Day 1 :
- Pancreatic Tumor
Co-founder and Scientific Director of ACOBIOM Company
Dr. David Piquemal is the co-founder and scientifc Director of ACOBIOM company. His main aim is to develop innovative methods and software to analyze, integrate and contextualize large-scale biological data in the fields of health, agronomy and environment. He completed his PH.D in Molecular Biology from the institute of Human Genomic in the year 2000. His area of interest involves-Molecular Biology, Personalized Medicine,Translational Medicine and Bioinformatics.
Pancreatic cancer (PC) kills 98% of those it afflicts and is one of the most lethal cancers worldwide: patients diagnosed with PC have a poor prognosis partly because the cancer usually causes no symptoms early on, leading to metastatic disease at the time of diagnosis. The high mortality rate is partly due to the difficulty to diagnose and due to the lack of stratified patients to effective treatments. The capability of biomarkers to improve treatment and to reduce healthcare costs is potentially greater than in any other area of current medical research. Otherwise, Healthcare stakeholders are facing two major issues: the reduction of global Healthcare system expenditures and the growing need to improve the efficiency of therapies. Diagnostics are one of the most efficient solutions to respond to these needs by supporting physicians in the selection of the best treatment.
In a without a priori analysis and from a whole blood collection, from clinical trial phase III and based on a high throughput analysis of NGS data using the proprietary ACOBIOM genomics platform (Big Data system dedicated to Biomarker discovery), we identified a set of genes in a pre-discovery phase. Using Real-Time PCR, candidate genes were selected for test significance and a Gene Expression-based Score was established.
Acobiom developed a new In Vitro Diagnostic for patient stratification based on molecular analysis. The GemciTest® assay is an IVD associated with gemcitabine drug in PC treatment. GemciTest® is currently a prototype in an operational environment through a 15 Clinician Peer Network. This IVD is a quantitative real-time PCR assay and is intended to quantitatively aid in the determination of high probability Progression- Free Survival and Overall Survival rates of patients diagnosed with pancreatic cancer and treated with gemcitabine as first-line therapy.
In this context, Acobiom is always looking for new partnerships, public or private, the right way to really open the opportunity to develop safe/better solution in PC for the patient (Bench-to-Bedside), assisting physicians in routine patient care.
Sir Ganga Ram hospital, India
Sangeeta Choudhury is Associate Professor & Senior Consultant @ Sir Ganga Ram hospital, New Delhi, INDIA. She has obtained her Doctoral degree from one of the premier institute of the country, Bhabha Atomic Energy Research Centre, Mumbai, India. Thereafter she was a Research Fellow at Department of Anatomy, Division of Cell Biology, University of New South Wales (UNSW), Sydney, AU and also did her Post Doctoral Fellowship at Division of Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, USA. On returning to the country, she was positioned as Research Scientist (Indian Council of Medical Research), National Institute of Immunology, New Delhi, India. She has been the recipient of national awards (Lady Tata Grants, Department of Atomic Energy, INDO-US Vaccine Action Program). Her major areas of interests are solid tumor biology and stem cell, cancer & obesity related metabolic disorders, transplantation immunology. She is in the review board of national journals and also scientific committee. She is a member of Cancer bodies and also Immunology & biochemistry national bodies [American Association for Cancer Research (USA); Indian Society of Oncology (India); American Society for Microbiology (USA), Society for Biological Chemists, India (India), Association of Clinical Biochemists India]. She has authored about 28 scientific articles and 3 book chapters too.
Over the years, pancreatic cancer has been established as a complicated disease with poor prognosis and survival rate. Standard chemotherapeutic agents/drugs have not shown any significant advancement in its regression. Several studies have indicated anti-angiogenesis and blocking the cancerous growth of breast, prostate, lung and colon by micronutrients like vitamin D, E, B12. Although, pancreatic cancer tissue expresses Vitamin D (VitD) receptor, the potential mechanism to exert anti-cancer effect remains underexplored.
