Theranostic Approach for Pancreatic Cancer

Theranostic Approach for Pancreatic Cancer modulates the biologic properties of stroma in pancreatic cancer by targeting the several chemotherapy resistance mechanisms to impede their malignant property through introducing new strategies and drugs for tackling the disease. It brings information about ongoing research as well as clinical data about pancreatic cancer and provides detailed descriptions about diagnostic and therapeutic options for easy understanding. The book discusses several topics related to pancreatic cancer, such as stem cells, drug resistance and pancreatic tumor microenvironment, the latest developments in chemotherapy for metastatic cancer and chemoprevention, and epigenome as a therapeutic strategy.

Additionally, it encompasses a discussion on theranostic clinical applications for personalized treatment and management of pancreatic cancer. The book is a valuable resource for cancer researchers, oncologists, and several members of the biomedical field who need to understand more about the diagnosis and treatment of pancreatic cancer.

• Provides information on the roadblocks of chemotherapy in patients with newly diagnosed and metastatic pancreatic cancer<
• Discusses treatment options available currently and prospective options for the future
• Focuses especially on stroma, tumor microenvironment, stem cells, stellate cells, transcription factors, growth factors, and important signaling pathways as already tested types of treatment

• Language: English
• Publisher: Academic Press
• Release date: Aug 19, 2019
• ISBN: 9780128194584

Book preview

Theranostic Approach for Pancreatic Cancer

Editors

Ganji Purnachandra Nagaraju, PhD, DSc, FAACC

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Sarfraz Ahmad, PhD, FAACC, FABAP

Department of Gynecologic Oncology, AdventHealth Cancer Institute, FSU and UCF Colleges of Medicine, Orlando, FL, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

About the editors

Preface

Chapter 1. Biology, pathophysiology, and epidemiology of pancreatic cancer

Introduction

Epidemiology of pancreatic cancer

Etiology of pancreatic cancer

Hereditary, genetic, and mutation factors

Environmental factors

Histopathophysiology of pancreatic cancer

Markers for diagnosis and prognosis

Biology of pancreatic cancer

Epigenetics in pancreatic cancer

DNA methylation

Histone deacetylase

Genetic alterations

Kristen rat sarcoma

p53

p16

Transforming growth factor-β–SMAD4

Molecular level expression

Tumor microenvironment

Extracellular matrix

Pancreatic stellate cells

Pancreatic cancer stem cells

Epithelial mesenchymal transition

Epidermal growth factor

Fibroblast growth factor

Insulin growth factor and insulin

c-Mesenchymal epithelial transition factor/hepatocyte growth factor

Hedgehog signaling pathway

Wnt signaling pathway

Notch signaling pathway

Conclusion

Chapter 2. Diagnosis of pancreatic cancer

Introduction

Clinical signs and symptoms

Ultrasonography

Computed tomography

Endoscopic ultrasound/fine needle aspiration

Magnetic resonance imaging

Positron emission tomography

Percutaneous biopsy

Endoscopic ultrasound-guided biopsy

Biomarkers in pancreatic adenocarcinoma

Other blood-based markers

Combination biomarkers

Conclusions and future perspectives

Chapter 3. Current knowledge on drug resistance and therapeutic approaches to eliminate pancreatic cancer stem cells

Introduction

Pancreatic cancer stem cell microenvironment

Pancreatic cancer stem cell and chemoresistance

Targeted therapies for pancreatic cancer stem cells

Conclusion

Competing interest

Authors contribution

Chapter 4. Drug resistance and microenvironment in pancreatic cancer

Introduction

Pancreatic cancer

Tumor microenvironment

Cells in tumor microenvironment

T lymphocytes

B lymphocytes

Natural killer and natural killer T cells

Tumor-associated macrophages

Suppressor cells of myeloid lineage

Dendritic cells

Tumor-associated neutrophils

Cancer-associated fibroblasts

Vascular endothelial cells

Pericytes

Extracellular matrix of tumor microenvironment

Drug resistance by altered metabolism

Exosomes and miR-mediated chemoresistance

Conclusion

Chapter 5. The role of the tumor microenvironment in the metastasis of pancreatic cancer and immunotherapy

List of abbreviations

Introduction

What is the role of the tumor microenvironment in regulating cancer cell metabolism?

