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PI3K/AKT/mTOR signaling promotes cell survival, proliferation and progression in cancer cells. Targeting this pathway may lead to the development of novel therapeutic approaches for human cancers. Here, we examined the effects of (-)-epigallocatechin-3-gallate (EGCG) on the PI3K/AKT/mTOR pathway in pancreatic cancer cells, and assessed its therapeutic potential. In this study, the proliferation and apoptosis of PANC-1 cells were examined by MTT assay and flow cytometry, respectively. The expression of genes and proteins involved in the PI3K/AKT/mTOR pathway were measured by RT-PCR and western blotting, respectively. Our results revealed that EGCG dramatically inhibited the proliferation of PANC-1 cells and induced apoptosis simultaneously. Furthermore, it upregulated PTEN mRNA and protein expression levels, as well as downregulating the expression of phospho-AKT and phospho-mTOR. In conclusion, these results suggest that EGCG can suppress proliferation and induce apoptosis of PANC-1 cells in a time- and dose-dependent manner; moreover, EGCG also can upregulate PTEN expression and downregulate the expression of pAKT and p-mTOR to modulate the PI3K/AKT/mTOR signaling pathway.

Pancreatic cancer cells overexpress the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R). Activating these receptors, insulin and insulin-like growth factor-1 increase the growth and glycolysis of pancreatic cancer cells. The high glycolysis in pancreatic cancer cells increases whole-body energy expenditure and is therefore involved in the pathogenesis of cancer cachexia. The antagonism of IR and IGF1R may sabotage pancreatic cancer cells and attenuate cancer cachexia. Previous studies have shown that the intracellular regulating system of IR/IGF1R may be functionally interrelated to another intracellular system whose master regulator is hypoxia-inducible factor-1 (HIF-1). In this study, we investigated how the IR/IGF1R and HIF-1 systems are interrelated in pancreatic cancer cells. We also investigated whether a phytochemical, penta-O-galloyl-$\beta$-D-glucose ($\beta$-PGG), antagonizes IR/IGF1R, sabotages pancreatic cancer cells and alleviates cancer cachexia. We found in MiaPaCa2 pancreatic cancer cells that IR/IGF1R activation increased both the $\alpha$-subunit of HIF-1 and caveolin-1. This result suggests that IR/IGF1R, HIF-1$\alpha$, and caveolin-1 may constitute a feed-forward loop to mediate the effect of IR/IGF1R activation. $\beta$-PGG inhibited IR/IGF1R activity and decreased glycolytic enzymes in MiaPaCa2 and Panc-1 pancreatic cancer cells. When MiaPaCa2 cells were transplanted in athymic mice, their growth was inhibited by $\beta$-PGG or by a HIF-1$\alpha$ inhibitor, rhein. $\beta$-PGG and rhein also decreased glycolytic enzymes in the tumor grafts and reduced liver gluconeogenesis, skeletal-muscle proteolysis and fat lipolysis in the tumor carriers. Cancer-induced body-weight loss, however, was prevented by $\beta$-PGG but not rhein. In conclusion, $\beta$-PGG combats pancreatic cancer cells and cures cancer cachexia.

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-$\beta$-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

Hypoxia-inducible factor-1 (HIF-1) is an $\alpha$/$\beta$ heterodimeric transcription factor. In normal mammalian cells, HIF-1$\alpha$ is hydroxylated and degraded upon biosynthesis. However, HIF-1$\alpha$ is frequently expressed in cancer and adds to cancer malignancy. In this study, we investigated whether green tea-derived epigallocatechin-3-gallate (EGCG) decreased HIF-1$\alpha$ in pancreatic cancer cells. After MiaPaCa-2 and PANC-1 pancreatic cancer cells were exposed to EGCG in vitro, we performed a Western blot to determine native and hydroxylated HIF-1$\alpha$, which was in turn used to assess HIF-1$\alpha$ production. In order to assess HIF-1$\alpha$ stability, we determined the HIF-1$\alpha$ after MiaPaCa-2 and PANC-1 cells were switched from hypoxia to normoxia. We found that EGCG decreased both production and stability of HIF-1$\alpha$. Further, the EGCG-induced decrease in HIF-1$\alpha$ reduced intracellular glucose transporter-1 and glycolytic enzymes and attenuated glycolysis, ATP production, and cell growth. Because EGCG is known to inhibit cancer-induced insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R), we created three MiaPaCa-2 sublines whose IR, IGF1R, and HIF-1$\alpha$ were decreased using RNA interference. From wild-type MiaPaCa-2 cells and these sublines, we found evidence that suggested that the EGCG-induced inhibition of HIF-1$\alpha$ was both dependent on and independent of IR and IGF1R. In vivo, we transplanted wild-type MiaPaCa-2 cells in athymic mice and treated the mice with EGCG or vehicle. When the resulting tumors were analyzed, we found that EGCG decreased tumor-induced HIF-1$\alpha$ and tumor growth. In conclusion, EGCG decreased HIF-1$\alpha$ in pancreatic cancer cells and sabotaged the cells. The anticancer effects of EGCG were both dependent on and independent of IR and IGF1R.