Thus, our study aimed to find out the mechanistic effect caused by the VitD analogue (Calcitriol) in pancreatic cancer cells. Pancreatic cancer cells (PCC lines; MiaPaCa2 and PanC-1) treated with calcitirol for longer duration (24hrs-to-96hrs) showed decreased expression of metastatic phenotype, CXCR4/CCL12, EpCAM/Vimentin along with decreased chemoresistant-MUC-1 expression, although no inhibitory effect was observed on their proliferative capacity. But, addition of Gemcitabine (Gem) to calcitirol-treated PCC lines increased their apoptotic capacity than cells treated only with Gem, suggesting that calcitirol treated-PCC cells are susceptible to chemotherapeutic drug. Further, with the emergence of stroma playing a major role in pancreatic cancer, we attempted to elicit the involvement of VitD in Sonic Hedgehog (SHH) signaling. Enhanced apoptosis was observed when salinomycin (SHH inhibitor) was administered to calcitirol treated-PCC cells. Copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) were observed to show increased expression in treated PCC lines in comparison to untreated cells.
In conclusion, our experimental evidence postulates a potential mechanism by which VitD- analogue, calcitirol modulated its stromal interaction via its action on the cell-membrane protein MUC-1.
Dr. Mohamed Gamil A Ramadan MD, FACS Professor of Surgical Oncology Head of GI Endoscopy Unit NCI, Cairo University Ex-president of Egyptian Society of Surgical Oncology (EGSSO )
Pancreatic cancer is the forth cause of cancer death worldwide .Difficulty in early diagnosis is the main cause of its poor diagnosis. CT and MRI equally perform in diagnosis and evaluation of respectability of pancreatic cancer. Ultra-sound had a lower sensitivity and specifity. EUS is a reference method for diagnosis and staging of different pancreatic disease. At this time no major professional groups recommended routine screening for pancreatic cancer in average risk people .The aim of this study is to compare EUS,CT and MRI in early diagnosis of pancreatic tumors .
Patients and Methods
Ninety eight patients with various pathological types of pancreatic mases were enrolled in this study. They were examined using the three diagnostic modalities and compared to the gold standard which is the cytological and histopathologic diagnosis of an EUS guided biopsy
EUS detected 100% of pancreatic tumors even those smaller than 1 CM in diameter .EUS detected nodal metastasis in 65% of cases verses 37.5% in MRI and 7.5% in CT.EUS detected vascular invasion in 50% of cases verses 32.5% in MRI and 7.5% in CT. EUS and MRI detected hepatic metastases in 20% of cases verses 7.5% by CT .EUS has sensitivity of 100% and specifity of 75% which is the highest values among the three diagnostic modalities
Endoscopic ultra sound is a very sensitive method for detection and staging of pancreatic cancer.
Department of Research, Sir Ganga Ram hospital, India.
Neha Chopra is pursuing her PhD from Jamia Hamdard in association with Sir Gangaram hospital, New Delhi. She was a university topper in post graduate program and presently a DST- INSPIRE fellow. Her work from post graduate thesis is under publication in an international journal. She has presented her PhD research work at national and international conferences (AACR). She has co-authored a book chapter and currently in process of submitting 2 original research papers.
Pancreatic cancer has an extremely poor prognosis, due to not only being a highly complex and aggressive malignancy (higher invasion and metastasis) but also is resistant to most therapies. Stem cell based treatments are being increasingly explored especially for those cancers that cannot be treated with targeted therapy. In the last decade, Mesenchymal stem cells (MSCs) have attracted significant attention as a result of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. We propose a novel strategy of using MSCs as a cell-based anticancer therapeutic option. Till date, MSC-based therapy for pancreatic cancer has not been demonstrated.
Our study demonstrates the feasibility using the pancreatic cell-line-based model (MiaPaCa-2 and PanC1). Expression of classical pancreatic cancer stem-cell markers ie., CD44+/CD24+ in MiaPaCa-2 was 71.7±5.5% and PanC-1 showed 64.6±5.2% as compared to fibroblast cell line NIH-3T3 (19.1±1.4%) (p=0.0001). Sensitivity (IC50 dose response) towards Gemcitabine (Gem) and 5-Fluorouracil (5FU) was derived from MTT assay. PanC-1 showed relatively more resistance than MiaPaCa-2 (Gem–600nM vs 350nM & 5-FU–>1000nM vs 400nM) respectively suggesting PanC1 is more resistant.