Tumor immunology for metastatic pancreatic cancer

Immunoediting

Development of strategies that target immune checkpoints

Conclusion

Conflict statement

Chapter 6. Latest developments in chemotherapy for metastatic pancreatic cancer

Introduction

Pathophysiology

Clinical scenario of metastatic disease

Challenges in diagnosis

Current chemotherapeutic options

Mechanisms of action of current chemotherapeutic agents

Understanding the mechanisms of resistance to chemotherapy

Emerging treatment agents

Agents against specific molecular targets

Conclusions

Chapter 7. Genetic manipulations with chemotherapy in pancreatic cancer

Introduction

Pancreatic cancer: unique challenges

Therapy

Newer therapeutic directions

Conclusions and future perspectives

Chapter 8. Genetic predisposition for pancreatic cancer

Introduction/background

Single nucleotide polymorphisms and pancreatic cancer

BRCA1/2 gene polymorphism and pancreatic cancer

PALB2 gene polymorphism and pancreatic cancer

Vitamin D receptor gene polymorphism and pancreatic cancer

ABO system gene polymorphism and pancreatic cancer

XRCC2/XRCC3 gene polymorphism and pancreatic cancer

MTHFR gene single nucleotide polymorphism and pancreatic cancer

GSTM1 and GSTT1 gene single nucleotide polymorphisms in pancreatic cancer

Steroid hormone receptor polymorphism and pancreatic cancer

Mitochondrial gene polymorphism and pancreatic cancer

Conclusions

Chapter 9. Pancreatic cancer resistance to chemotherapy: resensitization strategies using resveratrol

Introduction

Chemotherapy and radiotherapy

Resveratrol

Resveratrol as an adjunct to chemotherapeutic drugs

Conclusions

Funding

Conflict of interest

Chapter 10. Anticancer activity of a small molecule, tolfenamic acid: an emphasis on pancreatic cancer

Tolfenamic acid

Pancreatic cancer

Specificity protein 1 and survivin

Tolfenamic acid inhibitor of specificity protein transcription factor 1 and survivin

Toxicity analyses

Radiation and tolfenamic acid combination

Tolfenamic acid combined with other investigational agents

Tolfenamic acid and mithramycin combination

Tolfenamic acid and curcumin combination

Conclusion

Chapter 11. Targeting the epigenome as a therapeutic strategy for pancreatic tumors: noncoding RNAs and chromatin remodelers

Introduction

Chromatin remodeling factors

Conclusions and future perspectives

Chapter 12. Pancreatic cancer chemoprevention: a review on molecular pathways involved in carcinogenesis and targeting with terpenoids, and new potential antitumor drugs

Introduction

Pathogenesis of pancreatic cancer

Current treatment options and limitations

Terpenoids as potential chemopreventive agents for pancreatic cancer

Conclusions and future perspectives

Chapter 13. Meta-analysis of MTHFR polymorphisms and pancreatic cancer susceptibility

Introduction

Materials and methods

Statistical analysis

Results

Quantitative synthesis

Sensitivity analysis and publication bias

Discussion

Chapter 14. Therapeutic vaccines for pancreatic cancer

Whole cancer cell–based vaccines

Algenpantucel-L

Granulocyte macrophage colony-stimulating factor vaccine

Peptide and protein vaccines

KRAS

Telomerase

Vascular endothelial growth factor receptor

Survivin

Gastrin

Heat shock proteins

Dendritic cell vaccines

Recombinant virus-based vaccines

Listeria-based vaccines

Perspectives and conclusion

Chapter 15. Epidermal growth factor receptor role in pancreatic cancer

Introduction

Types of pancreatic cancer

Clinical features

Biology

Histopathologic factors

Structure of epidermal growth factor receptor

Signaling pathways (mechanisms) related to epidermal growth factor receptor in pancreatic cancer

Role of epidermal growth factor receptor in targeted therapies for pancreatic cancer

Adverse effects of epidermal growth factor receptor inhibitors

Drug resistance against epidermal growth factor receptor inhibitors

Impact of epidermal growth factor receptor in pancreatic cancer through precision medicine (biomarker assays)

Economic perspectives of epidermal growth factor receptor in pancreatic cancer

Future perspectives

Chapter 16. Recent advances in molecular diagnostics and therapeutic targets for pancreatic cancer

Background

Molecular markers for pancreatic cancer and their significance in diagnosis and treatment

Current diagnostics

Emerging diagnostics

Drug resistance

Conclusions

Index

Copyright

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Dedication

This book is dedicated to our families, teachers, contributors, and friends.

