoptotic and anti-proliferative properties, increases compared with control group (p < 0.05), whereas content of sphingosine-1-phosphate with anti-apoptotic and stimulating cellular proliferation properties is reduced in comparison with control group (p < 0.05). On the contrary, in cases of more advanced form of adenomatous polyps (tubulovillous adenomas with high-grade dysplasia), the ceramide level decreases compared with control group (p < 0.05) while sphingosine-1-phosphate concentration is elevated (p < 0.05). We found that concentrations of pro-apoptotic ceramide are decreased and pro-proliferative S1P levels are increased in polypoid lesions with high malignancy potential, and it was the opposite in those with low malignancy potential.

Topics: Adenoma; Adult; Aged; Colon; Colonic Polyps; Colorectal Neoplasms; Female; Humans; Lysophospholipids; Male; Middle Aged; Rectum; Sphingolipids; Sphingosine