ABSTRACT
In the past two decades, significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, affecting a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, representing one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement, and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their unrestrained action.
Subject(s)
Gene Expression Regulation, Neoplastic , Neoplasms/genetics , Neovascularization, Pathologic/genetics , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction/genetics , Animals , Disease Progression , Humans , Mutation , Neoplasms/blood supply , Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/prevention & control , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: To determine serum leptin concentrations from a sample of Rawalpindi population in relation to body mass index, age and gender. METHODS: The observational, comparative study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, and Benazir Bhutto Hospital, Rawalpindi from August 2008 to December 2008. Subjects were 100 including healthy obese, overweight and non-obese of both genders aged between 20-50 years. Sampling was done by non-probability convenience method. Body Mass Index was calculated by formula BMI = weight in kg/height in m2: non-obese subjects were defined as 18.5-23.0 kg/m2; overweight 23.1-27.4 kg/m2; and obese 27.5-40 kg/m2. Serum glucose was measured using Glucose oxidase-phenol amino phenazone (GOD-PAP) method and serum leptin by sandwich enzyme-linked immunosorbent assay method. RESULTS: Serum leptin concentrations were higher in obese subjects (mean 52.8 +/- 24.6 ng/mL; range 28.2-77.4 ng/mL; P < 0.001) than in non-obese subjects (mean 12.7 +/- 6.1 ng/mL, range 6.6-18.8ng/mL). Mean Body Mass Index in obese group was 31.7 +/- 3.1 kg/m2 (range 28.6-34.8 kg/m2) while it was 21.2 +/- 1.5 kg/m2 (range 19.7-22.7 kg/m2) in the nonobese group. Body Mass Index was strongly positively correlated with serum leptin concentration (r = 0.59, p < 0.001) in the obese group. The mean serum leptin concentration was much higher in the healthy obese and non-obese women (64.4 ng/mL and 8.7 ng/mL respectively) than in men of both categories (40.4 ng/mL and 5.5 ng/mL respectively). Age had no significant relation with serum leptin level (p = 0.416). CONCLUSIONS: In the study sample, serum leptin concentration was positively correlated with Body Mass Index in healthy obese and non-obese subjects of both genders. The levels were higher in women than in men. Age had no significant relation with serum leptin level in this age group.
Subject(s)
Body Mass Index , Leptin/blood , Obesity/blood , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Overweight/blood , Pakistan , Sex Factors , Young AdultABSTRACT
BACKGROUND: South Asians have a high tendency to develop type 2 diabetes even at low BMI. We evaluated serum leptin levels in a group of non-obese type 2 diabetics. METHODS: An observational study conducted on 90 subjects, 55 with Type 2 diabetes mellitus, and 35 normal controls (non-diabetics). BMI, waist circumference, serum leptin, and serum glucose were measured. The correlation between these variables was studied by multiple regression analysis. RESULTS: Serum leptin levels were positively correlated with BMI in obese (r = 0.976) and non-obese diabetics (r = 0.956). Serum leptin was related with diabetes (r = -0.153, p = 0.001). Serum leptin was highly correlated with waist circumference in obese than non-obese diabetics, (r = 0.753). Mean serum leptin level was 21.4 etag/ml in non-obese diabetics and 34.9 etag/ml in diabetic group. It is even lower than the non-obese, non-diabetics (23.3 etag/ml). Multivariate linear regression analysis between leptin and age, weight, BMI, waist circumference in patients shows only a strong association with BMI in diabetics (p = 0.0001), while in non-diabetic it was not significant (p = 0.07). Serum leptin was high in diabetics taking oral hypoglycaemic (37.8 +/- 19.1 etag/ml), while it was low in diabetics taking insulin injections (29.3 +/- 24.2 etag/ml). CONCLUSION: Low leptin levels are associated with type 2 diabetes mellitus independent of changes in BMI.