Contributors

Maen Abdelrahim,     Section of Gastrointestinal Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States

Ala Abudayyeh,     Department of General Internal Medicine, MD Anderson Cancer Center, Houston, TX, United States

Summia Afridi,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Sarfraz Ahmad,     Department of Gynecologic Oncology, AdventHealth Cancer Institute, FSU and UCF Colleges of Medicine, Orlando, FL, United States

Afroz Alam,     Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India

Saeed Ali,     Department of Internal Medicine, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Riyaz Basha,     Texas College of Osteopathic Medicine, UNT Health Science Center, Fort Worth, TX, United States

Astrid Belalcazar,     Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

L.V.K.S. Bhaskar,     Sickle Cell Institute Chhattisgarh, Raipur, India

Pallaval Veera Bramhachari,     Department of Biotechnology, Krishna University, Machilipatnam, Andhra Pradesh, India

Ryan Clay,     Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States

Begum Dariya,     Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India

K.G.K. Deepak,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Batoul Farran,     Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Murali Mohan Gavara,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Sriharika Gottipolu,     Texas College of Osteopathic Medicine, UNT Health Science Center, Fort Worth, TX, United States

Shailender Guganavath,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Manoj K. Gupta,     Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India

Ishtiaq Hussain,     Department of Gastroenterology and Hepatology, Cleveland Clinic, Weston, FL, United States

Sana Hussain,     Department of Internal Medicine, Khyber Teaching Hospital, Peshawar, Pakistan

Akriti Gupta Jain,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Abdul Kareem Khan,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Kishor Khanal,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Seema Kumari,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Rama Rao Malla,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Sathish Kumar Mungamuri,     Ramanujan Fellow, Indian Council of Medical Research – National Institute of Nutrition, Hyderabad, India

Ganji Purnachandra Nagaraju,     Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Irina Nakashidze,     Departments of Biology and Clinical Medicine, Faculty of Natural Sciences and Health Care, Batumi Shota Rustaveli State University, Batumi, Georgia

Madeline J. Nash,     Texas College of Osteopathic Medicine, UNT Health Science Center, Fort Worth, TX, United States

Jana Srinivas Rao

Department of Internal Medicine, Kakatiya Medical College, Warangal, Telangana, India

Mahatma Gandhi Memorial Hospital, Warangal, Telangana, India

Prasuja Rokkam,     Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India

L. Saikrishna,     Department of Zoology, Visvodaya Government Degree College, Venkatagiri, India

Zeeshan Sattar,     Department of Internal Medicine, Khyber Teaching Hospital, Peshawar, Pakistan

Farhan Sattar,     Department of Internal Medicine, Ayub Teaching Hospital, Khyber Pakhtunkhwa, Pakistan

Shadab A. Siddiqi,     Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States

Gowru Srivani,     Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India

Venkat R. Arva Tatireddygari,     Department of Zoology, Yogi Vemana University, Kadapa, India

Nilgun Tekkesin

Department of Biochemistry, Memorial Hospital, Istanbul, Turkey

School of Medicine, Nisantasi University, Istanbul, Turkey

Sermin Tetik,     Department of Biochemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey

Himanshu Tillu,     Sysmex India Private Limited, Mumbai, India

Ramakrishna Vadde,     Department of Biotechnology and Bioinformatics, Yogi Vemana University, Kadapa, India

Sarojamma Vemula,     Department of Microbiology, Sri Venkateswara Medical College, Tirupathi, India

Mohammed Wazir,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Hammad Zafar,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

Julie Zhou,     Department of Internal Medicine Residency Program, Graduate Medical Education, AdventHealth, Orlando, FL, United States

About the editors

Ganji Purnachandra Nagaraju, PhD, DSc, FAACC

Dr. Nagaraju is a faculty member in the Department of Hematology and Medical Oncology at the Emory University School of Medicine. Dr. Nagaraju obtained his MSc and PhD, both in biotechnology, from Sri Venkateswara University in Tirupati, Andhra Pradesh, India. He received his DSc from Berhampur University in Berhampur, Odisha, India. Dr. Nagaraju's research focuses on translational projects related to gastrointestinal malignancies. He has published over 70 research papers in highly reputed international journals and has presented more than 50 abstracts at various national and international conferences. He is the author and editor of several published books including Role of Tyrosine Kinases in Gastrointestinal Malignancies, Role of Transcription Factors in Gastrointestinal Malignancies, and Breaking Tolerance to Pancreatic Cancer Unresponsiveness to Chemotherapy. He serves as an editorial board member of several internationally recognized academic journals. He is an associate member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute. Dr. Nagaraju has received several international awards including Fellow of the American Association for Clinical Chemistry. He also holds memberships with the Association of Scientists of Indian Origin in America, the Society for Integrative and Comparative Biology, the Science Advisory Board, the RNA Society, the American Association for Clinical Chemistry, and the American Association of Cancer Research.

