Introduction
- Cancer epidemiology
- Cancer biology
- Carcinogenesis
- Molecular basis of cancer
- Cancer metastasis
- Pancreatic cancer
Epidemiology
In the current age of the cancer research, pancreatic ductal adenocarcinoma (PDA) is one of the most hostile and deadly cancer worldwide (Zhuo-Xin Cheng et al., 2011). Pancreatic cancer is a sixth leading cause of death due to cancer in Europe and in United States it is the sixth due to because of various reasons like poor diagnosis as well as prognosis, lack of screening tests, poor lifestyle, no effective treatment and various risk factors (Lakatos G et al., 2010). The risk factors for pancreatic cancer involve smoking, advancing age, gender, obesity, diabetes mellitus, high-fat diet, overweight, workplace exposure to particular chemicals, family history, chronic pancreatitis, inherited genetic syndrome. Cigarette smoking is a main cause of pancreatic cancer. Almost 20% of pancreatic tumours are due to the cigarette smoking because this smoking causes more genetic mutations in smokers (AudreyVincent et al., 2011).
Annually 168,000 deaths are caused by pancreatic cancer and it is also a ninth most common cause of cancer death. The rate of incidence is very high for cancer of the pancreas, it is even higher than the rate of mortality. The ratio of incidence rate and the mortality rate is very high and close to 98%. The mortality rate is extreme in developed countries whereas, the rate of mortality is not high as compared to developed countries in developing counties except central and temperate South America (Paola Pisani et al., 1999).
Ductal adenocarcinoma is a most common type of pancreatic cancer which has incidence of about 10 in 100,000 population annually. Men are more likely to have this cancer of pancreas than women, the ratio of male and females is 1.5:1. There is no such increase in the incidence since last few decades (Karger AG et al., 2010). The incidence of pancreatic cancer is maximum in ages between 60-80 and pancreatic cancer at below 40 years of age is very rare, but the incidence is approximately 200 in 100,000 annually in 80 years old age groups. In men, the pancreatic carcinoma is a 4th most prevalent cause od death by cancer and in women, it is fifth most frequent cause of death because of cancer (Krejs GJ, 2010).
The incidence rate of pancreatic carcinoma was highest in 2012 in Northern America i.e. 7.4 in 100,000 population and in western Europe 7.3 in 100,000 population followed by other regions like Australia, New Zealand and in other parts of Europe which was about 6.5 per 100,000 population. In South-Central Asia and Middle Africa, the rate of incidence was estimated was very low like 1 in 100,000 population. The differences between populations with high rates of incidence and low rates of incidence were twenty-fold (Milena Ilic and Irena Ilic, 2016). Worldwide, 458,918 new cases of incidence were estimated in 2018. The highest rate of incidence in 2018 was observed in Europe which was about 7.7 per 100,000 population and the lowest rate of incidence was estimated in Africa which was 2.2 in 100,000 population. The differences between the highest incidence rates and lowest incidence rates were 30-fold (Prashanth Rawla, et al., 2019).
In 2018, the mortality rate of pancreatic carcinoma was highest in western parts of Europe which estimated around 7.6 in 100,000 population and the incidence rate was also high in Eastern, Central and Northern Europe which recorded about 7.3 as well as in Northern America was about 6.5. the lowest rate of mortality was found in Eastern Africa (1.4), Western Africa and South-Eastern Asia (Evelina Mocci and Alison P. Klein, 2018). In men, the highest death rate was reported in Republic of Moldova which was 12.3 per 100,000 population and Uruguay which was 12.1 in 2018. Although, among women the death rate was highest in United Arab Emirates which was estimated about 10 per 100,000 population. On the other hand, the lowest death rate was observed in Guinea which was 2.0 and in Pakistan (Tagore Sunkara, et al., 2019).
Survival rates of pancreatic carcinoma is very low in both developed and developing countries and the rate of survival for five-year is around 6 %. Pancreatic carcinoma in both men and women and in all races were 9.4% which was diagnosed although, 29.3% was five-year survival for localized disease during 2006-2012 (Nation Cancer Institute, United States). The five-year survival rate was lower than 3% in men as well as women in England and Whales, it was 3.8% in Denmark and Sweden and in Italy it was 1.2%. the highest five-year survival rate in male was 7% in Estonia and in female, it was 7.5% in Czech Republic. Although there was almost zero survival rate in Malta and in females it was 1.3% in Slovenia (Lei Huang, et al., 2018).
