Insulin Promotes Pancreatic Cancer: Evidence for Endocrine Influence on Exocrine Pancreatic Tumors

1996 ◽  
Vol 63 (1) ◽  
pp. 310-313 ◽  
Author(s):  
William E. Fisher ◽  
Laszlo G. Boros ◽  
William J. Schirmer
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Endocrine Influence

scholarly journals Role of Endoscopic Ultrasonography and Endoscopic Retrograde Cholangiopancreatography in the Diagnosis of Pancreatic Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 238
Author(s):  
Yasutaka Ishii ◽  
Masahiro Serikawa ◽  
Tomofumi Tsuboi ◽  
Ryota Kawamura ◽  
Ken Tsushima ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endoscopic Retrograde Cholangiopancreatography ◽  
Endoscopic Ultrasonography ◽  
Treatment Decision ◽  
Needle Aspiration ◽  
Pancreatic Tumors ◽  
Decision Strategy ◽  
Endoscopic Retrograde ◽  
Small Pancreatic Cancer ◽  
Eus Elastography

Pancreatic cancer has the poorest prognosis among all cancers, and early diagnosis is essential for improving the prognosis. Along with radiologic modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), endoscopic modalities play an important role in the diagnosis of pancreatic cancer. This review evaluates the roles of two of those modalities, endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), in the diagnosis of pancreatic cancer. EUS can detect pancreatic cancer with higher sensitivity and has excellent sensitivity for the diagnosis of small pancreatic cancer that cannot be detected by other imaging modalities. EUS may be useful for the surveillance of pancreatic cancer in high-risk individuals. Contrast-enhanced EUS and EUS elastography are also useful for differentiating solid pancreatic tumors. In addition, EUS-guided fine needle aspiration shows excellent sensitivity and specificity, even for small pancreatic cancer, and is an essential examination method for the definitive pathological diagnosis and treatment decision strategy. On the other hand, ERCP is invasive and performed less frequently for the purpose of diagnosing pancreatic cancer. However, ERCP is essential in cases that require evaluation of pancreatic duct stricture that may be early pancreatic cancer or those that require differentiation from focal autoimmune pancreatitis.

scholarly journals The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3040
Author(s):  
Zainab Hussain ◽  
Jeremy Nigri ◽  
Richard Tomasini
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cell Communication ◽  
Pancreatic Tumors ◽  
Mediated Communication ◽  
Biological Impact ◽  
Physiological Relevance ◽  
Cellular Components ◽  
Tumoral Cells

Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients’ care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells’ proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows.

TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Chris D. Hermann ◽  
Benjamin Schoeps ◽  
Celina Eckfeld ◽  
Enkhtsetseg Munkhbaatar ◽  
Lukas Kniep ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Liver Metastasis ◽  
Mouse Models ◽  
Pancreatic Tumors ◽  
Primary Tumors ◽  
Increased Risk ◽  
Metastasis Development ◽  
Male Specific ◽  
Sex Disparity ◽  
Timp1 Expression

Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

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-[Formula: see text]-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.

scholarly journals Metabolic Alterations in Pancreatic Cancer Progression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Enza Vernucci ◽  
Jaime Abrego ◽  
Venugopal Gunda ◽  
Surendra K. Shukla ◽  
Aneesha Dasgupta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Precancerous Lesions ◽  
Genetically Engineered ◽  
Metabolic Reprogramming ◽  
Pancreatic Tumors ◽  
Metabolic Alterations ◽  
Genetically Engineered Mice

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

scholarly journals Pancreatic Fibrosis and Chronic Pancreatitis: Mini-Review of Non-Histologic Diagnosis for Clinical Applications

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 87 ◽  
Author(s):  
Chung-Tsui Huang ◽  
Cheng-Kuan Lin ◽  
Tzong-Hsi Lee ◽  
Yao-Jen Liang
Keyword(s):  
Pancreatic Cancer ◽  
Chronic Pancreatitis ◽  
Acoustic Radiation ◽  
Clinical Applications ◽  
Acoustic Radiation Force Impulse ◽  
Pancreatic Fibrosis ◽  
Pancreatic Tumors ◽  
Clinical Scenario ◽  
Histologic Diagnosis ◽  
Selection Of