Sarfraz Ahmad, PhD, FAACC, FABAP

Dr. Ahmad is Director of Clinical Research at the Gynecologic Oncology Department of AdventHealth (formerly Florida Hospital) Cancer Institute (FHCI), Orlando, Florida, United States. He earned his doctoral degree in biochemistry from North-Eastern Hill University, Shillong, India. Before joining FHCI in 2002, he spent 10 year researching and teaching at Loyola University of Chicago and the University of Illinois at Chicago's Division of Hematology/Oncology, College of Medicine. He has trained several fellows, residents, medical students, and graduate and undergraduate students during their scholarly research projects. He is also a professor of medical education at the University of Central Florida College of Medicine and professor of clinical sciences at the Florida State University College of Medicine, Orlando. Dr. Ahmad's current research focuses on analyzing clinicopathologic and surgical outcomes of oncology patients and a better understanding of the cellular and molecular mechanisms of cancer and related thromboembolic and hematologic disorders. His investigations also aim to evaluate novel treatment options (chemocellular, cellular, and immunotherapies) for better management of hemato-oncologic patients. His past research interests focused on the development of anticoagulant, antithrombin, antiplatelet, and thrombolytic drugs for the management of hematologic and cardiovascular patients. In these various areas of biomedical research, Dr. Ahmad has published nearly 200 peer-reviewed scholarly research articles and book chapters and nearly 400 scientific abstracts, which are extensively cited globally. He is a reviewer and has editorial responsibilities for several biomedical journals and books and has received several competitive research grants and national and international awards for his research accomplishments and contributions.

Preface

Pancreatic cancer (PC) remains one of the deadliest malignancies worldwide and its survival prospects are projected to become worse by 2020. This negative prognosis results from the lack of significant advances in the diagnostic and therapeutic tools available for the disease, as opposed to major improvements witnessed for other cancers. Hence, there is an urgent need to develop new screening and treatment options for PC based on a molecular and targeted approach. Although our knowledge of mechanisms underlying pancreatic carcinogenesis has improved, this tumor remains difficult to cure owing to chemoresistance. The frequently observed drug escape mechanisms characteristic of PC result from the dense stromal barrier that forms during cancer progression. This barrier results from intricate and complex interactions among the tumor microenvironment, pancreatic stellate cells, stem cells, and pancreatic cancer cells. Trends in PC research suggest that these interferences alter the signaling, molecular, and genetic landscape of PC cells, leading to various alternative chemo-evasion pathways. Hence, efficient treatment strategies for PC should focus on reprogramming the immune system and stromal milieu to resensitize cells to treatment.

As this preface illustrates, acquiring increased knowledge about the mechanisms of drug resistance in PC will help design effective therapies that can overcome chemoresistance. In this book, we try to fill the current gap in the peer-reviewed scientific literature by compiling and synthesizing the latest advances in diagnostic and therapeutic approaches in PC into one book. We have merged the strategies of diagnostics and therapeutics into the comprehensive term of theranostics, which promises to become the foundation of future precision medicine regimens. This book contains 16 chapters that explore the biology, pathology, and epidemiology of PC. Current findings on molecular and drug resistance mechanisms in PC are extensively discussed to provide readers with a holistic perspective on the topic. The contribution of the tumor microenvironment to these mechanisms is also examined to delineate its therapeutic and clinical potential. Novel areas of therapeutic development, such as genetic manipulation, vaccines, and small molecule–based treatments for PC are also discussed, highlighting innovative strategies undergoing evaluation. Furthermore, the antitumor activity of known natural compounds such as resveratrol and terpenoids is explored to illustrate their clinical significance as chemopreventive and chemosensitizing drugs. Finally, this book sheds light on the role of the epigenome in PC development, suggesting potential therapeutic solutions that target it.

It is our pleasure to present this exhaustive overview of the field to the scientific community to expand our understanding of current advances and future theranostic applications for PC. We hope that this book will motivate new research ideas, thoughts, and investigations for the ultimate benefit of PC patients and their families.