History of pancreatic cancer
In 4th century BC, the pancreas was first described by a Greek physician who is one of the founders of the school of medicine in Alexandria known as Herophilos. The name ‘pancreas’ is a Greek terminology for ‘all flesh’ and this passed to another physician of Greek Ruphos in the 2nd century AD. During 138-201 AD, Galen a Rome physician and also a Rome Emperor illustrated that the function of pancreas was to provide cushion and pad to protect large blood vessels which are directly trailing. As he was very famous physician and Galen’s word was law, his illustration was not challenged for over thousand years. In 1663, the pancreas was first demonstrated as an exocrine gland by Regnier de Graaf in Leiden. After this demonstration 10 years later the first experiment of pancreatectomies on animals was carried out by Johann Brunner in Paris (David Ljungman, 2013).
The studies on pancreas was commenced on March 2, 1642 and pancreatic duct in pancreas was discovered by a German émigré Johann Georg Wirsüng in the San Francisco monastery in Padua, Italy. However, the role of pancreatic duct was still unknown but then it was named as “Duct of Wirsüng”. During 1673-1683, Anthony Van Leeuwenhoek’s microscope models were being gradually improved. Then in 1852, the histology of pancreas was first described in Paris. In 1869, the islets of the pancreas, as well as endocrine system in pancreas, were elucidated by Paul Langerhans and then the islets of pancreas was named as “islets of Langerhans”. In 1889, total pancreatectomy in the dogs resulted in diabetes was proved by Joseph F. Von Mering. Then the Insulin was discovered by a medical student Charles Herbert Best in 1921. The resections of the cancers of the ampulla of Vater and head of the pancreas was undertaken by many surgeons in 1898 and Allen O. Whipple one of these surgeons was known as “Father of Pancreatic Surgery”. In 1974, the biochemical steps in synthesis of protein, transport, ultrastructure unit, secretion, storage and segregation in exocrine pancreatic cell was described by Romanian-American Georg Palade (John M. Howard, Pancreas club 2019).
The Pancreas
The pancreas is an upper abdominal organ which lies behind the stomach and surrounded by other organs like liver, small intestine and spleen. the pancreas is around 15.24 centimetres long, slender in shape. Although pancreas is mainly an exocrine gland which secretes variety of digestive enzymes, the pancreas also consists endocrine function. The pancreas is a part of gastrointestinal system in which it mainly plays role in digestion system by secreting important digestive enzymes and it also plays a role as endocrine gland secreting various hormones into the blood to regulate metabolism and storage throughout the body (Jessie Szalay, 2018).
There are mainly two parts of pancreas based on their function and nature,
Exocrine pancreas
Exocrine pancreas is one component which secrets digestive enzymes into the duodenum and this pancreas consists of acinar and duct cells associated with connective tissue, blood vessels and nerves. These exocrine portions of pancreas comprise more than 95% of pancreas mass.
Endocrine pancreas
It is a small portion of pancreas which produce the various hormones like insulin, glucagon, somatostatin and pancreatic polypeptide in islets and secretes directly into the blood. These islets comprise 1-2% of pancreatic mass.
Gross Anatomy
the long slender-shaped pancreas mass or body consists of three parts i.e. Head, body and tail. The head situated near the duodenum and tail extends to the hilum of the spleen. The head of the pancreas lies in between the loop of the duodenum which exits from the stomach. The body of pancreas is situated posterior to the distal region of stomach. The parts of pancreas which lie anterior to the aorta is bit thinner than adjacent portion of head and body and the common bile duct passes through the head and joins to the main duct of pancreas which is near to the duodenum. The minor papilla is region where accessory pancreatic duct empties into the duodenum and the place where the main pancreatic duct introduce into duodenum known as major papilla. The major papilla is also known as ampulla of Vater (Dan S. Longnecker, Anatomy and histology of pancreas, 2014)
Histology and Ultrastructure
There are very thin connective tissue capsules which surround the pancreas which invades into the glands which results in formation of septae between the glands which play as a stage for the large blood vessels. These septae divides the pancreas and ultimately forms distinctive lobules.
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The Acinus
The exocrine pancreas is also known as a compound tubuloacinous gland. The cells in exocrine pancreas which are arranged in grape-like clusters, synthesising and secreting various digestive enzymes known as acini. This acinus is very similar to the salivary gland.