To study the interaction between human Wharton’s jelly-derived mesenchymal stem cells (hWJMSCs) and pancreatic cancer cells, co-culture assays were performed (ratio of 1:1; 48 hrs). Markers of pro-apoptosis (Bax) and proliferation (Ki-67) were assessed by immunofluorescence. An inverse proportionate expression of Bax and Ki67 was observed when MiaPaCa-2/PanC-1 was treated with hWJMSCs (32.5% and 13% respectively). To verify these results, PKH-26 - labeled hWJMSCs were overlaid on pancreatic tumor cells (1D). It was observed microscopically that PKH-26 -labeled hWJMSCs proliferated two-fold in comparison to tumor cells. The effect of MSCs directly affecting the pancreatic tumor cell was reconfirmed with a proliferative marker Ki67. Functional properties EpCAM/CXCR4 (metastatic markers), Vimentin & E-cadherin (EMT markers) were evaluated using Flow cytometry and qPCR. EpCAM was significantly (p=0.0002) decreased when treated with hWJMSCs in comparison to untreated tumor cells (MiaPaCa-2- 23% vs 37%; PanC1- 20% vs 50%). However, no significant change in CXCR4 expression was observed.
To understand the cellular cross-talk between hWJMSCs and pancreatic tumor cells, the conditioned media derived from hWJMSC (CM) was studied. Expression of Bax was significantly further increased (58%) when treated with CM in comparison to hWJMSCs alone (32.5%). However, inhibition of EpCAM expression did not differ from hWJMSCs alone treatment. Migration and invasion potential of tumor cells were inhibited when treated with CM (MiapaCa-2- 2.2 vs 9 cells/field; PanC-1- 5 Vs 10.5 cells/field), compared to untreated tumor cells. On frequency distribution histograms (flow cytometry) apoptotic events were characterized by a distinctive “sub-G1" peak that represents oligonucleosomal DNA fragments. MiaPaCa-2 and PanC1 cells treated with CM showed significant (p<0.005) reduced number of cells entering G1 phase of the cell cycle ie., at G0M phase. This result was also evident as per DNA- fragmentation assay.
Thus, our results suggest that Wharton’s jelly derived mesenchymal stem cells secretome can modulate the proliferation and migratory (oncogenic) capabilities of pancreatic tumor cells. In other words, paracrine factors released by hWJMSC might be act as a cytotoxic biological agent. Hence, CM could be a novel cell-free therapeutic candidate.
Presently, under investigation is the proteomic analysis of CM treated pancreatic tumor cells using 2-D and MALDI/MS techniques.
- Hepatitis B, C, and their vaccination
Department of Microbiology, Istanbul University, Turkey.
Bulent Cakal completed his PhD from istanbul University, Turkey. He worked Post-doctoral Research Fellow about molecular virology of Hepatitis B Virus (HBV) at Department of Microbiology and Immunology College of Medicine University of Illinois at Chicago / U.S.A. He has three publication over 20 times, and his publication H-index is 6.98 and he has worked department of medical microbiology and he has two research project about HBV.
Occult Hepatitis B Virus (HBV) infection (OBI) is considered as the possible a phase of the HBV natural history but it remains unclear the molecular mechanisms and clinical impact and epidemiology aspect of OBÄ° (1,2,3). We investigated the prevalence of OBI and its clinical impact among patients with Hepatitis C virus (HCV) infection and with cryptogenic hepatitis. This study protocol was approved by the ethics committee of Ä°stanbul University Ä°stanbul School of Medicine (No: 2015/1519). This prospective cohort study included a total of 60 HBsAg-negative patients (27 patients with chronic HCV and 33 patients with cryptogenic hepatitis) were enrolled in department of gastroenterology, Istanbul Faculty of Medicine. Liver tissue samples had been obtained by percutaneous needle liver biopsy and immediately frozen and stored at -80°C. Total nucleic acids were extracted from frozen liver biopsies using QIAamp DNA Mini Kit (Qiagen) according to the manufacturer’s instructions. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction PCR using 4 sets of primers in preS-S (S), precore-core (C), Pol, and X viral regions of the HBV genome. Plasmid HBV DNA 4.1 kb and liver biopsy samples obtained from patients with chronic HBV infection (positive control) were used. Statistical analyses were evaluated using Mann–Whitney, Chi-square test and Kruskal Wallis tests. The baseline characteristics of patients are presented in Table 1. The prevalence of OBI was %25.9 (7/26) with %27.3 (9/33), %26.7 (16/60) in patients anti-HCV (+),cryptogenic hepatitis, and totaly respectively (Table 2). There wasn’t significant differences for prevelance of OBÄ° between patients with Chronic HCV infection and cryptogenic hepatitis (P=0.907). Patients with anti-HCV (+), OBÄ° (+) were older compared with patients anti-HCV (+), OBÄ° (-), (P: 0.033). As it is expected that cryptogenic hepatitis patients had higher serum alkaline phosphatase and gamma-glutamyltransferase level (P<0.05). Clinical signifance and role of OBI in patients with chronic HCV infection is controversial (4,5,6). According first results of the study to prevelance of OBÄ° is correlated with endemicity of Hepatitis B infection moreover OBÄ° can be associated with liver injury rather than chronic HCV infection. Therefore, it appears that host factors rather than viral factors are more responsible for OBI.