Ganji Purnachandra Nagaraju, PhD, DSc, FAACC

Sarfraz Ahmad, PhD, FAACC, FABAP

Chapter 1

Biology, pathophysiology, and epidemiology of pancreatic cancer

Begum Dariya¹, Afroz Alam¹, and Ganji Purnachandra Nagaraju²     ¹Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, India     ²Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths and will become the second most prevalent one by 2030 owing to its aggressive nature. It has the worst prognosis and most limited efficiency of commonly available therapies. The incidence and mortality rate are high in developed countries. Variabilities in geography and gender are proportional to the increase in risk factors. Risk factors include an unhealthy lifestyle, and modifiable factors that cause PC are known but insufficient; therefore, a better understanding of the etiology and epidemiology of PC is essential for its prevention. Germ line mutations, hereditary disorders (familial adenomatous polyposis, familial atypical multiple mole melanoma syndrome, and hereditary nonpolyposis colorectal cancer), inherited disorders (BRCA2 mutations), and gene polymorphism are factors that control the detoxification of carcinogens from the environment and alter risk factors. Inherent resistance developed against chemotherapeutic drugs results from the occurrence of dense stroma developed, including extracellular matrix and nonneoplastic cells (fibroblasts, immune, and invasive and vascular cells), which significantly impairs the drug delivery mechanism. Hence, an increased understanding of cellular pathways including Notch, Wnt, Hedgehog, and Kristen rat sarcoma (Kras) involved in impairing DNA repair processes, cancer cell metabolism, and metastasis can provide new therapeutic strategies for developing novel therapeutic regimens. Clinically, the use of markers including diagnostic and prognostic markers and somatic altered genes such as Kras and TP53 has been investigated, although these tests remain inconsistent owing to their inappropriate clinical performance. Thus, elucidating crucial molecular mechanisms involved in the biology of PC is necessary and will enable future research aimed at developing novel and effective biomarkers for the early diagnosis and therapy of PC.