Pancreatic ducts
These digestive enzymes which are synthesized and secreted into the duodenum from acinar cells. These secretions of the acini pass through a tree like series of ducts. These duct cells secret watery fluid which is rich in bicarbonate that flush the enzymes through the ducts and play very important role in neutralizing acids. The pancreatic ducts are classified into four types;
Intercalated ducts
These ducts made up of flattened cuboidal epithelium cells which stretched up into lumen of the acinus which results in formation of centroacinar cells. It is a duct that receives secretion from acini.
Intralobular ducts
It is made up of classical cuboidal epithelium cells. This duct consists within the lobules which receive the secretion from intercalated ducts.
Interlobular ducts
These ducts are situated between the lobules and within the septae of connective tissue. These ducts differ in size. Smaller ducts are made up of cuboidal epithelium, whereas larger one is made up of columnar epithelium. These interlobular ducts carry the secretion from intralobular ducts forward to the major pancreatic duct.
The main pancreatic duct
This main pancreatic duct receives the secretion from interlobular ducts and penetrates through the wall of duodenum. In few species, including human, the pancreatic duct joins the bile duct before entering into the intestine (‘Pancreatic Histology: Exocrine Tissue’).
Function of pancreas
The pancreas has two primary functions, one is to synthesis the various enzymes to digest the proteins, fats, and carbohydrates in intestine and other is to produce the hormones such as insulin, glucagon (Szalay, Jessie, et al., 2018).
Exocrine function:
The pancreas consists of exocrine gland which produces different enzymes which are very essential for the digestion. These enzymes from exocrine gland are mainly trypsin, chymotrypsin to digest the variety proteins and it also includes amylase enzyme which digests the carbohydrates and lipase enzyme to breakdown the fats. These enzymes are produced when food reaches into the stomach and these enzymes travel through a series of ducts and arrive to the main pancreatic duct, then pancreatic duct meet the bile duct which arises from gall bladder and liver towards the duodenum. This meeting point is known as ampulla of Vater (‘The Pancreas and Its Functions | Columbia University Department of Surgery).
Endocrine function:
The endocrine portion of the pancreas includes islets which is also called as islets of Langerhans. This endocrine component produces essential hormones secret directly into the bloodstream. It produces two important hormones known as insulin and glucagon which regulates the blood sugar. Insulin lowers the blood sugar whereas, glucagon increases the blood sugar. Maintaining optimum blood sugar in bloodstream is a very crucial function of the endocrine pancreas (Héctor Del Zotto, et al., 1999).
Pancreas conditions
There are two main conditions of pancreas that includes diabetes type 1, diabetes type 2, cystic fibrosis, pancreatitis, pancreatic cancer, islet cell tumour, enlarged pancreas.
- Diabetes type 1: It is an autoimmune disorder in which body’s immune system attacks and destroy the insulin-producing cells.
- Diabetes type 2: In this condition, body becomes resistant to the insulin and no uptake of insulin by cells and blood sugar rises.
Cystic fibrosis:
It is a genetic disorder which affects multiple body systems that includes the pancreas.
Pancreatitis:
It is inflammation of pancreas in which pancreas produces digestive enzymes in excess so that it starts to digest the organ and it causes acute painful inflammation.
Pancreatic cancer:
Pancreatic adenocarcinoma is a most common type of pancreatic cancer in which tumour builds up from the cell lining of pancreatic duct. An endocrine tumour is a rare form of pancreatic cancer.
Islet cell tumour:
It is an endocrine tumour of pancreatic cancer. This tumour produces hormones in very large amounts. It divides and multiplies rapidly from a benign or malignant tumour.
Enlarged pancreas:
It is an anatomical abnormality in which pancreas is larger in size than the normal one.
- Types of pancreatic cancer
- The pancreatic cancer genome
- Ductal adenocarcinoma
- Panc-1
- Risk factors
- Biological and morphological features
- Etiology of panc-1 cell line
- Treatments for pancreatic cancers
- Surgical resection
- Radiotherapy
- Chemotherapy
- Chemoresistance in panc-1
- Pancreatic cancer stem cells
- Cancer stem cell markers
- Therapeutic resistance
- Origin
- Hypoxia
- Molecular biology of HIF
- Hypoxia induced EMT and CSCs
- NF-kB
- Activation pathway
- NF-kB & chemoresistance
- Role in hypoxia induced EMT
- Drug development
- New drug application
- Repurposing the drug
- Disulfiram
- Pharmacology of disulfiram
- Treatments – anti-alcoholisum , anti-cancer
- Mechanism of action
- Targeting CSCs with Disulfiram
- Proteasome/ NFkB Inhibition
- ALDH inhibition
- Cyclodextrin and its solubility with disulfiram
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