Pancreatic fibrosis is the dominant reversible pathological change and diagnostic factor in early chronic pancreatitis, defined by a mechanistic approach proposed in 2016. Main guidelines for chronic pancreatitis were published by the American Pancreas Association in 2014, the Japanese Society of Gastroenterology in 2015, and United European Gastroenterology in 2017. All three sets of guidelines mentioned that the staging of chronic pancreatitis is important but challenging. There are various image modalities for the non-histologic diagnosis of pancreatic fibrosis: (1) shear wave elastography, such as an acoustic radiation force impulse with a cut-off value of 1.4 m/s; (2) strain elastography using grades of strain; (3) endoscopic ultrasonography using the Rosemont criteria or endoscopic ultrasound criteria for early chronic pancreatitis proposed by the Japan Pancreas Society; (4) computed tomography using the Hounsfield scale or number of micro-calcifications; and (5) magnetic resonance imaging using the apparent diffusion coefficient and the T1w flash and T2w HASTE sequences. The clinical applications are to (1) evaluate pancreatic tumors and inflammatory disease; (2) monitor dyspepsia with early chronic pancreatitis; (3) monitor individuals with a high risk of pancreatic cancer; (4) analyze a fatty pancreas with fibrosis; (5) predict a fistula after pancreatic surgery; and (6) predict outcomes for chronic pancreatitis or pancreatic cancer. The selection of tools will be dependent on the clinical scenario. Conclusion: There are various modalities for the non-histologic diagnosis of pancreatic fibrosis. The selection of the optimal device will be dependent on the clinical scenario.

Mind Bomb 1 Promotes Pancreatic Cancer Proliferation by Activating β-Catenin Signaling

2020 ◽  
Vol 20 (12) ◽  
pp. 7276-7282
Author(s):  
Xiao Fu ◽  
Neng Tang ◽  
Weiqi Xie ◽  
Liang Mao ◽  
Yudong Qiu
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Mrna Level ◽  
Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Pancreatic Tumors ◽  
Mrna Levels ◽  
Cancer Proliferation

Mind bomb 1 (MIB1), an E3 ligase, plays a vital role in chemo-resistance and cancer metastasis. According to The Cancer Genome Atlas (TCGA), MIB1 gene is preferentially amplified in pancreatic cancer. Copy number alterations in MIB1 gene are associated with worse survival. Gene Expression Omnibus (GEO) also showed that pancreatic cancer with high mRNA level of MIB1 tend to be more resistant to gemcitabine and higher mRNA levels of MIB1 are found in pancreatic tumors compared with adjacent normal tissues. MIB1 knockdown (KD) in Panc-1 and HPAF2 cell lines significantly inhibit proliferation and colony formation of pancreatic cancer. The gene set enrichment analysis (GSEA) has also showed that β-catenin is the downstream of MIB1. Western blot analysis showed that total and active β-catenin levels are decreased in MIB1 KD cells. β-catenin inhibitor also inhibits proliferation of Panc-1 and HPAF2 cells. We in this study implanted HPAF2 scramble and MIB1 KD cells orthotopically in athymic nude mice. Gemcitabine was used to treat the mice. Results revealed that after MIB1 KD HPAF2 cells were more sensitive to gemcitabine. In conclusion, we demonstrated that MIB1 promotes pancreatic cancer proliferation through activating β-catenin signaling. MIB1 may thus be a therapeutic target in pancreatic cancer therapy.