Keywords

DNA repair; Epidemiology; Kras; Notch; Pancreatic cancer; Risk factors; Wnt

List of abbreviations

APC   Adenomatous polyposis coli

ARK   AMPK related kinase

BRCA   Breast cancer type 1

CA19-9   Carbohydrate antigen

CDCP1   CUB domain contained protein 1

CDH1   Epithelial or E-cadherin

CDKN2A   Cyclin dependent kinase inhibitor 2A

DHSA   Dihydrosanguinarine

DNMT   DNA methyltransferase

DPC4   Deleted in PC

ECM   Extracellular matrix protein

EMT   Epithelial mesenchymal transition

FAMMM   Familial atypical multiple mole melanoma syndrome

FOXC1   Forkhead box C1

GNAS   Guanine nucleotide binding protein

GSK3β   Glycogen synthase kinase 3β

HDAC   Histone deacetylase

HES   Hair enhance of split family

HP   Hereditary pancreatitis

IGF   Insulin growth factor

IPMN   Intraductal papillary mucinous neoplasma

LEF   Lymphoid enhancing factor

LITAF   Lipopolysaccharide induced tumor necrosis-α factor

LRP5   Lipoprotein receptor related protein

MCN   Mucinous cystic neoplasm

MGMT   Methylguanine methyl transferase

MiRNA   MicroRNA

MMP   Matrix metalloproteinases

MUC   Mucin

NICD   Notch intracellular domain

NOX   NAD(P)H oxidase

PCSC   Pancreatic cancer stem cells

PDAC   Pancreatic ductal adenocarcinoma

PDX   Patient-derived xenografts

PSC   Pancreatic stellate cells

RARβ   Retinoic acid receptor β

RB   Retinoblastoma

SEER   Surveillance, Epidemiology and End Results

SHH   Sonic Hedgehog

SIRT   Sirtuin

SPARC   Secreted protein acidic and rich in cysteine

TCF   T-cell factor

TGF-β   Transforming growth factor-β

TME   Tumor microenvironment

THOR   TERT hypermethylated oncologic region

UPSM   Ultra–pH sensitive micelles

Introduction

Pancreatic cancer (PC) is a lethal aggressive disease with high mortality rates. It represents the fourth most frequent cause of cancer-related deaths. It will soon be ranked as the second most malignant cancer worldwide, with an overall survival rate of 26% for 1 year, 8.5% for 5 years in advanced stages of the disease, and 22% for early-stage detection with surgical resection of the tumor. Statistical analysis for PC globally estimates 1,000,000 new cases with 65,000 deaths annually [1]. According to reports from the National Cancer Institute Surveillance, Epidemiology and End Result Program, estimated new cases in 2018 were 55,440, with 44,330 deaths. The diagnosis of PC in later stages, its high inherent resistance against conventional chemotherapy, the lack of biomarkers, and insufficient treatment options result in its poor prognosis. Clinical and epidemiological studies demonstrated that early detection of neoplastic precursors and early diagnosis are effective means to regulate cancer-related mortality. Hence, the detection of pancreatic precursor lesions including mucinous cystic neoplasm (MCN), macroscopic intraductal papillary mucinous neoplasma (IPMN), and microscopic pancreatic intraepithelial neoplasia, could reduce the incidence and mortality rate of PC patients [2,3] and has been successfully tested in individuals with a strong family history of PC by imaging and surgical techniques [4–6]. PC progresses in a multistep fashion involving the transformation of healthy cells into malignant ones. This mass of malignant cells is a heterogeneous complex of tumor cells consisting of endothelial cells, immune cells, and stromal and hematopoietic cells driven by genetic alterations [7]. The most common risk factors identified include the onset of diabetes mellitus (DM), hereditary and recent pancreatitis, smoking, obesity, age, and hereditary PC, which are responsible for developing 50%–60% of PCs, whereas 5%–10% is due to genetic mutations in certain genes such as Kristen rat sarcoma (Kras). In addition to genetic mutations, epigenetic aberrations of oncogenes and silencing of tumor suppressor genes such as p16, TP53, and cyclin-dependent kinase inhibitor 2A (CDKN2A) are risk hallmarks of PC. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC), which represents about 90% of PC cases. Novel therapeutic routes targeting epigenetics, modulators, and regulators of oncogenes and tumor suppressors are emerging, although molecular and pathological insights into the fatal cancer entity remain essential to improve early detection of the disease, survival time, and quality of life. This chapter highlights the epidemiology, biology, and histopathology of PC, providing an entity of tumor for therapeutic approaches to develop the survival rate and provide a better prognosis.

Epidemiology of pancreatic cancer

The asymptomatic nature of PC restricts its diagnoses to only its advanced stage with a poor prognosis. Thus, it is essential to improve methods to detect precursors at earlier stages. Furthermore, knowing and understanding the disease epidemiology could be important for primary prevention, allowing the elucidation and identification of etiology risk factors including environmental and genetical factors associated with PC. The epidemiology of PC generally measures the accurate difference of incidence and mortality rates, in which the incidence rate is the new cases and the mortality rate is the number of deaths occurring annually in a specified group. In 1999, Parkin et al. first obtained a data bank for a incidence and mortality rate from 23 areas around the world, comparing registries of cancer. They arrived at the conclusion that PC ranked ninth as the most common cause of cancer-related mortality, with 168,000 calculated deaths and the 13th cause of death in both sexes [8]. GLOBOCAN is Windows-based software that uses International Agency for Research on Cancer data to estimate the incidence and mortality rate by country. In the 2012, GLOBOCAN estimated that there were 338,000 new cases and 331,000 deaths, and thus that PC ranked seventh for mortality in both sexes [9]. It was further estimated that PC ranked 14th for new cases in 2018, with very low variations seen in males and females, but that it ranked seventh for cancer-related morality worldwide and caused 330,000 deaths per year [9]. The incidence and mortality rate are always identical because of the high fatality of disease. The incidence and mortality rates of PC calculated were higher in developed countries; they ranked second in France, fourth in the United States (North America was 7.4 per 100,000), sixth in Europe (6.8 per 100,000), and lower in countries such as Africa (2 per 100,000) and Asia (3.2 per 100,000). However, it was more commonly noticed among men than women and varied geographically and according to gender. According to an estimation of the global incidence rate, about 178,000 men and 160,000 women were diagnosed with PC in the 2012. However, the PC mortality rate has been increasing in both genders in countries such as the United States, Japan, China, and Europe [10–13]. The high mortality rate was attributed to diagnosis of the fatal disease in its later stages. As revealed from Surveillance, Epidemiology. and End Results (SEER) data, only 10% of patients are diagnosed at early localized stages and 52% are diagnosed only at stage 4, with the disease having metastasized to the other organs of the body. Hence, a survival rate of only 5 years is estimated for PC despite novel technologies, although the rate varies owing to data quality worldwide [14]. The incidence and mortality rate correlate with an increase in age and represents predominantly a disease of elder populations diagnosed after 55 years of age [10,11,15], owing to the accumulation of DNA damage over time resulting from exposure to risk factors as well to certain biological processes. The incidence rate of PC in patients aged 55–59 years was 10.4 per 100,000 and 24.0 for age 65–69 years [16]. The occurrence of PC also varies with race, which could be because of differences at the molecular level. K-ras mutations to valine leading to PC are more frequently seen among the black race of the United States than the Caucasian race [17]; similarly, differential expression in K-ras and P53 showed a racial difference among Chinese and Japanese patients [18,19]. However, this estimation is not clear. The Cancer Statistics Review as well as SEER revealed that the incidence rate of PC has increased over the years [11]. Quante et al. from Germany also reported that the incidence rate of PC surpassed CRC and that PC might rank second for cancer-related mortalities by 2030 [20].

