Pancreatic cancer Flashcards
What is the pancreas?
Pale-grey gland located in the upper abdomen behind the stomach
Between the duodenum and spleen
Around the left side
What does the pancreatic duct do?
It joins the pancreas to the common bile duct, supplying pancreatic juice (exocrine) which aids in digestion
What is pancreatic juice?
A mixture of water, salts, bicarbonate, and many different digestive enzymes (amylases, lipases, proteases)
What is one of the factors (related to anatomy) which makes surgery on the head of the pancreas difficult?
The mesenteric artery is pressing right around the head of the pancreas
What does the exocrine pancreas do?
It secretes enzymes that digest carbs, proteins, fats, and bicarbonate for neurtalising acid chyme
What is the functional unit of the exocrine pancreas?
Acini
Where do the acini get their name?
The are formed by acinar cells
What are the cellular units of the endocrine pancreas?
Islets of langerhans
What is the main difference between the exocrine and endocrine pancreas?
Endocrine: released directly into blood
Exocrine: released into pancreatic duct
What would you see in a slide of the pancreas?
Acini and ducts
Islets of langerhans
Blood vessels
Stroma
What cells do the islets of Langerhans contain (and what do they secrete)?
A cells - glucagon B cells - insulin D cells - somatostatin G cells - pancreatic polypeptide E cells - ghrelin
What is one of the things somatostatin does?
glucagon and insulin regulation
what does ghrelin do?
causes the sensation of hunger
Why is pancreatic cancer something we should care about (other than all diseases generally sucking)?
It is one of the top 10 most lethal forms of cancer (<7% survival)
What percentage of pancreatic cancers develop in the head?
75%
what is the incidence of pancreatic cancer per year?
10 per 100,000
What sort of metastases are typical of pancreatic head tumours?
Going through the bile duct to the liver
What are the limitations in pancreatic cancer?
Highly fibrotic stroma acting as a mechanical barrier to drugs
Inter and intra tumoural heterogeneity
genetic complexity (many different mutations)
MDR
TRUE or FALSE? Pancreatic cancer like many other cancers has had huge improvements in survival.
FALSE
While other cancer prognoses have improved, pancreatic cancer survival has remained very bad over the years
TRUE or FALSE? It is expected that pancreatic cancer will continue to kill the same number of people as it is now in the future
FALSE
We think it’ll kill more people
What proportion of patients are diagnosed as an emergency and how does this affect their prognosis?
Half
Late diagnosis –> worse prognosis
What is the gender distribution of pancreatic cancer?
About equal between men and women but is now affecting men more than women
Does pancreatic cancer research get much money?
No, because the survival is so low and people die so quickly
When people are diagnosed with pancreatic cancer how much does this increase their survival?
x10 their five year survival
What percent of people diagnosed with pancreatic cancer survive beyond 5 years?
4%
What is one simple factor which is contributing to the increase in pancreatic cancer?
The aging population
What are the inherited risk factors for pancreatic cancer?
Family history: The risk is increased 6-fold in those with 2 affected relatives
The BRCA2 gene conveys a 3.5 fold risk of pancreatic cancer
What percentage of pancreatic cancer is inherited?
10%
What are acquired pancreatic cancer risk factors?
Top : Obesity Smoking Diabetes Pancreatitis
Check name as many pancreatic cancer risk factors as you can
Family history diet: too much meat and not enough veg obesity race smoking gender age diabetes pancreatitis Alcohol: >5yrs of heavy drinking, not binges,only x1.2%
How much does smoking cessation reduce risk in 2 years?
48%
How much of pancreatic cancer is caused by smoking?
20-30%
Which ethnic groups are more likely to get pancreatic cancer?
African-americans
ashkenazi jews
Maori
incidence increasing in Asia
Define pancreatitis and its acute and chronic form
Pancreatitis: Inflammation of the pancreas
Acute: Episodic, pancreas heals, no sequelae
Chronic: Protracted, pancreatic damage, permanent
- a condition where the pancreas becomes permanently damaged due to inflammation
very simply, what causes pancreatitis?
Inflammation can, for example, block off the opening into the common bile duct –> autodigestion –> inflammation –> autodigestion –> and so on
Explain the pathogenesis of pancreatitis
Damage to acinar exocrine cells –> activation of pancreatic enzymes (e.g. trypsin) –> local inflammation, oedema, autodigestion, release of cytokines, activation of leucocytes
What can damage acinar exocrine cells?
direct toxic effect (alcohol)
obstruction and back pressure
reflux of bile
increased Ca2+
What are the symptoms of pancreatic cancer?
Clinically silent until advanced stage
Loss of appetite Jaundice Pain in abdomen and back Change in bowel habits Nausea Weight loss New onset diabetes
What is the peak age of onset for pancreatic cancer?
65-75 yrs
Where in europe is pancreatic cancer more common?
Portugal, Denmark, Ireland
What are the main types of pancreatic neoplasms?
Exocrine:
Ductal adenocarcinoma - 90%
Cystic neoplasms - <1%
Endocrine: Neuroendocrine tumours (islet tumours) - <5%
What are the most lethal and least lethal pancreatic neoplasms?
Most: ductal adenocarcinoma
Least: Neuroendocrine tumours (slow growth) - people live longer because it is less agressive althoug there is no cure
- steve jobs had this
What are the requirements for a pancreatic tumour to be considered benign and give an example?
<3cm in size
e.g. serous cystadenoma
Give 2 examples of malignant pancreatic tumours
Mucinous cystadenoma: cyst filled with a thick fluid called mucin (tail, women)
Intraductal papillary mucinous neoplasm: cystic tumour that grows from the main pancreatic duct of from side branches of the duct
Give us a brief idea of what the differential diagnoses for a pancreatic cyst can be
Benign: Pseudocyst, serous cyst adenoma
Malignant potential: mucinous cyst adenoma, intraductal papillary mucinous neoplasm (branch duct IPMN)
Malignant: pancreatic duct adenocarcinoma, solid pseudopapillary neoplasms, PNET
Why is pancreatic cancer a complex disease?
