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Molecular Basis of Disease > Pancreatic cancer > Flashcards

Pancreatic cancer Flashcards

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1
Q

What is the pancreas?

A

Pale-grey gland located in the upper abdomen behind the stomach

Between the duodenum and spleen

Around the left side

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2
Q

What does the pancreatic duct do?

A

It joins the pancreas to the common bile duct, supplying pancreatic juice (exocrine) which aids in digestion

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3
Q

What is pancreatic juice?

A

A mixture of water, salts, bicarbonate, and many different digestive enzymes (amylases, lipases, proteases)

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4
Q

What is one of the factors (related to anatomy) which makes surgery on the head of the pancreas difficult?

A

The mesenteric artery is pressing right around the head of the pancreas

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5
Q

What does the exocrine pancreas do?

A

It secretes enzymes that digest carbs, proteins, fats, and bicarbonate for neurtalising acid chyme

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6
Q

What is the functional unit of the exocrine pancreas?

A

Acini

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7
Q

Where do the acini get their name?

A

The are formed by acinar cells

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8
Q

What are the cellular units of the endocrine pancreas?

A

Islets of langerhans

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9
Q

What is the main difference between the exocrine and endocrine pancreas?

A

Endocrine: released directly into blood
Exocrine: released into pancreatic duct

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10
Q

What would you see in a slide of the pancreas?

A

Acini and ducts
Islets of langerhans
Blood vessels
Stroma

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11
Q

What cells do the islets of Langerhans contain (and what do they secrete)?

A 
A cells - glucagon
B cells - insulin 
D cells - somatostatin
G cells - pancreatic polypeptide
E cells - ghrelin
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12
Q

What is one of the things somatostatin does?

A

glucagon and insulin regulation

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13
Q

what does ghrelin do?

A

causes the sensation of hunger

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14
Q

Why is pancreatic cancer something we should care about (other than all diseases generally sucking)?

A

It is one of the top 10 most lethal forms of cancer (<7% survival)

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15
Q

What percentage of pancreatic cancers develop in the head?

A

75%

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16
Q

what is the incidence of pancreatic cancer per year?

A

10 per 100,000

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17
Q

What sort of metastases are typical of pancreatic head tumours?

A

Going through the bile duct to the liver

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18
Q

What are the limitations in pancreatic cancer?

A

Highly fibrotic stroma acting as a mechanical barrier to drugs

Inter and intra tumoural heterogeneity

genetic complexity (many different mutations)

MDR

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19
Q

TRUE or FALSE? Pancreatic cancer like many other cancers has had huge improvements in survival.

A

FALSE

While other cancer prognoses have improved, pancreatic cancer survival has remained very bad over the years

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20
Q

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

A

FALSE

We think it’ll kill more people

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21
Q

What proportion of patients are diagnosed as an emergency and how does this affect their prognosis?

A

Half

Late diagnosis –> worse prognosis

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22
Q

What is the gender distribution of pancreatic cancer?

A

About equal between men and women but is now affecting men more than women

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23
Q

Does pancreatic cancer research get much money?

A

No, because the survival is so low and people die so quickly

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24
Q

When people are diagnosed with pancreatic cancer how much does this increase their survival?

A

x10 their five year survival

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25
What percent of people diagnosed with pancreatic cancer survive beyond 5 years?
4%
26
What is one simple factor which is contributing to the increase in pancreatic cancer?
The aging population
27
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
28
What percentage of pancreatic cancer is inherited?
10%
29
What are acquired pancreatic cancer risk factors?
``` Top : Obesity Smoking Diabetes Pancreatitis ```
30
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% ```
31
How much does smoking cessation reduce risk in 2 years?
48%
32
How much of pancreatic cancer is caused by smoking?
20-30%
33
Which ethnic groups are more likely to get pancreatic cancer?
African-americans ashkenazi jews Maori incidence increasing in Asia
34
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
35
very simply, what causes pancreatitis?
Inflammation can, for example, block off the opening into the common bile duct --> autodigestion --> inflammation --> autodigestion --> and so on
36
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
37
What can damage acinar exocrine cells?
direct toxic effect (alcohol) obstruction and back pressure reflux of bile increased Ca2+
38
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 ```
39
What is the peak age of onset for pancreatic cancer?
65-75 yrs
40
Where in europe is pancreatic cancer more common?
Portugal, Denmark, Ireland
41
What are the main types of pancreatic neoplasms?
Exocrine: Ductal adenocarcinoma - 90% Cystic neoplasms - <1% ``` Endocrine: Neuroendocrine tumours (islet tumours) - <5% ```
42
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
43
What are the requirements for a pancreatic tumour to be considered benign and give an example?
<3cm in size e.g. serous cystadenoma
44
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
45
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
46
Why is pancreatic cancer a complex disease?
Progressive accumulation of genetic alterations in different oncogenes and tumour suppressing genes are associated with PanCa progression.
47
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
48
What are PanINs?
Pancreatic intraepitheial neoplasias: Histological changes associated with the early development of PanCa Most common precursor lesions of PDAC.
49
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: 1. Telomere shortens 2. Mutations of K-RAS 3. Inactivation of p16 4. Inactivation of p53, SMAD4, BRCA2
50
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.
51
What process allows pancreatic tumours to metastasize?
Epithelial-mesenchymal transition
52
What are the steps of EMT?
1. cells get different characteristics that allow them to move 2. Intravasation: invasion of cancer cells through the basal membrane into a blood or lymphatic vessel 3. Systemic dissemination 4. Extravasation 5. Dormancy 6. Colonization 7. Formation of a secondary tumour
53
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.
54
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
55
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)
56
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
57
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 ```
58
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
59
What factors activate pancreatic stellate cells
1. Cytokines (IL-1, IL-6, TNF–α) 2. Growth factors (PDGF, GF–1) 3. Ethanol and its metabolites 4. Oxidative stress 5. Pressure 6. Extensive changes in ECM (composition and organization)
60
What is the source of PS activating factors
Endothelial cells in inflamed pancreas | pancreatic cancer cells
61
How do you manage pancreatic cancer?
20% - Surgery | 80% - (locally advanced and metastatic) –Palliative treatment
62
What does pallative treatment involve?
chemotherapy + best supportive care
63
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)
64
What are neuroendocrine tumours (PNETs)?
Neoplasms that arise from endocrine stem cells
65
How do PNETs differ from PDAC?
Less common and better prognosis (usually small, < 1cm) Slow growing and are often best treated surgically Rare: <5%
66
What are the types of PNETs?
Functional (secrete hormones: e.g. insulin, glucagon) or non-functional
67
What markers do PNETs secrete?
synaptophysin and chromogranin
68
TRUE or FALSE? PNETs usually metastasize before becoming symptomatic
TRUE
69
Which are more dangerous functional or non functional PNETs?
Functional
70
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
71
How do non functional PanNETs present and what do they secrete?
Secrete: pancreatic poly peptide, neurotensin, ghrelin Symptoms: Mass-related= jaundice, pancreatitis
72
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
73
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
74
What are the biological targets for cancer therapy?
1. GFs and their receptors 2. Signal transduction pathways 3. Tumour associated antigens/markers 4. Proteosome 5. Cell survival pathways 6. ECM/angiogenic factors

Molecular Basis of Disease (28 decks)

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