- Pancreatic tumours and cancers
King Faisal Specialist Hospital & Research Center, Jeddah, KSA.
Mr Aldouri trained as a General and Pancreatic Surgeon in the united Kingdom and acquired further Knowledge and shared experience with multiple surgical institutions in Japan.
Area of Interest:
- Gallstone disease
- Hernia repair
- Pancreatic cancer surgery
- Laparoscopic treatment of gallstone disease, inguinal and incisional hernia.
- Pancreatic and bile duct cancer treatment.
Specialized In: Hepatobiliary
Background No studies have reported the impact of visceral fat on anatomy of the superior mesenteric vessels. We aim to clarify the anatomical relationships between the superior mesenteric artery, vein and their tributaries relative to levels of patient visceral fat to assess applicability of artery first pancreatoduodenectomy in obese patients. Methods 176 triple-phase computed tomography scans were retrospectively analysed to determine the positioning and distance of the superior mesenteric artery relative to the superior mesenteric vein at varying levels, and to jejunal veins. Patients were categorised into high and low visceral fat groups based on mean sagittal abdominal diameter. Hypothesis testing was performed to highlight anatomical differences. Results No statistical significance was found to suggest that either the distance between superior mesenteric artery and superior mesenteric vein (at gastrocolic trunk level), or the distance between superior mesenteric artery and ventral jejunal vein varied with level of visceral fat (p=0.26 and 0.08, respectively). Superior mesenteric artery originating caudal to the spleno-mesenteric confluence was significantly more prevalent.
Day 2 :
- Pancreatic tumours and cancers
Dr. Vincenzo Neri was born in Bari, Italy, on 15th March, 1946, graduated on 1970 in Medicine and Surgery in the University of Bari. He is full Professor of General Surgery in the Medical School of the University of Foggia, Polyclinic. He is Director of the Residency School of General Surgery and Department of General Surgery. He was President of the Course of Degree of Medicine and Surgery, University of Foggia, in the years from 1996 to 2002. He was Director of Department of Surgical Sciences , University of Foggia in the years from 2002 to 2008. He obtained the certificate of “Maitrise Universitaire en Pedagogie des Sciences de la Santè”on the Universitè Paris – Nord Bobigny. He is author of more than 330 scientific paper edited on national and international journals and chapters of books. His research interest is hepatobiliopancreatic surgery. He is member of scientific societies : SIC, IHPBA,AISP,EASL,NESA,SLS.
The complications of biliopancreatic surgery have a very variable range of incidence showing surgical procedures with low incidence of complications such as simple cholecystectomy and complex or very complex procedures such as pancreatic resections followed by high incidence of postoperative complications. The purpose of this editorial is to examine a number of specific complications unique to biliopancreatic surgery such as: pancreatic fistula in relation to the different types of pancreatic digestive anastomosis and biliary injuries after biliary surgery. Pancreatic and biliary surgical complications include a large range of conditions with overlapping clinical presentations and diverse therapeutic choices. The true incidence of pancreatic and biliary complications is difficult to determine due to selection and reporting bias. The treatment of these complications continues to evolve and patients may require endoscopic, surgical, and/or percutaneous techniques.
Keywords: Pancreatic surgery; Biliary surgery; Pancreatic fistula; Biliary injuries
- Pancreatic Cancer Analysis
Managing Director at PH Miracle Medical Association Lives in Valley Center, California.