Progressive accumulation of genetic alterations in different oncogenes and tumour suppressing genes are associated with PanCa progression.
What are the 4 major driver genes for pancreatic cancer?
KRAS
CDKN2A/p16
TP53
DPC2/SMAD4
but there are many other genetic and epigenetic changes all leading to aberrant signalling pathways
What are PanINs?
Pancreatic intraepitheial neoplasias: Histological changes associated with the early development of PanCa
Most common precursor lesions of PDAC.
How does PDAC progress?
Gene mutations, transcriptomic, proteomic, and epigenetic changes occur in parallel with the development of PanIN lesions.
Meanwhile, inflammatory cells infiltration promotes growth and invasion.
Mutations in order:
- Telomere shortens
- Mutations of K-RAS
- Inactivation of p16
- Inactivation of p53, SMAD4, BRCA2
What are the roles of different mutated genes in PDAC progression?
KRAS mutations - predominantly driving activating mutations
CDKN2A inactivation and P53 loss - deregulation of cell cycle
SMAD4 mutations - disregulation of TGF-β signalling.
What process allows pancreatic tumours to metastasize?
Epithelial-mesenchymal transition
What are the steps of EMT?
- cells get different characteristics that allow them to move
- Intravasation: invasion of cancer cells through the basal membrane into a blood or lymphatic vessel
- Systemic dissemination
- Extravasation
- Dormancy
- Colonization
- Formation of a secondary tumour
What are the main drivers of EMT in pancreatic cancer?
Transcription factors: Snail, Slug and Zeb1
which are in turn regulated by cytokines (TNF-α), growth factors (TGF-β), and microRNAs.
What do these transcription factors do to cells leading to EMT?
Epithelial: non- invasive, chemo-sensitive cells, making E-cadherin and cytokeratin
into
Mesenchymal: invasive, chemo-resistant cells that have stem-cell-like properties, making vimentin and fibronectin
What is a hallmark of PDAC?
Very fibrotic stroma: dense collection of fibroblasts (pancreatic stellate cells)
+
new blood vessels and ECM proteins (connective tissue: collagen type 1, glycoproteins)
What effect does the fibrosis have on the aggressiveness of the cancer?
It makes it more aggressive, decreases drug delivert
Cancer-associated fibroblasts are implicated in multiple tumour promoting roles
What are the characteristics of activated pancreatic stellate cells?
Increased proliferation migration ECM deposition Myofibroblast -like MMP secretion making alpha-SMA, fibroblast activating protein, glial fibrillary acid protien, tenascin C
What effects do activated pancreatic stellate cells have on other cells?
Beta cells: increase apoptosis, decrease insulin
Neurons: Increase cancer-directed migration and growth
Endothelial cells: increased proliferation and tube formation
Cancer cells: Increase proliferation, migration, decrease apoptosis
T cells: decrease activity
Mast cells: increase activation
Myeloid-derived suppressor cells: increased migration
What factors activate pancreatic stellate cells
- Cytokines (IL-1, IL-6, TNF–α)
- Growth factors (PDGF, GF–1)
- Ethanol and its metabolites
- Oxidative stress
- Pressure
- Extensive changes in ECM (composition and organization)
What is the source of PS activating factors
Endothelial cells in inflamed pancreas
pancreatic cancer cells
How do you manage pancreatic cancer?
20% - Surgery
80% - (locally advanced and metastatic) –Palliative treatment
What does pallative treatment involve?
chemotherapy + best supportive care
Same different treatments for pancreatic cancer
Gemcitambine (first line) +capecitabine
Folfirinox - side effects are horrible
Gamcitabine +abraxane (nab-paclitaxel) - very expensive (controversy about whether people can get it)
What are neuroendocrine tumours (PNETs)?
Neoplasms that arise from endocrine stem cells
How do PNETs differ from PDAC?
Less common and better prognosis (usually small, < 1cm)
Slow growing and are often best treated surgically
Rare: <5%
What are the types of PNETs?
Functional (secrete hormones: e.g. insulin, glucagon) or non-functional
What markers do PNETs secrete?
synaptophysin and chromogranin
TRUE or FALSE? PNETs usually metastasize before becoming symptomatic
TRUE
Which are more dangerous functional or non functional PNETs?
Functional
What kind of functional PNETs are there and what do they do?
Insulinoma - hypoglycemia
Gastrinoma (gastrin) - peptic ulcer, diarrhea, GERD
glucagonoma - necrolytic migratory erythema, diabeters, depression
Somatostatinoma - diarrhea, diabetes, hypochlorhydria, cholelithiasis
VIPoma - watery diarrhea, hypokalemia, achlohydria
How do non functional PanNETs present and what do they secrete?
Secrete: pancreatic poly peptide, neurotensin, ghrelin
Symptoms: Mass-related= jaundice, pancreatitis
Since early detection is so important, how is early pancreatic cancer diagnosis done?
Blood/urine samples can be collected and checked for biomarkers
Tumours shed proteins: CA125,CA19-9, PSA
Body responding to tumour: inflammatory response
What does the drug abraxane do and what are the problems with it?
It attacks the stroma but because there are 4 types of fibroblasts you might kill the good ones and lead to increased cancer growth
What are the biological targets for cancer therapy?
- GFs and their receptors
- Signal transduction pathways
- Tumour associated antigens/markers
- Proteosome
- Cell survival pathways
- ECM/angiogenic factors