Safety and tolerability of combined gemcitabine (G) and erlotinib (E) plus sorafenib (S) in the first-line treatment of metastatic pancreatic cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15594-e15594 ◽  
Author(s):  
D. J. Cohen ◽  
T. Ryan ◽  
T. Moskovits ◽  
N. Cazeau ◽  
E. Newman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Kinase Inhibitor ◽  
Bowel Perforation ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Median Number ◽  
Metastatic Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Disease Stabilization ◽  
Ecog Ps

e15594 Background: The addition of E to G results in improved survival for patients(pts) with locally advanced and metastatic pancreatic cancer. Many pancreatic tumors have constitutively activated ras/raf pathways and overexpress VEGF. Sorafenib, a multitargeted tyrosine kinase inhibitor which targets VEGR 1–3, PDGFR-α and β and the RAF/MEK/ERK pathway, when combined with G and E may synergize with these agents resulting in a more complete blockade of the signal transduction cascade in pancreatic cancer growth and progression and therefore improve outcome. Methods: Pts with previously untreated, histologically confirmed, unresectable pancreatic adenocarcinoma, ECOG PS 0–1, and adequate organ function were eligible and received G 1,000 mg/m2 over 30 min weekly × 3 every 4 weeks. E 150 mg PO daily and S 400 mg PO bid were given continuously. CT scans were performed every 2 cycles (8 weeks). Endpoints included safety and tolerability of the novel combination, PFS at 4 months, response rate, and OS. Results: Between 9/07–12/08 19 pts were enrolled with a median age 59 (range 45- 75), M/F 13/6, PS (0/1) 14/5. All 19 had metastatic disease. 17 pts are evaluable for toxicity and efficacy. The median number of cycles on treatment was 2 (range 1–10). The most common grade (gr) 3 toxicities were thrombocytopenia (24%), venous thrombosis (12%), and hyperbilirubinemia (12%). The most common gr 4 toxicity was infection (12%). 1 pt each experienced gr 3 HFSR, gr 3 diarrhea, gr 3 bleeding (epistaxis) and 1 had a non-fatal bowel perforation. There was 1 PR and 6 SD for an overall RR of 6% and a DCR of 41%. Conclusions: The combination of G and E plus S in the treatment of advanced pancreatic cancer is a well tolerated regimen without significant increased toxicity as compared to gemcitabine alone, except for very manageable cutaneous reactions. Further follow up is required to determine the combination's efficacy, though some patients have achieved prolonged disease stabilization. Supported in part by grants from Bayer Healthcare Pharmaceuticals/Onyx and OSI. [Table: see text]

Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 195-195 ◽  
Author(s):  
M. Bloomston ◽  
C. Marsh ◽  
J. Walker ◽  
W. Coyle ◽  
H. Marx ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Tumor Vaccine ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Kinase Gene ◽  
Early Results ◽  
Cell Immunity ◽  
Dose Levels

195 Background: More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and have a median survival of only 6 months. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) is an approach that generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug and synergy with chemoradiation. The mechanisms of action involve tumor cytotoxicity, activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Safety with potential efficacy has been demonstrated in multiple clinical studies. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into locally advanced tumors via EUS or CT-guidance before and during week 3 of standard 5-FU-chemoradiation. Valacyclovir (Valtrex, GSK) prodrug was given for 14 days after each of 2 AdV-tk injections. Results: The study completed accrual with 13 patients enrolled and 12 completing therapy with 3 at each of the 4 dose levels. One patient refused further participation during course 1 after recovering from azotemia. Median age was 64 years (range 55-81) and median baseline CA19-9 was 1634 U/ml. No dose limiting toxicities and no injection related complications occurred. Possibly related grade 3-4 toxicities, all of which were transient, included dehydration, azotemia and worsening elevation of bilirubin and AST. Kaplan-Meier estimated median survival is 12.2 months with 6 patients still alive at 8-20 months. Two patients achieved a partial response by RECIST criteria. One occurred in week 6 despite discontinuing 5-FU/radiation during week 1. The other had gradual decrease of a 7 cm tumor over 11 months. Serum CA19-9 levels decreased in 8/8 evaluable patients by 32-91% at 3 months after treatment initiation. Conclusions: AdV-tk can be safely injected into pancreatic tumors and combined with standard chemoradiation. Early results are highly encouraging and justify further evaluation in a phase II study. [Table: see text]

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