Pancreatic Cancer, Leptin, and Chemoresistance: Current Challenges

Pancreatic cancer (PC) remains a leading cause of cancer-related deaths. Currently, conventional chemotherapies have showed only limited benefits for PC patients. Main factors affecting PC treatment failures are due to late detection, lack of early symptoms and biomarkers, and the development of desmoplasia and chemoresistance. Various mechanisms have been implicated in PC chemoresistance that includes stem cells, epigenetic changes, and alteration of signaling pathways, among others. Obesity is a modifiable factor for PC risk, which is characterized by high levels of the adipokine leptin that is a proinflammatory, proangiogenic, survival factor that affects chemotherapy effectiveness. Here, we will discuss on the mechanisms of PC chemoresistance and the influence of obesity and leptin signaling. Furthermore, the potential use of nontoxic leptin antagonists as a novel sensitization strategy for PC chemotherapeutics will also be discussed

Magnetically Targeted Endothelial Cell Localization in Stented Vessels

ObjectivesA novel method to magnetically localize endothelial cells at the site of a stented vessel wall was developed. The application of this strategy in a large animal model is described.BackgroundLocal delivery of blood-derived endothelial cells has been shown to facilitate vascular healing in animal models. Therapeutic utilization has been limited by an inability to retain cells in the presence of blood flow. We hypothesized that a magnetized stent would facilitate local retention of superparamagnetically labeled cells.MethodsCultured porcine endothelial cells were labeled with endocytosed superparamagnetic iron oxide microspheres. A 500:1 microsphere-to-cell ratio was selected for in vivo experiments based on bromo-deoxyuridine incorporation and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assays. Stents were magnetized and implanted in porcine coronary and femoral arteries using standard interventional equipment. Labeled endothelial cells were delivered locally during transient occlusion of blood flow.ResultsThe delivered cells were found attached to the stent struts and were also distributed within the adjacent denuded vessel wall at 24 h.ConclusionsMagnetic forces can be used to rapidly place endothelial cells at the site of a magnetized intravascular stent. The delivered cells are retained in the presence of blood flow and also spread to the adjacent injured vessel wall. Potential applications include delivering a cell-based therapeutic effect to the local vessel wall as well as downstream tissue

INHIBITING CELL SURVIVAL OF OBESITY-RELATED CANCER WITH LEPTIN ANTAGONISTS

Obesity is a comorbidity in many aggressive diseases and has been identify as a risk factor for at least 13 different types of cancers. Adverse outcomes associated with obesity-related cancer progression have been demonstrated previously in both breast and pancreatic cancer. The mechanisms regulating obesity-related cancer outcomes are still unclear; however, it has been demonstrated that leptin signaling induces survival of human cancer cells in vitro and in vivo. Leptin is a 16kD cytokine that is secreted from adipocytes and normally functions to control satiety and energy balance. Clinical studies indicate that circulating leptin levels increase in proportion to an individual’s body fat. Literature also shows that several types of cancer cells overexpress the leptin receptor (OB-R). Leptin signaling pathways can lead to increased proliferation and survival of cancer cells. Leptin/OB-R binding initiates Stat3 phosphorylation by recruitment of JAK2 kinase to the intracytoplasmatic tail of OB-R. Phosphorylated Stat3 forms dimers that trigger the expression several genes involved in cell cycle activation and progression. Our laboratory previously demonstrated a link between leptin-induced S-phase progression of the cell cycle, angiogenesis, apoptosis evasion, and cell invasion and migration in highly aggressive breast and pancreatic cancer cell lines. Consequently, our group has developed several novel leptin antagonists as inhibitors of obesity-related cancer cell survival. Our current study demonstrates that antagonists are non-toxic in non-malignant breast cells. Furthermore, the results show a significant reduction of pStat3 levels and other molecules in triple negative breast and pancreatic cancer cells treated with leptin. It is envisaged that blocking leptin signaling could be a new strategy to treat obesity-related cancers

The Role of Notch Signaling and Leptin-Notch Crosstalk in Pancreatic Cancer

There is accumulating evidence that deregulated Notch signaling affects cancer development, and specifically pancreatic cancer (PC) progression. Notch canonical and non-canonical signaling has diverse impact on PC. Moreover, the actions of RBP-Jk (nuclear partner of activated Notch) independent of Notch signaling pathway seem to affect differently cancer progression. Recent data show that in PC and other cancer types the adipokine leptin can modulate Notch/RBP-Jk signaling, thereby, linking the pandemic obesity with cancer and chemoresistance. The potential pivotal role of leptin on PC, and its connection with Notch signaling and chemoresistance are still not completely understood. In this review, we will describe the most important aspects of Notch-RBP-Jk signaling in PC. Further, we will discuss on studies related to RBP-Jk-independent Notch and Notch-independent RPB-Jk signaling. We will also discuss on the novel crosstalk between leptin and Notch in PC and its implications in chemoresistance. The effects of leptin-Notch/RBP-Jk signaling on cancer cell proliferation, apoptosis, and drug resistance require more investigation. Data from these investigations could help to open unexplored ways to improve PC treatment success that has shown little progress for many years

Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer

Estrogen-receptor-negative breast cancer (BCER−) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER− progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER− patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER− patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER− patients. Targeting OBR signaling could improve chemotherapeutic efficacy