The low survival rate noted in PC results from high serum albumin levels, modalities in therapy, health care system differences, and the size of the tumor, in addition to the advanced-stage diagnosis. The increase in the incidence rate is always proportional to the increase in risk factors and detecting the risk factors is not simple.

Etiology of pancreatic cancer

Exploring and identifying the critical risk factors in the group is essential because the screening techniques of PC could detect the disease only at the advanced stage. The risk factors are determined to be 40% responsible for the development of PC. They can be differentiated as unmodifiable hereditary risk factors (10%) and modifiable environmental risk factors. As discussed, black people are at higher risk for developing PC compared with white, Asian, and Hispanic people. In the case of gender, men are more highly prone to PC than are women. However, increased age makes both genders at higher risk for PC.

Hereditary, genetic, and mutation factors

Many other inherited genetic disorders constitute risk factors for PC. The risk for PC is about 62%–67% in patients with first-degree relatives with a medical history of PC, as estimated from metaanalyses and pooled analyses [21,22]. People with hereditary nonpolyposis colorectal cancer, also called Lynch syndrome, with a microsatellite instability in the mismatch repair genes PMS2, MSH2, MSH6, EPCAM, and MLH1 at chromosomes 2 and are prone to early-onset colorectal cancer (CRC) and PC [23]. Familial adenomatous polyposis is another syndrome characterized by the onset of polyps in the tract of gastrointestine, which later become malignant; they develop owing to a mutation in the adenomatous polyposis coli (APC) gene affected at chromosome 5q12-21 [24]. Its occurrence is uncertain and is misdiagnosed as ampulla. Hereditary breast and ovarian cancer syndrome also causes 17%–19% of hereditary PC. It is generally caused by a mutation in the genes breast cancer type 1 (BRCA1) and especially BRCA2, with chromosome 13 affected [25]. Peutz–Jeghers syndrome, otherwise called hamartomatous polyposis syndrome, results from a germinal mutation in STK11/LKB1 at chromosome 19p; it causes PC as well gastrointestinal neoplasia [26]. Patients with familial atypical multiple mole melanoma syndrome (FAMMM) are at increased risk for PC. This is because of the gene mutation in p16INK4a at chromosome 9p21, which dysregulates the normal cellular cycle, in addition to a mutation in CDKN2A and a family history of familial melanoma [27]. When detected, it is characterized as malignant melanoma in a first- or second-degree relative, who are highly prone for the occurrence of PC (a 13- to 20-fold increased risk). Hereditary pancreatitis (HP) is a disease caused by a mutation in the PRSS1 gene, resulting in recurrent acute pancreatitis from childhood leading to dysregulation and chronic inflammation in the pancreas; it causes an increased risk for PC [28]. The lifetime risk estimate owing to this disease is 40%. Cystic fibrosis is disorder similar to HP; it is caused by a mutation in the cystic fibrosis transmembrane gene and results in recurrent acute pancreatitis, and thus the developing onset of PC [29]. Chronic pancreatitis is again an increased risk for PC, with an estimated risk of 4% [30]. Chronic inflammation of the pancreas provokes the production of interleukin (IL)-6, IL-8, tumor necrosis factor-α, transforming growth factor-β (TGF-β), and inducing cellular proliferation [17]. Hereditary diseases and their estimated risks for causing PC are listed in Table 1.1. DM is detected in almost 80% of PC; however the relation is still unclear. The onset of DM types 1 and 2 can double the risk of PC, and DM type 2 is often detected with higher levels of insulin growth factor-1 (IGF-1) and hyperinsulinemia. From studies on the PC burden, it was estimated from a population in Italy that 9.7% of cases of PC result from DM [31–34]. Researchers observed that hyperinsulinemia and hyperglycemia create an interaction between tumor-associated macrophages and pancreatic stellate cells (PSCs), inducing fibrosis, inhibiting apoptosis, and promoting the proliferation of cells [35,36]. Furthermore, certain bacteria called Helicobacter pylori cause inflammation in the stomach; they are also at increased risk for stomach cancer and PC. However, the estimated risk was high in the stomach compared with the pancreas (4%–25%). Hepatitis virus was also studied as a risk for PC, because it is commonly detected in PC patients.