Over the past three decades, Robert O Young has been widely recognized as one of the top research scientists in the world in the nutritional sciences . He has a PhD in Nutrition, an MSc and a DSc in biology and chemistry. He also has a ND in the naturopathic sciences. Throughout his career, his research has been focused at the cellular level having a specialty in cellular nutrition, he has devoted his life to researching the true causes of "disease," subsequently developing The New Biology™ to help people balance their life. In 1994, he discovered the reality of biological transformation of red blood cells into bacteria and bacteria to red blood cells. He has documented several such transformations. His research findings have been published in several noted journals, including The Journal of Alternative and Complementary Medicine. (Sympathetic Resonance Technology, Scientific Foundations and Summary of Biologic and Clinical Studies, Dec. 2002, Vol. 8, No. 6: 835-842). Metabolic and Dietary Acids are the Fuel that Lights the Fuse that Ignites Inflammation that Leads to Cancer!. Int J Complement Alt Med 3(6): 00094. DOI: 10.15406/ijcam.2016.03.00094 He is the author of numerous articles (Herbal Nutrition 1988) and author and co-author of many books including: Herbal Nutritional Medications (1988), One Sickness, One Disease, One Treatment (1992), Sick and Tired (Woodland Publishing, 1995), Back to the House of Health (Woodland Publishing, 1999), The pH Miracle (Warner Books, 2002), The pH Miracle for Diabetes, (Warner Books,2003), Back to the House of Health 2, (Woodland Books, 2003), The pH Miracle for Weight Loss (Warner Books, 2004), The pH Miracle revised and updated book 2 (Hachett Books 2010), The Cure for Type I and Type II Diabetes (Hikari Media 2013), Reverse Cancer Now (Hikari Media, 2014), The pH Miracle for Cancer (Hachett Books 2015) and The pH Miracle for Heart Disease. He has currently sold over 5 million pH Miracle books in 191 countries and his books are translated in 29 different languages.
Due to the evident ineffectiveness of conventional cancer treatments (e.g. chemotherapy and radiation), more efficient alternatives are needed. The potential of Alkaline Nutritional Infusion (ANI) as a legitimate alternative to chemotherapy and radiation is examined. While largely ignored in conventional oncology, the pH of the interstitial fluids is suggested as paramount in identifying a cancerous condition. It is further suggested that cancer is an over-acidic condition of the body that can be reversed and prevented with alkalizing treatments such as ANI. Full Body Bio-Electro Scan (FBBES) is presented as a noninvasive means to examine body pH and the presence of pancreatic and liver cancer. In addition, non-invasive Full-Body Thermography (FBT) and Full-Body Ultrasound (FBU) are presented as a noninvasive means to examine the physiology and the anatomy of the organs, glands and tissues for inflammation, calcifications, cysts and tumors in the prevention and subsequent treatment of any cancerous condition. Finally, Live Blood Analysis (LBA) and Dried Blood Analysis (DBA) are non-invasive hematology tests for evaluating the health of the red and white blood cells and to view inflammatory and malignancy at the cellular level. In contrast to conventional cancer treatments, ANI methods such as Intravenous Nutritional Infusion (INI) and Rectal Nutritional Infusion (RNI) provide an alkalizing approach to cancer treatment and prevention.
CEO and President, founded Universal Medical Imaging Group that centers on the importance and principles of wellness and early detection.
Galina Migalko, M.D., N.M.D. brings more than 30 years of excellence in non-invasive Diagnostic Medical Imaging. After graduating with her M.D. from Uzghorod Medical University, Ukraine in 1988, Dr. Magalko worked for years in wellness clinics and diagnostic medical centers as practitioner and administrator. She has pioneered and developed a revolutionary Full Body Comprehensive Medical Diagnostic Non-Invasive, Painless, Non-Radioactive Scan which includes a Full Body Medical Bio-Electric Scan, Interstatial Metabolic pH Testing, detailed medical reports and consultation to evaluate all physiological, anatomical and functional information about all tissues, glands and organ systems.
Dr. Migalko is the world’s leader in non-invasive, non-radioactive diagnosis treatment and early detection of cancer, heart disease, diabetes, metabolic acidosis, circulatory and lymphatic issues, infertility, and other preventable and treatable health challenges.
Dr. Migalko relocated to the United States in 1998. In 2011 she received her NMD from the University of Science, Arts & Technology in Montserrat, West Indies, and as CEO and President, founded Universal Medical Imaging Group that centers on the importance and principles of wellness and early detection.
Currently she is working on her dissertation in Quantum Medicine showing the benefits of combining the best from the conventional Western medicine with complementary and alternative diagnostic services and therapies.
While a growing body of research now suggests that x-ray mammography is causing more harm than good in the millions of women who subject themselves to breast screenings, annually, without knowledge of their true health risks, the primary focus has been on the harms associated with over-diagnosis and over-treatment, and not the radiobiological dangers of the procedure itself.