Stereology and stochastic geometry can be used as auxiliary tools for diagnostic purposes in tumour pathology. The role of first-order parameters and stochastic–geometric functions for the classification of the texture of biological tissues has been investigated recently. The volume fraction and surface area per unit volume, the pair correlation function and the centred quadratic contact density function of epithelium were estimated in three case series of benign and malignant lesions of glandular tissues. This approach was further extended by applying the Laslett test, i.e. a point process statistic computed after transformation of the convex tangent points of sectioned random sets from planar images. This method has not yet been applied to histological images so far. Also the nonlinear deterministic approach to tissue texture was applied by estimating the correlation dimension as a function of embedding dimension. We used the stochastic–geometric functions, the first-order parameters and the correlation dimensions for the classification of cases using various algorithms. Learning vector quantization was applied as neural paradigm. Applications included distinction between mastopathy and mammary cancer, between benign prostatic hyperplasia and prostatic cancer, and between chronic pancreatitis and pancreatic cancer. The same data sets were also classified with discriminant analysis and support vector machines. The stereological estimates provided high accuracy in the classification of individual cases. The question: which category of estimator is the most informative, cannot be answered globally, but must be explored empirically for each specific data set. The results obtained by the three algorithms were similar.

In this paper, we investigate a mathematical model of pancreatic cancer, which extends the existing pancreatic cancer models with regulatory T cells (Tregs) and Treg inhibitory therapy. The model consists of tumor-immune interaction and immune suppression from Tregs. In the absence of treatments, we first characterize the system dynamics by locating equilibrium points and determining stability properties. Next, cytokine induced killer (CIK) immunotherapy is incorporated. Numerical simulations of prognostic results illustrate that the median overall survival associated with treatment can be prolonged approximately from 7 to 13 months, which is consistent with the clinical data. Furthermore, we consider cyclophosphamide (CTX) therapy as well as the combined therapy with CIK and CTX. Intensive simulation results suggest that both CTX therapy and the combined CIK/CTX therapy can reduce the number of Tregs and increase the overall survival (OS), but Tregs and tumor cells will gradually rise to equilibrium state as long as therapies are ceased.

Of all cancers, pancreatic cancer has a significantly low rate of survival, mostly due to lack of early screening. Thus, once detected, pancreatic cancer is usually in later stages, reducing the likelihood of full recovery. The most common treatment strategy is chemotherapy, although several immunotherapeutic drugs show promising results in extending the patient’s lifespan. In this paper, we provide a validated mathematical model for the pancreatic cancer after fitting the parameter values, such as tumor growth rate, inverse carrying capacity, activation and decay rate of pancreatic stellate cells, with the use of the experimental data presented by Cioffi et al. cioffi2015inhibition For treatments with the chemotherapeutic drugs, Abraxane and Gemcitabine, and the immunotherapeutic drug, Anti-CD47, we modified the model accurately and compared the simulation results with the experimental data not only to model pancreatic cancer treatment correctly but also to move forward with other drug trials. Then, we include the cancer stem cells, which are known to initiate tumors and cause a relapse post-chemotherapy, per cancer stem cell hypothesis so that cancer progression can be assessed based on this phenomenon. In addition, we investigate optimal drug protocols. We find out that the most effective treatment is dual therapy due to extending survival time when compared to other drugs. Moreover, this study reveals that drug dose is more effectual than frequency of drug injection on account of different treatment scheduling with the same dose over a week. The model could be a starting point to investigate pancreatic cancer progression based on cancer stem cell hypothesis and shed light on novel drug discoveries.

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Pancreatic resection is associated with a number of long term gastrointestinal complications that can lead to malnutrition and a consequent reduction in the quality of life. These are predominantly the manifestation of exocrine and endocrine insufficiency, gastrointestinal dysmotility, biliary dysfunction and bacterial overgrowth. Such sequelae can lead to reduced oral intake, macro- and micronutrient malabsorption, and impaired glucose homeostasis, which adversely impact on the patient's well-being. In order to minimise these complications after major pancreatic resection, it is imperative to identify these deficiencies and closely monitor the patient's energy consumption, symptoms and nutritional status. The management needs to be coordinated using a multi-disciplinary approach and in each case treatment individualized and based on an understanding of the anatomical, physiological and nutritional sequelae caused by the loss of pancreatic parenchyma through surgical resection.