Table 1.1

Environmental factors

Although the incidence rate increases with an increase in risk factors, not all risk factors are easy to detect. However, few unmodifiable hereditary and modifiable environmental factors are detected as associated risk factors for the cause of PC. Environmental factors include alcohol consumption, smoking, DM, and chronic pancreatitis. Smoking produces carcinogens from tobacco, which makes its way to the pancreas through the bloodstream from the upper aerodigestive tract. In a few cases, the consumed tobacco is also directly refluxed into the ducts of the pancreas, released from the duodenum. As published in various reports, the risk for PC is twofold higher in patients habituated to smoking and was estimated at 20%–35% [37]. Furthermore, the prevalence of PC is significantly higher in males because of temporal trends in cigarette smoking. Tobacco intake mutates Kras and p53 genes and induces chronic inflammation, leading to pathological differences in the mechanism promoting cytokine induction and the activation of growth factors, which finally results in cellular transformation. Consumption of alcohol causes the production of metabolites that promote chronic inflammation and genetic instability. The relative risk calculated was 1.22–1.36 for developing PC [38]. Besides smoking, there are certain risk factors including physical inactivity, obesity, and dietary factors that also influence PC mortality. Developing countries are also high in mortality rate in the same way as developed countries because of their adaptations to the lifestyle of developed countries. Epidemiological data showed that dietary food including red meat and a high caloric food intake cause obesity and lead to higher risk for PC. Furthermore, a few studies demonstrated that the estimated relative risk for PC was 1.12 for every 5-kg/m² increase in body mass index (BMI). Adiposopathy is a disorder observed in obese people; it is also called chronic adipose disease. It causes a hormonal imbalance with high levels of leptin and low levels of adiponectin observed owing to proinflammatory cytokines produced by macrophages, which indicates a relationship between PC and high BMI. However, regular physical activity and the consumption of low-calorie foods including green vegetables, fruit, tofu, and fish in Japan reduced the risk to a certain extent. Furthermore, chemicals are risk factors for PC, because exposure to certain chemicals including aspirin, pesticides, petrochemicals, and benzenes may cause PC.

Histopathophysiology of pancreatic cancer

The clinical, anatomical, and molecular pathology represent a bridge between research and medicine. Tumors in the pancreas are mostly exocrine and include adenosquamous carcinoma, colloid carcinoma, acinar cell carcinoma, signet ring cell carcinoma, pancreatoblastoma, cystadenocarcinoma, and hepatoid carcinoma. The malignant tumor that commonly occurs in pancreas is ductal adenocarcinoma; it is characterized as a glandular structure and is also called PC. Clinically, the carcinoma arises in the head of the pancreas and rarely in the body and tail of the organ. It has nonspecific symptoms and varies with the region. PC that occurs in the head (75%) of the pancreas is commonly seen in patients with pancreatitis and obstructive jaundice. This cancer causes blockage in the common bile duct, resulting in jaundice with symptoms including nausea, vomiting, itching, dark urine, and light-colored stool. Carcinoma in the body (15%) and tail (10%) of the pancreas are diagnosed later and have a worse prognosis, with symptoms including abdominal pain that exudes toward the sides of the back [39]. It is also reported that the intensity of pain is associated with immune and inflammatory cells, leading to perinuclear invasion. The progression of PC is a stepwise process involving the activation and deactivation of oncogenes and tumor suppressor genes, respectively, with deregulation of the cell cycle. A better understanding of genetics and their molecular biology by the scientific community may be achieved by determining the precursor lesions of the cancer and their classification. This may pave the way for further research studies that could lead to early diagnosis. The first transgenic mouse model developed in 2003 described low-grade precursor lesions in metastatic cancer and improved knowledge about cellular interactions and molecular mechanisms involved in initiating and developing PC, which were essential in the field of drug testing [40].

On the basis of biology, morphology, and clinical behavior, pancreatic neoplasia is differentiated into three neoplasias with distinct precursor lesions.

Intraductal papillary mucinous neoplasm: These are cystic neoplasms that differ in their potential to developing malignancy, according to their origin and histological subtypes. They arise in the head of the pancreas and develop into chief pancreatic ducts. Their main branches are mucin (MUC)-producing neoplastic cells. Dilation of the branches and duct irregularly filled with mucin are observed on sectioning the tissue. Their size was observed to be several centimeters in length of papillary formation from microscopic projections to visible papillae. Mutations observed in IPMN lesion are Kras (mutation in codon 12 or 13) and guanine nucleotide binding