In 2006, a paper published in the British Journal of Radiobiology, titled “Enhanced biological effectiveness of low energy X-rays and implications for the UK breast screening programme,” revealed the type of radiation used in x-ray-based breast screenings is much more carcinogenic than previously believed.
Recent radiobiological studies have provided compelling evidence that the low energy X-rays as used in mammography are approximately four times – but possibly as much as six times – more effective in causing mutational damage than higher energy X-rays. Since current radiation risk estimates are based on the effects of high energy gamma radiation, this implies that the risks of radiation-induced breast cancers for mammography X-rays are underestimated by the same factor .
- Pancreatic Problems & Treatment
- Pancreatitis Analysis
Institute for Medical Research Israel-Canada, Hadassah Medical School - Hebrew University, Jerusalem, Israel.
Prof. Katzav is the Bernard L. and Mary T. Sachs Professor of Cancer Studies. She earned her Ph.D. at the Weizmann Institute of Science and her post-doctorate at the National Cancer Institute in Frederick, Maryland. Prof. Katzav was a visiting scientist at St. Jude Children's Research Hospital in Memphis, Tennessee and an Associate Professor at McGill University in Montreal, Canada. Since 1995, Prof. Katzav is a member of the Institute of Medical Research Israel-Canada (IMRIC) at the Hebrew University, Jerusalem, Israel.
The main focus of Prof. Katzav’s laboratory is the link between signal transduction and cancer. For that, she is investigating a signal transducer protein, Vav, which is involved in coupling extracellular events to alterations in gene expression in the hematopoietic system. Prof. Katzav discovered Vav when she tested DNA from five esophageal carcinomas for transforming activity. This newly identified gene represented the sixth transforming gene (oncogene) detected in the laboratory and it was designated Vav, the sixth letter of the Hebrew alphabet. Recently, she was the first scientist to demonstrate that Vav plays a major role as an oncogene in human cancer such as neuroblastoma, breast and lung cancer. Vav was also shown to be important for the development of pancreatic cancer. This indicates that Vav can be a promising target protein in anti-tumor therapy.
Prof. Katzav served as the Chairperson of the Research Committee of the Faculty of Medicine (2005-2009). In this capacity, she was responsible for the research activity at the faculty of medicine. This also included allocation of grants to various scientists at the faculty and being responsible in part for the future direction of research. She was also the Chairperson of the Search Committee for recruitment of young academic members ("Vaadat Sinun") and the Chairperson of the Department of Development Biology and Cancer Research at the Faculty of Medicine, the Hebrew University (2009-2014). Prof. Katzav is currently the vice dean of the Faculty of Medicine, the Hebrew University, Jerusalem. She also participated in activities outside the Hebrew University as the Chairperson of several study sections of the Israel Science Foundation and a member of a study section at the Israel Health Ministry.
Pancreatic Ductal Adenocarcinoma (PDAC), the predominant form of pancreatic cancer, develops via acinar-ductal metaplasia (ADM) and neoplastic precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN). Mutant K-Ras is present in >90% of PDAC and represents the most frequent and the earliest genetic alteration found in low-grade PanIN1A lesions. Identification of additional molecular lesions that affect PDAC is of cardinal importance. One such potential protein is Vav1, a hematopietic specific signal transducer. Overexpression of Vav1 is implicated in human PDAC and is indicative of a worse survival rate. We generated transgenic mice that express Vav1, K-RasG12D, or both Vav1 and K-RasG12D (K-RasG12D;Vav1) in the pancreas. The number of lesions in the pancreata of K-RasG12D;Vav1 mice exceeded at least 3 times the number obtained in K-RasG12 mice already at 3-months post transgene induction. Also, the number of Ki-67 (indicative of proliferation) positive cells in K-RasG12D;Vav1 mice was significantly higher than in Vav1 or K-RasG12D transgenic mice. Thus, expression of Vav1 together with K-RasG12D in the pancreas has a dramatic synergistic effect enhancing ADM formation. Also, continuous Vav1 expression is needed for maintenance of the ADM lesions formed. Interestingly, a dramatic increase in phosphorylation of EGFR and activation of Rac1 was noted in pancreatic malignant lesions of K-RasG12D;Vav1 mice compared to the pancreas of the control transgenic mice. These results suggest that Vav1 regulates a cross-talk between tumor cells and the microenvironment resulting in upregulation of signal transduction pathways.
Identification of Vav1 as a protein that synergizes with mutant K-Ras in PDAC development might pave the way to choosing good candidates for therapeutic drug design.